key: cord-260069-v5qvqxgy authors: yuan, shou-tao; zhang, wen-hao; zou, lei; sun, jia-kui; liu, ying; shi, qian-kun title: practice of novel method of bedside postpyloric tube placement in patients with coronavirus disease 2019 date: 2020-04-07 journal: crit care doi: 10.1186/s13054-020-02863-0 sha: doc_id: 260069 cord_uid: v5qvqxgy nan practice of novel method of bedside postpyloric tube placement in patients with coronavirus disease 2019 shou-tao yuan 1,2 , wen-hao zhang 1,2 , lei zou 1,2 , jia-kui sun 1,2* , ying liu 1,2 and qian-kun shi 1, 2 during our clinical work against the epidemic of coronavirus disease 2019 (covid-19) in wuhan [1] , we observed a high incidence of malnutrition in critically ill patients (data unpublished). therefore, nutritional therapy was very important. in patients with dysphagia and a very high aspiration risk, postpyloric enteral nutrition (en) was required [2] . however, how to place the postpyloric tube was a challenge in covid-19 patients. patients with masks removed (to expose the nasal cavity) were seriously infectious to doctors. besides, it was difficult to perform the tube placement bedside for doctors with heavy medical protective clothes, goggles, and face shield. here, we shared our practice of novel placing method in wuhan. a 130-cm-long non-spiral transpyloric tube with a guide wire (ch10-130, inner diameter 2.0-2.1 mm, flocare, nutricia ltd., wuxi, china) ( fig. 1a) was used in our isolation unit. the procedure of placement was similar to the method reported by our previous study [3, 4] . patients were placed in right decubitus position about 30-45°with bed head raised at about 30°. after esophageal placement and gastric placement, the postpyloric placement was performed by advancing the tube at 5-10 cm intervals gradually and checking its tip position each time. subsequently, the tip position would be confirmed by abdominal plain radiographs or gastrointestinal ultrasound bedside. the tube that we used has several advantages compared with spiral tube. first, the price of flocare tube (approximately $22) is 1/3 less compared with spiral tube (approximately $71) in china. second, the flocare tube has two side holes near its tip (fig. 1b) ; it is less likely to be blocked. third, the guide wire is shorter in length compared with the tube; therefore, the rigid tip could not damage the digestive tract during our placing procedure there have been three patients who received our novel method of postpyloric tube placement. the 3 cases were all successful at the first attempt (fig. 1c) . the median time of procedure was 19 (14-25) minutes, and the median insertion length was 105 (95-110) cm. no operation-and tube-related complications were found. considering the less expensive tube and high success rate, our novel blind bedside postpyloric placement may be easier to perform in patients with covid-19 worldwide. china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china espen guideline on clinical nutrition in the intensive care unit a novel method of blind bedside placement of postpyloric tubes application of blind bedside non-spiral nasointestinal tubes in critically ill patients publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. yuan st, zhang wh, and zou l wrote the manuscript; liu y, shi qk, and sun jk modified the manuscript. all authors read and approved the final manuscript. the work has not been published previously nor is under consideration for publication elsewhere. this study was supported by the national natural science foundation of china (no. 81701881) and the nanjing medical science and technology development foundation (no. ykk17102). not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests.received: 18 march 2020 accepted: 30 march 2020 key: cord-252890-of29g89s authors: villarreal-fernandez, eduardo; patel, ravi; golamari, reshma; khalid, muhammad; dewaters, ami; haouzi, philippe title: a plea for avoiding systematic intubation in severely hypoxemic patients with covid-19-associated respiratory failure date: 2020-06-12 journal: crit care doi: 10.1186/s13054-020-03063-6 sha: doc_id: 252890 cord_uid: of29g89s nan a plea for avoiding systematic intubation in severely hypoxemic patients with covid-19-associated respiratory failure eduardo villarreal-fernandez 1 , ravi patel 1 , reshma golamari 2 , muhammad khalid 2 , ami dewaters 2 and philippe haouzi 1* in early february 2020, yang et al. [1] reported an alarming high mortality rate in patients with covid-19associated acute respiratory failure requiring mechanical ventilatory support. such a dreadful outcome was regarded as the fundamental tenet dictating our strategy to treat patients with covid-19 acute respiratory failure. two essential recommendations were offered to the medical community in keeping with these first reports: (1) early intubation of hypoxemic patients [2] . indeed, since a profound hypoxemia appears to be the hallmark of covid-19-associated pneumonia, the initial consensus [2] was to start invasive mechanical ventilation as soon as possible due to the overwhelming number of patients in respiratory failure presenting at the same time in a hospital and to prevent the risk of hypoxic cardiac arrest; (2) avoidance of high-flow nasal cannula (hfnc) to reduce respiratory droplet aerosolization for healthcare workers [3] in what was seen as "inevitable" intubations. during the very initial weeks preceding the anticipated surge in central pennsylvania, ten patients with confirmed infection by sars-cov-2, who had extremely high oxygen requirement, were admitted in our institution (harrisburg/hershey region): all patients required a high flow of oxygen by nasal cannula (nc) or via nonrebreather (nrb) ( fig. 1 ) with documented episodes of spo 2 < 90%. the first four patients underwent endotracheal intubation by day 2 of hospital admission without a trial of high flow nasal cannula (hfnc) or non-invasive ventilation (niv), following the recommendations for early intubation [2] . however, we reconsidered in other patients the rationale behind these early intubations and revisited the initial proposal of avoiding high flow oxygen in hypoxemic patients. in addition, we felt that the actual consequences of aerosolization posed by hfnc and niv [4] remain quite hypothetical as reported in h1n1 pneumonia [5] . our main concern was that a systematic intubation of every hypoxemic patient may prove to be untenable, facing a limitation of capacity and resources of intensive care units (icu) to safely maintain a high number of patients on mechanical ventilation during the expected surge. we therefore selected a different strategy in the following six patients whose initial oxygen requirement was in the same range as the patients who were intubated by day 2. empiric limit of hypoxic events~88% was considered acceptable as long as the spo 2 was maintained at or above this level during most of the day and could be improved by self-prone positioning. this strategy was adopted in the absence of preexisting chronic respiratory failure, morbid obesity, concurrent clinical signs of respiratory distress, hypercapnia, alteration in hemodynamics, or lactic acidosis. we used a flow of oxygen up to 6 l/min nc and hfnc whenever higher fio 2 was needed (fig. 1) . out of these six patients, two required invasive mechanical ventilation after failing hfnc: one patient developed respiratory fatigue and required intubation at day 3, while the second patient had intolerance to niv and self-prone positioning with an episode of emesis that led to intubation on day 6. the non-intubated patients were instructed to rest in a prone position as much as feasible. after an initial increase in oxygen requirement through day 6, patients in this group were all able to be discharged at a time when most of the early-intubated patients were still mechanically ventilated (fig. 1) . strikingly, this occurred despite similar initial oxygen requirements. in summary, avoiding endotracheal intubation is possible in significantly hypoxemic covid-19 patients. the rationale that led to the practice patterns suggested in earlier reports must be reevaluated, and a controlled graduated method of escalating oxygen therapy, based on individual clinical judgment, in otherwise nondistressed patients should be instituted as much as possible. such an approach remains to be standardized. fig. 1 a oxygen flow requirement (median and range) during the first 48 h of admission in the group of patients who were intubated within the first 2 days based on the level of hypoxemia (4 patients, white bars) and those who were not immediately intubated (6 patients, grey bars). b evolution of o 2 requirement in patients that were not intubated initially and did not require any mechanical ventilation thereafter (4 out of 6). note that o 2 requirement increased over the first week in this group and required the use of hfnc in many patients. they all recovered within 12 days. c duration of intubation in the "early-intubation" group and length of stay in the patients that were not initially intubated. the 2 patients whose intubation was delayed are displayed as (1) and (2). patient 1 was extubated at day 16, while the second patient was still intubated at day 19 (when this report was submitted) clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical management of severe acute respiratory infection (sari) when covid-19 disease is suspected staff safety during emergency airway management for covid-19 in hong kong aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review high-flow nasal therapy in adults with severe acute respiratory infection: a cohort study in patients with 2009 influenza a/ h1n1v publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. all authors read and approved the final manuscript. no funding was required for the development of this manuscript. all data generated or analyzed during this study are included in this published article. the work did not require approval from ethics committee. no consent was required in the elaboration of this research. the authors declare that they have no competing interests. key: cord-267942-ykl2xy7y authors: stiers, michiel; bleeser, tom; mergeay, matthias; pinson, hannah; janssen, luc; schepens, tom title: successful ventilation of two animals with a single ventilator: individualized shared ventilator setup in an in vivo model date: 2020-08-27 journal: crit care doi: 10.1186/s13054-020-03248-z sha: doc_id: 267942 cord_uid: ykl2xy7y nan dear editor, as the ongoing covid-19 crisis is spreading from developed into developing nations, a shortage of ventilators in icus can be expected during peak prevalence. sharing a ventilator among patients has been put forward as a rescue solution [1, 2] ; in this setting, the so-called pairing of patients with similar characteristics is needed [3] [4] [5] . we have developed a modified shared ventilator design that allows for individualization of tidal volumes and driving pressures, positive end-expiratory pressure (peep), and inspired oxygen fraction (fio 2 ) [6] , which can thus substantially individualize the delivered breaths, removing the need of pairing (see fig. 1 ). we have now successfully used this ventilator setup in an in vivo model in a pair of ventilated sheep with different lung compliance, further supporting the potential of this shared ventilator setup as a lifesaving intervention in a crisis setting. after ethical approval, two healthy swifter sheep (62 kg and 60 kg, 1 year old) received general anesthesia (buprenorphine-sevoflurane), intubation, arterial catheter, and a c-section. after baseline blood gas and respiratory mechanics measurements, both sheep were connected to a single ventilator. animal 1 had a lung compliance of 38 ml cmh 2 o − 1 , while animal 2 had a lung compliance of 28 ml cmh 2 o − 1 , differences in compliance could be explained by their position. ventilator settings and measurements are shown in table 1 . the targeted tidal volume of the shared ventilator was set by adding together the individual tidal volumes of animal 1 (600 ml) and 2 (800 ml), creating a combined tidal of 1400 ml. we measured individual airway pressures, with a fluid-air interfaced pressure transducer (edwards lifesciences, irvine, usa), and individual end-tidal co 2 (etco 2 ) levels (see fig. 1 ). we then partially closed the inspiratory flow for animal 1 until the measured etco 2 levels for each animal were similar to those measured at baseline. this titration was successfully achieved within a few breaths, and the total set tidal volume could be distributed accurately among the two animals. with the added in-line individual peep valve, animal 2 received a peep of 7 cmh 2 o, whereas the other received 3 cmh 2 o of peep. the individually measured airway pressures demonstrated that the set peep levels were successfully achieved for each animal. fio 2 could be adjusted as expected, with one animal receiving an fio 2 of~0.3 and the other~0.8 with added o 2 to its breathing circuit during a short test period. adequacy of ventilation and oxygenation in this setup was demonstrated with repeated blood gas measurements. both paco 2 , pao 2 , and ph values remained within normal range, thus we can assume that the individual tidal volumes before and after sharing the ventilator were similar. hemodynamic parameters remained unchanged from baseline during the shared ventilator period. the animals were sacrificed after 3 h of mechanical ventilation. we demonstrated the potential to modulate delivered tidal volumes and pressures, peep and fio 2 in a shared ventilator setup in this in vivo model. the added ventilator circuit modifications are inexpensive and readily available or can be 3d-printed. this setup has allowed to safely ventilate a pair of animals with different lung compliance with a single ventilator, while monitoring and adjusting individual airway pressures and tidal volumes. however, i/e ratios and respiratory remain identical, and supplemental monitoring is required for safety reasons. we must stress that this setup is only to be used temporarily in a crisis setting while arranging for safer and more structural alternatives. the lung compliances were similar to what is frequently seen in ards. we think that this is a relevant step in the progressive development abbreviations peep: positive end-expiratory pressure; fio 2 : inspiratory fraction of oxygen; i/ e: inspiratory/expiratory time ratio; ppeak: peak pressure; vent: as measured by ventilator; indiv: individually measured on circuit; etco 2 : end-tidal carbon dioxide; pao 2 : partial pressure of oxygen, arterial; paco 2 : partial pressure of co 2 , arterial table 1 shows the settings of the ventilator per animal and for the shared ventilator in a volume-controlled ventilation. in animal 2, inline peep was applied; in animal 1, the flow restriction with our valve was applied to distribute the pressures as desired among the two animals. a single ventilator for multiple simulated patients to meet disaster surge increasing ventilator surge capacity in disasters: ventilation of four adult-human-sized sheep on a single ventilator with a modified circuit two for one with split-or co-ventilation at the peak of the covid-19 tsunami: is there any role for communal care when the resources for personalised medicine are exhausted? one ventilator for two patients: feasibility and considerations of a last resort solution in case of equipment shortage ventilator sharing during an acute shortage caused by the covid-19 pandemic individualized mechanical ventilation in a shared ventilator setting: limits, safety and technical details publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank prof. dr. jan deprest and his lab personnel in facilitating this experiment. authorship was based on the icmje guidelines. all authors contributed to the study conception and design. material preparation were performed by ms, tb, mm, lj, and ts. the data collection and analysis were performed by ms, mm, hp, lj, and ts. the figure and tables were designed and edited by hp, ms, and ts. the first draft of the manuscript was written by ts and ms. all authors commented on previous versions of the manuscript. all authors read and approved the final manuscript. the authors received no specific funding for this work. hannah pinson acknowledges a fellowship from the research foundation flanders (fwo), under grant no. 11a6819n. key: cord-260822-4bselbkq authors: lotz, christopher; notz, quirin; kranke, peter; kredel, markus; meybohm, patrick title: unconventional approaches to mechanical ventilation—step-by-step through the covid-19 crisis date: 2020-05-18 journal: crit care doi: 10.1186/s13054-020-02954-y sha: doc_id: 260822 cord_uid: 4bselbkq nan unconventional approaches to mechanical ventilation-step-by-step through the covid-19 crisis christopher lotz , quirin notz, peter kranke, markus kredel and patrick meybohm * health care systems around the world face extreme challenges during the pandemic of sars-cov-2. it has been reported that up to 20% of the patients develop an acute respiratory distress syndrome (ards) and approximately 12% require mechanical ventilation. in many countries, this may lead to a rapid shortage of intensive care (icu) ventilators. as such, a stepwise approach and triage utilizing all available types of ventilators might be necessary. this includes unconventional ideas that have been recently promoted in social media (https://www.youtube.com/watch?v= uclq978oohy, https://www.youtube.com/watch?v=esvb wwanqri). as uncertainties of the correct sequence of ventilator utilization seem to exist, we aim to provide a quick overview of the possibilities and shed some light on recently discussed ideas. under normal circumstances, all patients in the icu requiring mechanical ventilation are ventilated with an intensive care ventilator. icu ventilators provide the highest performance, fast responding efficient triggering mechanisms, and often a plethora of different ventilation modes to best suit the individual patient. however, anesthesia ventilators as the next step in line have made considerable technical progress. their performance is comparable to icu ventilators, in particular when using controlled ventilation modes. current generation piston ventilators include fresh-gas decoupling to minimize volu-or barotrauma and offer pressure-support modes with sufficient triggering and pressurization even under low fresh-gas flows. as such, one should not hesitate to use them if icu ventilators are not available. a current apsf/asa guidance on purposing anesthesia machines as icu ventilators emphasizes this (https://www.asahq.org/ in-the-spotlight/coronavirus-covid-19-information/purposi ng-anesthesia-machines-for-ventilators). third in line are transport ventilators, which vary largely in performance according to generation and model. many different models are marketed. the simplest pneumatic models are gasdriven pumps that provide 100% oxygen, control of rate and tidal volumes, and a pressure relief valve. on the other hand, new sophisticated transported ventilators offer a variety of modes including pressure-support ventilation and advanced monitoring. turbine-driven transport ventilators even demonstrated performance comparable with that of icu ventilators. however, as they are supplied by ambient air, they can only be used with 100% oxygen to prevent contamination of the device itself and its surroundings. this is a major downfall and limits their use to bridging, e.g., during the required testing of anesthesia ventilators. however, limited accuracy exists when prompted to deliver small tidal volumes (tidal volumes ≈ 50 ml). this would be required in small children [1, 2] . unconventional, improvised, and desperate methods as recently emphasized on social media (https://www. youtube.com/watch?v=uclq978oohy, https://www.youtu be.com/watch?v=esvbwwanqri) might be the next step if all of these resources are exhausted. the concept of supporting multiple patients with a single ventilator emerged in the aftermath of september 11, 2001. neyman et al. created a setup where a single ventilator could deliver a sufficient tidal volume to four identical human lung simulators in parallel [3] . the concept was further supported by an animal experiment in which four sheep were successfully oxygenated for 12 h with a single ventilator [4] . there is also a case study reporting a oneventilator technique during air medical transport of twin newborns [5] and an article that pressure controlled ventilation was simultaneously achieved in two healthy volunteers via mask ventilation [6] . however, branson et al. further investigated this concept with detailed measurements of tidal volumes (v t ) while varying the compliance and resistance. they found that four test lungs with different compliances (here 50-70 ml/cmh 2 o) received a wide fluctuation of v t (257-621 ml) in parallel ventilation. tidal volumes could not be controlled for each subject. the authors concluded that the concept of parallel ventilation for mass-casualty respiratory failure should not be supported [7] . this seems particularly true in case of a mass outbreak of sars-cov-2 and subsequent ards. differences in lung compliance, required f i o 2 , and peep levels are paramount in these patients. insufficient ventilation of one or more patients may be the consequence, which could go undetected as the monitored ventilation parameters reflect the whole group of patients. it is of further importance to emphasize that in case of icu ventilator shortage, the allocation of the ventilators to each patient requires triage. as clearly outlined by emanuel et al., the allocation of resources cannot be done on a first come first served basis [8] . a triage committee might be the best answer to spread the burden of these difficult decisions [9] . however, exact knowledge of the individual cases is required. ventilator triage would likely require switching of the ventilators during the course of treatment according to disease severity and stage as well as weaning capabilities, e.g., from anesthesia ventilator to icu ventilator. in conclusion, modern anesthesia ventilators as well as new-generation transport ventilators provide a valuable resource. in case of icu ventilator shortage, this resource can and should be primarily used with a clear conscience in ards patients (fig. 1) . furthermore, it must be emphasized that unconventional, improvised methods are only justified if all of these resources are exhausted as the risks go up and the quality of care rapidly declines. fig. 1 although intensive care ventilators represent the standard of care, anesthesia ventilators can be used without difficulty if their conceptual differences are accounted for (e.g., the presence of trained personnel). modern transport ventilators, albeit comparable in performance, can only be used for bridging as they are supplied by ambient air. unconventional methods such as ventilator splitting should be treated with great caution and are only justified if all other resources are exhausted evaluation of ventilators used during transport of critically ill patients: a bench study evaluation of 4 new generation portable ventilators a single ventilator for multiple simulated patients to meet disaster surge increasing ventilator surge capacity in disasters: ventilation of four adult-human-sized sheep on a single ventilator with a modified circuit simultaneous transport of twin newborns simultaneous ventilation of two healthy subjects with a single ventilator use of a single ventilator to support 4 patients: laboratory evaluation of a limited concept fair allocation of scarce medical resources in the time of covid-19 the toughest triage -allocating ventilators in a pandemic publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. christopher lotz, quirin notz, and patrick meybohm wrote the manuscript. peter kranke and markus kredel co-wrote and revised the manuscript for intellectual content. all authors agree to be accountable for all aspects of the work. the authors read and approved the final manuscript. none received for this study.availability of data and materials not applicable.ethics approval and consent to participate not applicable. all authors provided their final approval for manuscript submission. none.received: 7 april 2020 accepted: 7 may 2020 key: cord-003416-c22kw6f4 authors: baek, moon seong; lee, sang-min; chung, chi ryang; cho, woo hyun; cho, young-jae; park, sunghoon; koo, so-my; jung, jae-seung; park, seung yong; chang, youjin; kang, byung ju; kim, jung-hyun; oh, jin young; park, so hee; yoo, jung-wan; sim, yun su; hong, sang-bum title: improvement in the survival rates of extracorporeal membrane oxygenation-supported respiratory failure patients: a multicenter retrospective study in korean patients date: 2019-01-03 journal: crit care doi: 10.1186/s13054-018-2293-5 sha: doc_id: 3416 cord_uid: c22kw6f4 background: although the utilization of extracorporeal membrane oxygenation (ecmo) is increasing and its technology is evolving, only a few epidemiologic reports have described the uses and outcomes of ecmo. the aim of this study was to investigate the changes in utilization and survival rate in patients supported with ecmo for severe respiratory failure in korea. methods: this was a multicenter study on consecutive patients who underwent ecmo across 16 hospitals in korea. the records of all patients who required ecmo for acute respiratory failure between 2012 and 2015 were retrospectively reviewed, and the utilization of ecmo was analyzed over time. results: during the study period, 5552 patients received ecmo in korea as a whole, and a total of 2472 patients received ecmo at the participating 16 hospitals. we analyzed 487 (19.7%) patients who received ecmo for respiratory failure. the number of ecmo procedures provided for respiratory failure increased from 104 to 153 during the study period. the in-hospital survival rate increased from 30.8% to 35.9%. the use of prone positioning increased from 6.8% to 49.0% (p < 0.001), and the use of neuromuscular blockers also increased from 28.2% to 58.2% (p < 0.001). multiple regression analysis showed that old age (or 1.038 (95% ci 1.022, 1.054)), use of corticosteroid (or 2.251 (95% ci 1.153, 4.397)), continuous renal replacement therapy (or 2.196 (95% ci 1.135, 4.247)), driving pressure (or 1.072 (95% ci 1.031, 1.114)), and prolonged ecmo duration (or 1.020 (95% ci 1.003, 1.038)) were associated with increased odds of mortality. conclusions: utilization of ecmo and survival rates of patients who received ecmo for respiratory failure increased over time in korea. the use of pre-ecmo prone positioning and neuromuscular blockers also increased during the same period. extracorporeal membrane oxygenation (ecmo), which provides respiratory and/or cardiac support, allows treatment of patients with refractory gas-exchange abnormalities [1] . the use of ecmo to support patients with respiratory failure is increasing worldwide following the use of ecmo for severe acute respiratory failure during the 2009 influenza a pandemic [2] [3] [4] [5] . recently, the eolia trial reported that in patients with severe acute respiratory distress syndrome (ards) there was no significant difference in 60-day mortality between patients who received early ecmo and those who received conventional mechanical ventilation that included ecmo as rescue therapy [6] . however, crossover to ecmo occurred in 28% of patients in the conventional group, who showed a high mortality rate of 57%. this suggests that ecmo can be used in severe ards patients who do not benefit from conventional treatment. survival of patients who received ecmo is also gradually increasing over time [7] . a recent epidemiologic report in germany showed that ecmo utilization for severe respiratory failure significantly increased from 2007 until 2012, and in-hospital survival increased over time as well [8] . sauer et al. [9] reported that the annual rates of ecmo cases increased by 433% from 2006 to 2011 in the united states, and that, albeit not statistically significant, there was an improving trend in the survival rate as well. in a single-center study in korea, the survival rates associated with the ecmo procedure increased between 2009 and 2011 [10] . however, as we have previously reported, there was a discrepancy in the survival rate between those of the extracorporeal life support organization (elso) registry and korean ecmo patients [11] . the in-hospital survival rate of ecmotreated patients with acute respiratory failure was 46% from 2014 to 2015 in korea, whereas the survival rate was 58% in the elso registry patients [7] . also, we have suggested that age is an important factor in the survival of patients who received ecmo. therefore, we sought to determine whether there has been an improvement in the survival rate of patients who received ecmo support for acute respiratory failure in korea. specifically, we evaluated the changes over time in the survival rates of patients supported with ecmo for severe respiratory failure and the factors associated with the survival rate. this was a multicenter study of consecutive patients who received ecmo at 16 hospitals in korea. the records of all patients who required ecmo for acute respiratory failure between 2012 and 2015 were retrospectively reviewed and the utilization of ecmo was analyzed over time. the decision to use ecmo was made at the discretion of the attending physicians at each center without standardization. the study protocol was approved by the institutional review board of asan medical center, and by the local institutional review boards of all other participating centers. the requirement for informed consent was waived due to the retrospective design of the study. data were collected from electronic medical records of patients older than 19 years who received ecmo support. included variables were as follows: demographic information, acute physiology and chronic health evaluation (apache) ii and sequential organ failure assessment (sofa) scores at intensive care unit (icu) admission, etiology of respiratory failure, cardiac arrest, immunocompromised status, central nervous system (cns) dysfunction, pre-ecmo hemodynamic data, mechanical ventilation parameters, and arterial blood gas data. immunocompromised status and cns dysfunction were defined according to the resp study [12] . immunocompromised status included hematological malignancies, solid tumors, solid-organ transplantation, high-dose or long-term corticosteroid and/or immunosuppressant use, and human immunodeficiency virus infection. cns dysfunction included diagnoses of neurotrauma, stroke, encephalopathy, cerebral embolism, seizure, and epileptic syndrome. we collected information on adjunctive therapy such as the use of vasopressors, steroids, continuous renal replacement therapy (crrt), prone positioning, nitric oxide, bicarbonate infusion, and neuromuscular blockers. we also collected data such as the ecmo mode, ecmo duration, duration of mechanical ventilation to ecmo initiation, hospital stay, and tracheotomy. the ecmo mode was categorized as veno-venous, veno-arterial, and veno-arteriovenous. outcome variables of the study were survival at discharge and ecmo weaning (survival within 48 h after weaning from ecmo). demographics, pre-ecmo parameters, and outcomes were compared between 2012 and 2015. differences with p < 0.05 were considered statistically significant. categorical variables are expressed as the number (percentage). continuous variables are expressed as the median (interquartile range). pearson's chi-square test or fisher's exact test was used to compare categorical data. the kruskal-wallis test was used to compare medians between groups. multiple logistic regression analysis using the backward elimination method was performed to identify the factors associated with survival at discharge. candidate variables for inclusion in the multiple logistic regression model were chosen from the univariate analysis; variables with p < 0.1 in the univariate analyses were included in the multivariate analysis, and collinearity was assessed before the multivariate analysis. calibrations of the models were evaluated with the hosmer-lemeshow goodness-of-fit test. statistical analyses were performed using the statistical package for the social sciences (spss) version 22.0 (ibm corporation, armonk, ny, usa). during the study period (2012-2015), 5552 patients received ecmo support in korea. ecmo support was given to 2472 patients in the participating 16 hospitals. we analyzed 487 (19.7%) patients who received ecmo specifically for respiratory failure. the annual number of ecmo cases at 16 institutions varied widely: eight centers had fewer than 20 cases per year and the other eight survival prediction, arf acute respiratory failure, ards acute respiratory distress syndrome, copd chronic obstructive pulmonary disease, ild interstitial lung disease, cns central nervous system, crrt continuous renal replacement therapy, map mean arterial pressure, pao 2 partial pressure of arterial oxygen, paco 2 partial pressure of arterial carbon dioxide, hco 3 − bicarbonate, sao 2 oxygen saturation, fio 2 fraction of inspired oxygen, peep positive endexpiratory pressure, pip peak inspiratory pressure, mv mechanical ventilation a "immunocompromised" included hematological malignancies, solid tumors, solid-organ transplantation, high-dose or long-term corticosteroid and/or immunosuppressant use, and human immunodeficiency virus infection b "cns dysfunction" included diagnoses of neurotrauma, stroke, encephalopathy, cerebral embolism, seizure, and epileptic syndrome centers had more than 30 cases per year, with two of those centers having had more than 120 cases per year. the patients' median age was 58 years (range 45-66 years), and the median body mass index was 22.2 kg/m 2 (range 20.6-23.2 kg/m 2 ). pre-ecmo mechanical ventilation was provided in 92.2% of patients and corticosteroid therapy was used in 16.8% of patients. prone positioning was applied in 29.5% of patients and neuromuscular blockers were used in 45.4% of patients. the majority of patients were initially supported with veno-venous ecmo (88.1%), and the median duration of support was 8 days (interquartile range (iqr) 4, 18 days). survival and weaning rates were 38.8% and 57.1%, respectively (table 1) . the number of ecmo procedures for respiratory failure increased from 104 to 153 during the study period ( fig. 1 ). there were no significant differences in age, sex, apache ii score, sofa score, immunocompromised status, cns dysfunction, cardiac arrest, crrt, use of nitric oxide and bicarbonate infusion, pao 2 /fio 2 ratio, ecmo duration, and duration of mechanical ventilation to ecmo initiation between groups. use of prone positioning increased from 6.8% to 49.0% (p < 0.001) and the use of neuromuscular blockers also increased from 28.2% to 58.2% (p < 0.001; table 2 ). although the survival rate remained relatively low, it increased over time from 30.8% to 35.9% (p = 0.005; table 3 ). post-hoc analysis showed that the survival rate in 2014 was significantly higher than the rates in 2012 and 2015. factors associated with mortality in patients supported with ecmo multiple regression analysis was performed using age, sex, year, apache ii score, sofa score, immunocompromised status, cns dysfunction, corticosteroid, crrt, prone positioning, nitric oxide, neuromuscular blocker, 1.031, 1.114) ), and prolonged ecmo duration (or 1.020 (95% ci 1.003, 1.038)) were associated with increased odds of mortality ( table 4 ). the median age was older in the nonsurvivors (61 years; iqr 52, 69 years) than in survivors (51 years; iqr 37, 62 years) (p < 0.001). the survival rate decreased with age, with patients older than 60 years having a survival rate of 30.8% (fig. 2) . ecmo duration was significantly longer in the nonsurvivors (9 days; interquartile range (iqr) 4, 22 days) than in survivors (7 days; iqr 3, 13 days) (p = 0.002). compared with the survival rate within 2 weeks of ecmo support, the overall survival rate after 2 weeks of ecmo support showed a significant decrease from 43.4% to 27.8% (p = 0.001). this multicenter study was conducted to evaluate the change in survival rates of patients who received ecmo support for acute respiratory failure in korea. utilization of ecmo for respiratory failure increased over time, and the survival rate was improved with increasing use of adjunctive management. also, patient age and the duration of ecmo were significantly associated with survival. a notable change during the study period was that the administration of neuromuscular blockades and use of prone positioning before ecmo had significantly increased from 28.2% to 58.2% and from 6.8% to 49.0%, respectively. papazian et al. [13] reported that early use of neuromuscular blockades in patients with severe ards may improve survival. in the elso registry-based resp study, neuromuscular blockade agents before ecmo were independently associated with hospital survival [12] . in addition, in patients with severe ards, early application of prolonged prone positioning was significantly associated with improved survival [14] . schmidt et al. [15] demonstrated that use of prone positioning before ecmo was also associated with survival. these results are in accordance with those in a recent systematic review and meta-analysis [16] . moreover, for patients with severe ards, prone positioning before and during ecmo may be helpful for weaning from ecmo [17, 18] . another distinctive finding was the change in pre-ecmo ventilator parameters. in recent years, the driving pressure was lower and minute ventilation was decreased. therefore, improvement in hospital survival of ecmo-supported patients with respiratory failure might be the result of increasing experience with ecmo over time, including evolving adjuvant therapies and improved management of mechanical ventilation. the results of this study showed that the number of ecmos carried out for respiratory failure increased from 104 to 153 from 2012 to 2015, and that the in-hospital survival rate increased from 30.8% to 35.9% during the same period. the overall survival rate of 39% in "cns dysfunction" included diagnoses of neurotrauma, stroke, encephalopathy, cerebral embolism, seizure, and epileptic syndrome ecmo-supported respiratory failure patients in korea is lower than the reported rate of 58% in the elso registry [7] . meanwhile, an ecmo epidemiologic study performed in germany reported that from 2012 to 2014 the in-hospital survival had steadily increased and the rate of survival was approximately 40%, which is similar to our findings [8] . in addition, sauer et al. [9] reported that in the united states the survival rate of the patients who received ecmo was approximately 40%. in the german study, approximately 80% of patients were older than 40 years and increasing numbers of older patients had received ecmo. in the us study, the mean age of the patients who received ecmo was 50 years, which is higher than that of the patients included in the elso registry. taken together, the discrepancies in demographics between the patients of ecmo centers not included in the elso and those in the elso registry may explain the difference in survival rates. also, another explanation for the relatively low survival rate of korean ecmo patients could be the infrequent use of prone positioning. the use of prone positioning and use of neuromuscular blockers were low compared with those in the eolia trial [6] , in which prone positioning was applied in 90% of patients in the conventional ventilator support group, who showed a 54% survival rate. the relatively low survival rate in korean ecmo patients may be due to excessive use of ecmo in patients who may have shown good response to prone positioning. accordingly, the use of prone positioning is gradually increasing in korea. another interesting finding of our study was that the survival rate was associated with the ecmo duration. the survival rate of patients who required prolonged ecmo (longer than 14 days) was significantly lower than that of patients who had shorter ecmo duration (28% vs 43%, respectively, p = 0.001). recently, posluszny et al. [19] reported that ecmo duration was inversely correlated with the survival rate in ecmo-supported patients with respiratory failure; the survival rate in patients who had longer ecmo duration was 10% lower than that in those with shorter ecmo duration. nonetheless, the investigators suggested that prolonged ecmo was not futile because there was a significant improvement in survival from 37% to 49% in recent years. on the other hand, the aforementioned german epidemiologic study reported that prolonged ecmo was associated with poorer outcome; that the survival rate rapidly declined to 20% within 10 days after ecmo initiation [8] . therefore, further studies are needed to provide a more solid association between ecmo duration and the survival rate. our study has several limitations. this study was retrospective and had a relatively short study period. because not all patients treated with ecmo for respiratory failure in korea were included, selection bias is possible. in addition, long-term outcomes and quality of life could not be assessed, which warrants an extended observation period of our study populations or further epidemiologic studies. despite such limitations, our current multicenter study, which is not based on the elso registry, provides information on the change in the survival rate of ecmo patients with respiratory failure and the factors associated with survival, and adds to the understanding of survival in patients who receive ecmo due to respiratory failure. this multicenter study performed in korea showed that utilization of ecmo for respiratory failure had increased over time, and that the survival rates of ecmo-supported respiratory failure patients had improved with increasing utilization of adjunctive management. patient age and duration of ecmo were significantly associated with survival at discharge. extracorporeal membrane oxygenation for ards in adults extracorporeal membrane oxygenation for 2009 influenza a(h1n1) acute respiratory distress syndrome extracorporeal membrane oxygenation for pandemic h1n1 2009 respiratory failure the italian ecmo network experience during the 2009 influenza a(h1n1) pandemic: preparation for severe respiratory emergency outbreaks referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza a(h1n1) extracorporeal membrane oxygenation for severe acute respiratory distress syndrome extracorporeal life support organization registry international report extracorporeal membrane oxygenation: evolving epidemiology and mortality extracorporeal membrane oxygenation use has increased by 433% in adults in the united states from the effect of an improvement of experience and training in extracorporeal membrane oxygenation management on clinical outcomes age is major factor for predicting survival in patients with acute respiratory failure on extracorporeal membrane oxygenation: a korean multicenter study predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score neuromuscular blockers in early acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome the preserve mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome systematic review and meta-analysis of complications and mortality of veno-venous extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome prone positioning before extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: a retrospective multicenter study prone positioning during veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in adults outcome of adult respiratory failure patients receiving prolonged (>/=14 days) ecmo not applicable. this study was supported by a grant from the korea health technology r&d project through the korea health industry development institute funded by the ministry of health & welfare, republic of korea (hc15c1507). the datasets used and analyzed during the current study are available from the corresponding author on reasonable request. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-004327-ofqay81v authors: wu, tung-ho; lin, hsing-lin; chou, yi-pin; huang, fong-dee; huang, wen-yen; tarng, yih-wen title: facilitating ventilator weaning through rib fixation combined with video-assisted thoracoscopic surgery in severe blunt chest injury with acute respiratory failure date: 2020-02-12 journal: crit care doi: 10.1186/s13054-020-2755-4 sha: doc_id: 4327 cord_uid: ofqay81v background: severe blunt chest injury sometimes induces acute respiratory failure (arf), requiring ventilator use. we aimed to evaluate the effect of performing rib fixation with the addition of video-assisted thoracoscopic surgery (vats) on patients with arf caused by blunt thoracic injury with ventilator dependence. methods: this observational study prospectively enrolled patients with multiple bicortical rib fractures with hemothorax caused by severe blunt chest trauma. all patients received positive pressure mechanical ventilation within 24 h after trauma because of arf. some patients who received rib fixation with vats were enrolled as group 1, and the others who received only vats were designated as group 2. the length of ventilator use was the primary clinical outcome. rates of pneumonia and length of hospital stay constituted secondary outcomes. results: a total of 61 patients were included in this study. the basic demographic characteristics between the two groups exhibited no statistical differences. all patients received operations within 6 days after trauma. the length of ventilator use was shorter in group 1 (3.19 ± 3.37 days vs. 8.05 ± 8.23, p = 0.002). the rate of pneumonia was higher in group 2 (38.1% vs. 75.0%, p = 0.005). the length of hospital stay was much shorter in group 1 (17.76 ± 8.38 days vs. 24.13 ± 9.80, p = 0.011). conclusion: rib fixation combined with vats could shorten the length of ventilator use and reduce the pneumonia rate in patients with severe chest blunt injury with arf. therefore, this operation could shorten the overall length of hospital stay. severe blunt chest trauma can cause multiple rib fractures accompanied by hemothorax or pneumothorax [1, 2] and lung contusions, compromising the facility for gas exchange in the lung parenchyma. together with severe pain, all these complications can induce acute respiratory failure (arf)-oximeter saturation of less than 90% and pao 2 level of less than 60 mmhg, as determined through a venturi mask with 100% fio 2 , such that mechanical ventilation is required-the most serious posttrauma complication, which may induce high mortality. intubation with positive pressure ventilation is widely accepted as an initial treatment for arf [3, 4] . this method can be rapidly applied to provide sufficient tissue oxygenation in patients with lung contusion as well as rib fracture, contributing to impaired gas exchange in the lungs. however, long-term ventilator use should be avoided because ventilator-acquired pneumonia can become another contributor to increased morbidity and length of hospital stay. therefore, reducing ventilator dependence following major complications is crucial. studies have demonstrated that early video-assisted thoracoscopic thoracic surgery (vats) can decrease the rate of posttrauma pneumonia and empyema in blunt chest trauma [5, 6] . some studies have claimed that rib fixation can also decrease ventilator dependence [7, 8] , but others have considered this claim to be controversial [9, 10] . the results might vary depending on the surgical approach used during rib fixation. in our hospital, we combine vats and rib fixation in severe blunt chest injuries with arf. in our previous study, we found that rib fixation exhibited some benefits in patients without respiratory failure [11] . in this study, we hypothesize that rib fixation with vats could provide a better outcome in intubated patients with arf. the two study periods overlapped. however, the patient groups were not the same. the main purpose of this study was to evaluate the effects of this approach on the length of ventilator use and length of hospital stay. this prospective observational study was established in october 2014. the patient enrollment period was from march 2015 to june 2018 in a level 1 trauma medical center in southern taiwan that receives approximately 15,000 emergency trauma visits per year. patients included in this study were 18 years of age or older and had a site of a major blunt chest injury. all of them had arf within 24 h after trauma. the imaging studies exhibited at least 3 bicortical rib fractures combined with hemothorax, pneumothorax, and lung contusions (fig. 1a) . the abbreviated injury scores (aiss, 2008 edition) for the chest injuries of the patients were 3 or 4 indicated severe injuries. tube thoracostomies were applied to these patients in the emergency department (ed). injuries in other regions were evaluated during a secondary survey. the study protocol was approved by our hospital's ethics committee (vghks17-ct12-13). patients not receiving intubation with ventilator support were excluded. patients whose aiss for other regions were higher than 3 or exceeded their chest aiss were excluded to avoid any confounding bias from associated injuries. patients with bilateral rib fractures were also excluded. patients with hemodynamic instability or mediastinal great vessel injuries were also excluded. finally, patients with severe medical diseases, such as liver cirrhosis, end-stage renal disease, chronic obstructive pulmonary disease, or cancer, were excluded as well. all patients received detailed evaluations in the ed, including chest computed tomography. the number of rib fractures, volume of pleural collections, and conditions of lung contusions were realized in detail [12, 13] . after resuscitation, patients were admitted to the intensive care unit (icu) for further evaluation. in the icu, fig. 1 a right side 5th to 8th rib bicortical fractures (white arrow) along with lung contusions. b vats evacuation of hemothorax combined with localization of fractured rib (white arrow). c fixation of fractured ribs using titanium plates with locking screws on the outer surface of ribs. d chest x-ray after the operation ventilators with positive end-expiratory pressure (peep) were used for fully sedated patients. intravenous analgesics were also administered and adjusted by nursing staff according to the critical care pain observation tool. because all patients were under sedation, patients' closest relatives were informed of the treatment plans by trauma surgeons. the main treatment goal is to decrease the ventilator-dependent days. vats for pleural collection and rib fixation for chest wall stability are two primary treatment methods. patients whose relatives agreed to rib fixation with vats were enrolled in group 1, and those who only agreed to vats without rib fixation were included in group 2. these family members provided consent for the procedures. the treatment algorithm is illustrated in fig. 2 . all surgical procedures were performed in operating rooms, and patients were under general anesthesia. as per our other studies [14, 15] , in the vats-only group, vats was applied for the evacuation of residual blood clots and the resection of pulmonary lacerations under endoscopic visions. in patients who received rib fixation, vats was also first used to treat the pleural and lung parenchyma lesions. the surgical wound incisions were then designed according to the fracture sites of the ribs that were localized using vats (fig. 1b) . the fractured sites were approached using the chest wall musclesparing method [16] [17] [18] . titanium plates with locking screws (matrixrib™, products of depuy synthes, companies of johnson & johnson) that were specifically designed for fractured ribs were selected and applied at the outer surfaces of the ribs (fig. 1c) . one dose of firstgeneration cephalosporins as prophylactic antibiotics was administered before the operations. after the operations, all patients underwent chest tube drainage. the chest tubes were connected to a lowpressure suction device (− 15 cm, h 2 o) to reduce residual pleural effusions (fig. 1d ). ventilators were still applied after operations. a weaning ventilator protocol was planned. when patients achieved optimal oxygen saturation, their endotracheal tubes were removed. chest tubes were removed when the air leaks were absent, and fluid drainage was less than 100 ml per day. routine follow-up chest x-rays and close observations for wounds were performed after operations. residual pleural effusions after operations were managed with secondary vats. for patients who required ventilator dependence for longer than 14 days, tracheostomies were performed. the demographic data of all patients were collected, including age, sex, number of fractured ribs, pulmonary contusion score, and trauma mechanism. the ais of each associated injury was also collected, and the injury severity score (iss) was calculated. duration of ventilator use, duration of chest tube use, rates of infection, and total dose of analgesics were recorded. the lengths of stay (loss) in the icu and hospital were recorded as secondary outcomes. if a fever occurred, sputum and blood samples were collected immediately and over the following 3 days for analysis of microbial cultures. in addition, cultures from chest fluid were collected during vats. the protocol for pain control in the patients with rib fractures was the same as that used in both the study groups for which only morphine was used. total doses of morphine were also calculated and recorded. all patients' care followed the same guidelines regarding ventilator settings, and the two groups did not differ during intubation or protocols for extubation. an initial descriptive analysis was performed on all variables to determine the frequencies and averages in the two groups. numerical variables are presented as means ± standard deviation (sd). the chi-square and fisher's tests were used to evaluate the categorical and proportional variables, respectively, between the two groups. continuous variables were compared using analysis of variance. we considered p < 0.05 to be statistically significant. all data were analyzed using spss 20.0 (ibm corp., armonk, ny, usa). for this study to achieve a power greater than 0.8 to detect a significant difference in hospital los between patients and controls (twosided equality, two-sample), a sample size of at least 60 patients was required (α = 5%, sampling ratio = 0.5). multivariate logistic regression was used to assess the associated variables of rib fixation. confounders were controlled using a running entry model of logistic regression analysis. subsequently, all independent variables were entered into the multivariate logistic regression analysis to detect the independent variables for rib fixation. the hosmer-lemeshow test was used to evaluate the goodness of fit. significant associations of the independent variables with the dependent variables were assessed using a 95% confidence interval (ci) and the respective adjusted odds ratio (aor). during the study period, a total of 61 patients were enrolled. all patients had arf and received emergent endotracheal tube insertions and positive pressure ventilator support within 24 h after trauma. these patients all had pneumothorax and hemothorax, resulting in tube thoracostomy being performed in the ed. twenty-one patients receiving rib fixation with vats were included in group 1, and the other 40 patients receiving vats only belonged to group 2. the collection was terminated after statistical power reached 0.8. table 1 presents the basic demographic characteristics of the two groups. the means of age and the distribution of sex between the two groups had no statistically significant differences. factors that could affect the ventilator dependence-including consciousness levels, number of fractured ribs, percentage of flail chest, lung contusion scores, aiss, and isss-all exhibited no statistically significant differences. all patients were evaluated for pain levels in the ed initially, and the 10-point pain scores between the two groups exhibited no differences. thus, the two groups were satisfactorily matched and could be compared on the basis of their similar characteristics. all patients in this study received vats within 6 days after trauma [19] . the time periods from trauma to operation were equal between the two groups, without statistical significance. in this study, a total of 17 (27.9%) patients received lung repair during vats. the proportions of patients receiving lung repair in the two groups were similar (table 1) . lobectomy procedures were not performed in this study. after rib fixations, most patients with arf could be weaned off the ventilator within 4 days or much faster than vats-only patients (3.19 ± 3.37 days vs. 8.05 ± 8.23, p = 0.002). the total ventilator-dependence time durations were also much shorter in the rib fixation group (7.71 ± 3.65 days vs. 12.55 ± 8.22, p = 0.002). a patient was defined as having high peep if pressure was greater than 5 cmh 2 o. patients in group 2 required significantly more days of total ventilator use (5.71 ± 3.65 vs. 10.55 ± 8.22, p = 0.013). eight patients had prolonged ventilations that required a tracheostomy; all these patients belonged to group 2 (0 vs. 20.0%, p = 0.042). because of early weaning from the ventilator in the rib fixation group, the rate of pneumonia was also much lower (38.1% vs. 75.0%, p = 0.005). the time of chest tube use after the operation was also shorter in the rib fixation group (6.33 ± 2.13 days vs. 8.75 ± 4.04, p = 0.003). because of early weaning from the ventilator and shortened periods of chest tube use, the loss in the icu and hospital were both shorter in group 1, with statistical significance (8.81 ± 3.40 days vs. 12.08 ± 4.95, p = 0.008; 17.76 ± 8.38 days vs. 24.13 ± 9.80, p = 0.011). in this study, all patients had normal consciousness upon discharge. the pain scores at discharge were much lower in the rib fixation group (3.57 ± 1.03 vs. 5.18 ± 1.40, p = 0.001). table 2 illustrates all clinical outcomes after operations on patients with arf. we applied binary logistic regression to test the parameters, and the results are displayed in table 3 . according to the multivariate logistic regression, the only independent clinical outcome determinant of the two groups was the time periods of ventilator use (aor, 3.411; 95% ci 1.214-9.585, p = 0.020). these results indicate a strong association between rib fixation and ventilator dependence. calibration of the final model was assessed using the hosmer-lemeshow goodness of fit test. a p value of 0.726 (χ 2 = 5.290) suggested that the model was accurate. five patients in this study had residual pleural effusion after the operation. three patients belonged to group 1, and the other two were from group 2. all these patients successfully received secondary vats. one patient belonging to group 2 expired during the study period due to acute myocardium infarction. the mortality rate was 1.6% in all patients, without any statistical significance between the two groups (0 vs. 2.5%, p = 1). arf is a dangerous posttraumatic complication that occurs mainly when both chest wall and lung parenchyma are destroyed in severe blunt chest injuries [20] . this emergency situation requires rapid resuscitation through the immediate insertion of an endotracheal tube with ventilator support. the primary treatment goal for these patients is early weaning from the ventilator. in this study, rib fixation with vats in patients with such severe blunt chest trauma and arf could greatly decrease the length of ventilator dependence. other studies have usually targeted treatments of severe blunt chest trauma by managing the hemothorax or pneumothorax [21] [22] [23] . initially, fractured ribs were not the main target of treatment in our hospital [23] . in fact, fractured ribs, especially the bicortical fractured type, can produce an unstable thoracic cage that might not support the full expansion of lung parenchyma. although positive pressure ventilation can provide a supporting force for lung expansion, long-term ventilator dependence may be required to wait for the chest wall to heal. many orthopedic materials have been designed specifically for fractured ribs. several studies have successfully proven that reconstruction of a chest wall using rib fixation could reduce ventilator dependence [16, 24, 25] . in contrast with other studies, we performed rib fixation combined with vats to completely manage chest wall injury, lung laceration, and pleural collections. these two procedures can be performed simultaneously to accelerate ventilator weaning. the rate of ventilatoracquired pneumonia subsequently decreases, which may also shorten the whole course of treatment. the timing of the operation is another influential factor in blunt chest trauma. early vats may decrease the rate of pleural infection. our previous studies have demonstrated that vats should be performed within 1 week after trauma [19] . we thus adhered to this principle in this study. all patients received vats within 6 days after trauma. the rates of empyema for the two groups are similar without statistical significance. group 1 patients had rib fixation added during vats to enable the reconstructed chest wall to maintain a firm structure. a stable fractured ribs not only make the chest wall unstable but also result in the persistence of pleural collection, especially bicortical fractures [26, 27] . the fractured ends of ribs can produce an ooze from the bone marrow [28] . the fractured ribs could also scrub lung surfaces, which may induce persistent microair leakage. these complications both lengthen the usage time of chest tubes, which is another major factor that lengthens the total course of admission. in this study, rib fixation was observed to prevent these complications. chest tube usage time after rib fixation was much shorter than in the vats-only group. in this study, the pain score was difficult to estimate because all patients had endotracheal insertions with sedation during ventilator dependence. only one pain evaluation was conducted, upon initial arrival at the ed, and all patients had similar pain scores. during ventilator-dependent periods, pain agents were administered continuously. the longer the period was for ventilator dependence, the more analgesics and sedative agents were required. in this study, after patients were weaned from the ventilator, they all regained normal consciousness. the pain scores upon discharge were evaluated again and had decreased compared with initial admission scores. in the rib fixation group, the pain score upon discharge was lower than in the other group. therefore, pain can be greatly reduced for patients undergoing rib fixation compared with those who do not receive rib fixation. although vats combined with rib fixation has many advantages in patients with arf, this study has several limitations. the numbers of patients with arf are small for thoracic injuries because only 5 to 10% experience incidences after blunt chest trauma. however, in this study, we attempted to include a sufficient number of patients for the calculation power to reach 0.8. the other limitation of the study was that patient selection was not randomized, although the study protocol was designed prospectively. because all patients were initially intubated and sedated after trauma, all decisions regarding operation were made by patients' families. we considered that all patients in this study should receive fixation but that consent should be obtained from families. although we provided detailed information regarding rib fixation, some family members did not understand our explanations. therefore, we could only provide their families with choices to inform their final decisions. however, this condition provided a comparison group for the study. although the two groups were not matched initially, which may have caused selection bias, the demographic characteristics of the two groups exhibited no statistically significant differences. the binary logistic regression examination also indicated a high correlation between rib fixation and the length of ventilation use after adjustment for other variances. another limitation of the observationbased data was that different staff members recorded the observations. to mitigate this limitation, a senior surgeon reviewed all data for accuracy and consistency. all surgical procedures were performed by the same team, and the same surgeons were responsible for all decisions to perform rib fixation to avoid surgical confounding bias. the pain score evaluation comparison between the two groups was also a limitation in this study. in addition to the subjectivity of pain sensation, group 2 patients had longer icu stays that may have interfered with pain scores. fortunately, all patients in this study were lucid and conscious, decreasing the potential for such bias. the combination of rib fixation with vats may provide complete treatment of chest wall deformity and of lung and pleural lesions in severe blunt chest injuries. this combination surgery may decrease ventilator dependence, lower the rate of pneumonia, and shorten the course of admission. complex thoracic injuries 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of retained hemothorax in blunt head and chest trauma prospective randomized controlled trial of operative rib fixation in traumatic flail chest surgical rib fixation for flail chest deformity improves liberation from mechanical ventilation the morbidity and mortality of rib fractures a comprehensive analysis of traumatic rib fractures: morbidity, mortality and management the surgical stabilization of multiple rib fractures using titanium elastic nail in blunt chest trauma with acute respiratory failure publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank all hospitals (kaohsiung veterans general hospital, kaohsiung, taiwan), critically ill patients, and icu, and ed. authors' contributions yp carried out the collection, analysis, and interpretation of the data and drafted the manuscript. yw and hl recruited the patients and collected the clinical data. tw, hl, and yp carried out in the study design. yw, wy, and fd helped in the analysis and interpretation of the data. hl, th, and yp helped to draft the manuscript. all authors read and approved the final manuscript. the first two authors had equal contribution and are considered first author. availability of data and materials the datasets generated and analyzed during the current study are available from the corresponding author on reasonable request (tung-ho wu, hsing-lin lin1, yi-pin chou, fong-dee huang, wen-yen huang, yih-wen tarng). the study was approved by the ethical committee of the hospital and informed consent was waived with an observational study. the authors declare that they have no competing interests. 1 key: cord-048447-chz8luni authors: duffett, mark; choong, karen; ng, vivian; randolph, adrienne; cook, deborah j title: surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis date: 2007-06-15 journal: crit care doi: 10.1186/cc5944 sha: doc_id: 48447 cord_uid: chz8luni introduction: exogenous surfactant is used to treat acute respiratory failure in children, although the benefits and harms in this setting are not clear. the objective of the present systematic review is to assess the effect of exogenous pulmonary surfactant on all-cause mortality in children mechanically ventilated for acute respiratory failure. methods: we searched the medline, embase, cinahl and ovid healthstar databases, the bibliographies of included trials and review articles, conference proceedings and trial registries. we included prospective, randomized, controlled trials of pulmonary surfactant that enrolled intubated and mechanically ventilated children with acute respiratory failure. we excluded trials that exclusively enrolled neonates or patients with asthma. two reviewers independently rated trials for inclusion, extracted data and assessed the methodologic quality. we quantitatively pooled the results of trials, where suitable, using a random effects model. results: six trials randomizing 314 patients were included. surfactant use reduced mortality (relative risk = 0.7, 95% confidence interval = 0.4 to 0.97, p = 0.04), was associated with increased ventilator-free days (weighted mean difference = 2.5 days, 95% confidence interval = 0.3 to 4.6 days, p = 0.02) and reduced the duration of ventilation (weighted mean difference = 2.3 days, 95% confidence interval = 0.1 to 4.4 days, p = 0.04). conclusion: surfactant use decreased mortality, was associated with more ventilator-free days and reduced the duration of ventilation. no serious adverse events were reported. acute respiratory failure remains the primary indication for admission to north american paediatric intensive care units (picus) and accounts for significant mortality, morbidity and resource utilization [1] . respiratory infections, in particular pneumonia and severe bronchiolitis, are the most common causes of respiratory failure requiring mechanical ventilation in children [1] . alterations in endogenous surfactant play a role in the pathogenesis of many causes of acute lung injury (ali) and acute respiratory distress syndrome (ards) [2] . surfactant dysfunction, destruction and inactivation have also been demonstrated in children with acute respiratory insufficiency due to bronchiolitis [3, 4] . the administration of exogenous surfactant may reduce the need for mechanical ventilation and its associated sequelae by restoring surfactant levels and function. inspired by the success of surfactants in reducing mortality and the need for mechanical ventilation in neonatal respiratory distress syndrome [5] , investigators have studied exogenous surfactant in other populations with various causes of respiratory failure. trials of surfactant in adults with ali and ards have not demonstrated a mortality benefit [6] [7] [8] [9] , perhaps due to inherent differences in the aetiology of lung injury in adults, the design features of the trials, the mode and timing of surfactant administration or the type and dose of surfactant used. in children with respiratory failure, the efficacy of exogenous surfactant has been suggested in uncontrolled studies ali = acute lung injury; ards = acute respiratory distress syndrome; fio 2 = fractional inspired oxygen; pao 2 = arterial oxygen tension; picu = paediatric intensive care unit; rsv = respiratory syncytial virus. (page number not for citation purposes) [10, 11] . the relatively low mortality rate, the diversity of the study populations and the shorter duration of mechanical ventilation are factors that make large-scale randomized controlled trials in this population challenging to conduct. two of the largest trials were stopped early due to slower than expected enrolment [12, 13] . while the use of surfactant in ards/ali has not been previously systematically reviewed, its use in children with bronchiolitis has been [14] . we anticipated that including trials enrolling children with acute respiratory failure from a variety of causes would result in a heterogeneous population and would increase the generalizability of the results. our confidence in the results of the present review would also be increased if a consistent effect is shown in subgroups and across a spectrum of disease severity. the primary objective of the systematic review is to assess the effect of the administration of pulmonary surfactant compared with no therapy or with placebo on all-cause mortality (at or before hospital discharge) in mechanically ventilated children with acute respiratory failure. we included trials that were prospective, that were randomized, that enrolled children intubated and mechanically ventilated for acute respiratory failure and that compared the intratracheal administration or nebulization of at least one dose of natural or artificial pulmonary surfactant with a placebo or no intervention. we excluded trials exclusively enrolling neonates or patients with asthma. we used the trial authors' definitions of paediatric. the primary outcome measure was all-cause mortality at or before hospital discharge. secondary outcomes were ventilator-free days to day 28 (a composite of mortality and duration of ventilation, defined as days alive and free from mechanical ventilation) [15] , the duration of mechanical ventilation (from intubation to extubation, death or trial withdrawal), the duration of picu stay, the use of rescue therapy (such as extracorporeal membrane oxygenation, high-frequency oscillatory ventilation, open label surfactant and nitric oxide), and complications and adverse effects as reported by the trial authors. one of us searched for published and unpublished trials, examining trial registries, conference proceedings and the bibliographies of any identified trials and relevant reviews (the search strategy is available upon request). we polled paediatric intensivists and pharmacists at our institution for additional trials. we selected search terms from the keywords and mesh terms of previous surfactant trials and from the generic and brand names of commercially available surfactants. we imposed no language restrictions. one of us screened the title (and abstract if required) of all citations retrieved. we selected citations for further evaluation if they reported the administration of at least one dose of surfactant to at least one child or if the title or abstract did not give enough information to make an assessment. two reviewers independently reviewed all citations meeting criteria for further review and applied the inclusion criteria. disagreements between reviewers were resolved by consensus in consultation with a third reviewer. we considered agreement between reviewers to be acceptable if the kappa value was greater than 0.8. we used the following characteristics to assess the methodologic quality: allocation concealment (sealed envelopes or central randomization were considered adequate), blinding (which of the trial personnel and caregivers were blinded, and the methods used to ensure blinding), completeness of followup (assessed by the number of patients randomized for whom there were no outcomes), similarity of the groups at baseline (with respect to known prognostic factors: age, aetiology, severity of illness as measured by the pediatric risk of mortality score, and immunosuppression), whether a standard or recommended strategy for mechanical ventilation was used, and whether a priori criteria for the use of co-interventions were used. effective blinding of surfactant is challenging because of the large volumes of milky fluid administered, which can often be seen by caregivers in the patients' ventilator tubing or endotracheal tube, particularly during suctioning. we pretested and refined the developed forms on two trials of surfactant therapy for adults, and clarified definitions based on feedback from the reviewers. two reviewers then independently used these forms to abstract trial quality, blinded to the authors, the journal, the country of origin and the results. we resolved any disagreements by consensus in consultation with a third reviewer if needed. after pretesting and refining the forms on two trials of surfactant therapy in adults and clarifying definitions based on feedback from the reviewers, two reviewers then independently abstracted the data. reviewers were only provided with a full-text version of the trials from which the introduction, conclusions and discussion were omitted and from which the author, journal and country of origin were deleted. we thereafter examined these sections of the reports for any missing data. we resolved any disagreements between reviewers by consensus in consultation with a third reviewer if needed. we asked the authors to supply data not included in the published reports. two reviewers performed data entry in duplicate. we quantitatively pooled the results of individual trials when possible. we expressed the treatment effect as a relative risk for dichotomous outcomes and as a weighted mean difference for continuous outcomes with 95% confidence intervals. we considered effects statistically significant if p < 0.05. a z test was used to statistically test the estimates of treatment effect between groups [16] . we assessed heterogeneity among trials using the i 2 statistic, and considered an i 2 value greater than 50% to indicate substantial heterogeneity [17] . revman 4.2 software and a random effects model were used to perform the analyses [18] . we chose the random effects model because it gives a more conservative estimate of the precision of the treatment effects and because the true effect of the intervention probably varies given the different populations enrolled in these trials [19] . a subgroup analysis was planned based on the aetiology of respiratory failure (trials enrolling exclusively patients with respiratory syncytial virus (rsv)/ severe bronchiolitis compared with all other trials) if sufficient data were available, because these trials were likely to enrol a younger, more homogeneous, population with a lower predicted risk of mortality. we also planned sensitivity analysis based on methodological features of the included trials (trials reporting adequate allocation concealment compared with all other trials). we identified 742 unique citations, six of which met our inclusion criteria ( figure 1 outlines the reasons for exclusion). most reports excluded enrolled neonates or were retrospective or uncontrolled in design. chance corrected agreement was excellent (kappa = 0.91, 95% confidence interval = 0.73-1.1). table 1 presents a complete description of our quality assessment. only one trial did not report allocation concealment [20] . although effective blinding of surfactant is challenging, two trials reported blinding of the picu team [12, 20] . the two flow diagram of included trials flow diagram of included trials. rcts, randomized controlled trials. groups were generally well matched in terms of baseline characteristics in most trials. the most significant imbalance was the numerically higher number of immunosuppressed patients in the placebo group. these patients had higher mortality (56%) than the immunocompetent group (13%). the authors attempted to adjust for this imbalance with logistic regression, which suggested that the treatment effect seemed to be relatively consistent between the two groups [12] . only one trial reported a priori criteria for rescue therapy [13] . table 2 describes the included trials. three trials enrolled exclusively infants with rsv-induced respiratory failure [20, 21] or with severe bronchiolitis [22] . the remaining three trials enrolled a heterogeneous group of patients with ards or ali [12, 23, 24] . while the individual treatment protocols varied, all trials used comparable doses (50-100 mg/kg phospholipids) of natural or modified natural surfactants and each patient typically received one or two doses. a variety of interventions were used in the control groups: no intervention, air placebo or similar sedation and ventilation manoeuvres without a placebo. although one study [20] used a modified natural surfactant, all the products used contained surfactant proteins b and c. all studies administered surfactant early in the course of respiratory failure; most patients were treated within 12-48 hours of requiring mechanical ventilation. the baseline characteristics of the patients are presented in table 3 . while there was significant heterogeneity among and within trials with respect to age and cause of respiratory failure, we considered the initial pediatric risk of mortality scores and the initial pao 2 /fio 2 ratios to be clinically comparable. mortality data were available for all six trials, randomizing 311 patients and reporting data for 305 patients. there were no deaths reported in the three rsv/severe bronchiolitis trials; thus our estimate is based on three trials randomizing 232 patients, 64 of whom died. in the pooled analysis, surfactant was associated with significantly lower mortality (relative risk = 0.7, 95% confidence interval = 0.4-0.97, p = 0.04). there was no evidence of heterogeneity (i 2 = 0%) ( figure 2 ). ventilator-free days to day 28 the number of ventilator-free days to day 28 was available for six trials randomizing 311 patients and reporting data for 305 patients. in the pooled analysis, surfactant was associated with significantly more ventilator-free days (weighted mean dif(figure 3 ). the duration of mechanical ventilation was available for six trials randomizing 311 patients and reporting data for 305 patients. in the pooled analysis, surfactant was associated with a significantly shorter duration of mechanical ventilation (weighted mean difference = 2.3 days, 95% confidence interval = 0.1-4.4 days, p = 0.04) (figure 4) . the duration of picu stay was available for five trials randomizing 273 patients and reporting data for 272 patients. in the pooled analysis, surfactant was associated with a shortened duration of picu stay (weighted mean difference = 2.6 days, 95% confidence interval = 0.02-5.2 days, p = 0.05), but this difference was not statistically significant ( figure 5 ). data on the use of rescue therapy were available for six trials randomizing 311 patients and reporting data for 305 patients. in the pooled analysis, the surfactant was associated with a significantly lower use of rescue therapy (relative risk = 0.4, 95% confidence interval = 0.3-0.7, p < 0.0001). there was no evidence of heterogeneity (i 2 = 0%). this summary estimate should be interpreted with caution as only one trial reported a protocol for initiating rescue therapy. the decision to use a rescue therapy, particularly an open-label surfactant, may be influenced by knowledge of the patient's allocation; furthermore, only two trials reported blinded caregivers and the methods used to ensure blinding may not be adequate. surfactant therapy was well tolerated (see table 4 ), but only three of the trials reported any definitions or a priori criteria or of collecting adverse events [12, 21, 23] . transient hypotension and transient hypoxia were the most commonly reported adverse events in the largest trial. these responded to a brief adjustment in ventilation, to a slowing of the rate of surfactant administration or to fluid administration. there was no difference in the incidence of air leaks in the two trials that reported this outcome. no patient was withdrawn from any of the trials because of adverse events. we did not pool the data on adverse events associated with the trial interventions from the six trials because of the inconsistent manner in which the events were documented and reported. the effect of surfactant on ventilator-free days, the duration of mechanical ventilation and the duration of picu stay was not significantly different when we compared the three trials that enrolled exclusively patients with rsv/severe bronchiolitis with the three other trials (table 5) . a 100% survival in the bronchiolitis trials subgroup precludes formal subgroup analysis for the primary outcome of mortality. all but one of the included trials reported adequate allocation concealment (defined as sealed envelopes or central telephone randomization). since there were no deaths in this trial we could not assess the effect of inadequate allocation concealment on mortality. pooling the five remaining trials did not change the direction of the effect and did not significantly meta-analysis of trials of surfactant in children with acute respiratory failure: mortality meta-analysis of trials of surfactant in children with acute respiratory failure: mortality. ali, acute lung injury; ards, acute respiratory distress syndrome; 95% ci, 95% confidence interval; rr, relative risk; rsv, respiratory syncytial virus. meta-analysis of trials of surfactant in children with acute respiratory failure: ventilator-free days meta-analysis of trials of surfactant in children with acute respiratory failure: ventilator-free days. ali, acute lung injury; ards, acute respiratory distress syndrome; 95% ci, 95% confidence interval; rsv, respiratory syncytial virus; sd, standard deviation; wmd, weighted mean difference. change the point estimates for the secondary outcomes of ventilator-free days, duration of ventilation or duration of picu stay (table 6 ). in the present systematic review and meta-analysis of the effect of surfactant for critically ill children with acute respiratory failure we found that surfactant therapy significantly reduced our primary outcome of mortality. surfactant was associated with more ventilator-free days, with decreased duration of ventilation and with less use of rescue therapy as compared with standard therapy. there was no significant difference in the duration of picu stay. surfactant therapy was well tolerated; while transient hypoxia and hypotension were reported during surfactant administration, no study reported any serious adverse events. the patients enrolled in these trials are representative of the heterogeneous group of children with early, severe acute respiratory failure that is seen in clinical practice. these patients had similar severity of illness scores and a similar degree of respiratory failure (as measured by pediatric risk of mortality scores and pao 2 :fio 2 ratios). the heterogeneity of results for our primary outcome of mortality was low. the presence of significant heterogeneity reduces the strength of inferences we can make regarding the effect of surfactant on the secondary outcomes of ventilator-free days, meta-analysis of trials of surfactant in children with acute respiratory failure: duration of mechanical ventilation meta-analysis of trials of surfactant in children with acute respiratory failure: duration of mechanical ventilation. ali, acute lung injury; ards, acute respiratory distress syndrome; 95% ci, 95% confidence interval; rsv, respiratory syncytial virus; sd, standard deviation; wmd, weighted mean difference. meta-analysis of trials of surfactant in children with acute respiratory failure: duration of picu stay meta-analysis of trials of surfactant in children with acute respiratory failure: duration of picu stay. ali, acute lung injury; ards, acute respiratory distress syndrome; 95% ci, 95% confidence interval; picu, paediatric intensive care unit; rsv, respiratory syncytial virus; sd, standard deviation; wmd, weighted mean difference. duration of ventilation and duration of picu stay. separately pooling the trials that exclusively enrolled patients with rsv/ severe bronchiolitis and those enrolling patients with ards/ ali from a variety of causes did not significantly reduce the heterogeneity. changing ventilation strategies and the use of a variety of natural and modified natural surfactants may have increased the heterogeneity of our results. ventilation strategies, such as the use of lower tidal volumes and earlier use of high-frequency oscillatory ventilation, have evolved significantly in the 10-year span over which the included trials were conducted [25] [26] [27] . the surfactants used in the included trials were all natural or modified natural surfactants; however, these surfactants may have slightly different effects on oxygenation and compliance due to the differences in phospholipid and surfactant protein composition, which may have influenced individual study results. the strengths of the present review include a comprehensive search strategy, broad inclusion criteria (resulting in a representative, heterogeneous population) and abstraction of clinically important outcomes in duplicate, independently blinded to information that may bias evaluation. the strength of the inference we can make from our subgroup analysis is limited because we were unable to extract all subgroup data from these trials. access to individual patient data would allow better examination of the treatment effect in subgroups of patients and would facilitate further exploration of possible causes of heterogeneity. we found that mortality was very different between the trials that exclusively enrolled patients with rsv/severe bronchiolitis and those that enrolled patients with ards/ali from a variety of causes. we pooled the results because both conditions result in abnormal surfactant function and because of the substantial overlap between the two groups; up to 17% of children in the ards/ali trials had rsv and up to 50% of the children in some bronchiolitis studies also had pneumonia. the reduction in mortality and the increased ventilator-free days have important implications as very few trials in paediatric critical care suggest a favourable impact on mortality [28] . the present review suggests that surfactant could be an important adjunct in the management of paediatric respiratory failure. uncertainty exists, however, about the reproducibility of treatment effects generated from relatively small unblinded trials; questions remain about adverse affects, which may be undetected or under-reported in this literature. also, a large proportion of patients and events are reported in one trial [12] . furthermore, issues of the optimal dose and the timing of administration, and which patients are most likely to derive benefit, should be studied in further adequately powered multicentre trials. the pediatric acute lung injury and sepsis investigators network is planning a large rigorous randomized trial enrolling children with acute hypoxemic respiratory failure to address these issues. surfactant use decreased mortality, was associated with more ventilator-free days and reduced the duration of ventilation. no serious adverse events were reported. most trials enrolled small numbers of children, and further well-designed and adequately powered multicentre trials are therefore required. â�¢ surfactant decreased mortality in a heterogeneous population of children with acute respiratory failure. â�¢ surfactant was associated with more ventilator-free days and a reduced duration of ventilation. â�¢ no serious adverse events were reported. â�¢ further well-designed and adequately powered multicentre trials are required. the feasibility of conducting clinical trials in infants and children with acute respiratory failure adult respiratory distress syndrome in pediatric patients. i. clinical aspects, pathophysiology, pathology, and mechanisms of lung injury harwood jl: abnormal surfactant composition and activity in severe bronchiolitis surfactant abnormalities in infants with severe viral bronchiolitis a controlled trial of synthetic surfactant in infants weighing 1250 g or more with respiratory distress syndrome. the american exosurf neonatal study group i, and the canadian exosurf neonatal study group aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. exosurf acute respiratory distress syndrome sepsis study group bovine surfactant therapy for patients with acute respiratory distress syndrome treatment of acute respiratory distress syndrome with recombinant surfactant protein c surfactant safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome exogenous surfactant therapy for pediatric patients with the acute respiratory distress syndrome calf's lung surfactant extract in acute hypoxemic respiratory failure in children effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study efficacy of interventions for bronchiolitis in critically ill infants: a systematic review and meta-analysis statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome the statistical basis of meta-analysis quantifying heterogeneity in a meta-analysis 2 copenhagen: the nordic cochrane centre, the cochrane collaboration meta-analysis in clinical trials exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis marraro g: multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure porcine-derived surfactant treatment of severe bronchiolitis instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study the acute respiratory distress syndrome network: ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome high-frequency oscillatory ventilation in pediatric respiratory failure: a multicenter experience prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure alternative outcome measures for pediatric clinical sepsis trials the authors would like to acknowledge the authors of the primary trials (dr marco luchetti, dr jens mã¶ller, dr shane tibby and dr douglas willson) for providing additional information or clarification. thanks to john duffett for reviewing the citations and for data entry. the authors declare that they have no competing interests. md conceived of this review. md, kc, vn and djc participated in the design. md and vn extracted data and assessed the quality of the included studies. md, kc, djc and ar helped to draft the manuscript. all authors read and approved the final manuscript. the following additional files are available online: a word file containing a table listing individual trial inclusion criteria and exclusion criteria. see http://www.biomedcentral.com/content/ supplementary/cc5944-s1.doc key: cord-030277-x9zvx3fp authors: ohta, yoshinori; miyamoto, kyohei; kawazoe, yu; yamamura, hitoshi; morimoto, takeshi title: effect of dexmedetomidine on inflammation in patients with sepsis requiring mechanical ventilation: a sub-analysis of a multicenter randomized clinical trial date: 2020-08-10 journal: crit care doi: 10.1186/s13054-020-03207-8 sha: doc_id: 30277 cord_uid: x9zvx3fp background: administration of dexmedetomidine has been reported to improve inflammatory response in animals. we explored the effects of administering dexmedetomidine on the levels of c-reactive protein (crp) and procalcitonin, and thus on inflammation, in patients with sepsis enrolled in a randomized clinical trial. methods: the desire trial was a multicenter randomized clinical trial in which adult patients with sepsis were sedated with (dex group) or without (non-dex group) dexmedetomidine while on mechanical ventilators. as a prespecified sub-analysis, we compared crp and procalcitonin levels during the first 14 days of treatment between the two groups. the 14-day mortality rate, albumin level, and the number of patients with disseminated intravascular coagulation (dic) were also assessed. we used generalized linear models to estimate the differences in these outcomes between groups. we also used the kaplan-meier method to estimate the 14-day mortality rate and the log-rank test to assess between-group differences. results: our study comprised 201 patients: 100 in the dex group and 101 in the non-dex group. crp and procalcitonin levels were lower in the dex vs. non-dex group during the 14-day treatment period [crp—range, 5.6–20.3 vs. 8.3–21.1 mg/dl (p = 0.03); procalcitonin—range, 1.2–37.4 vs. 1.7–52.9 ng/ml (p = 0.04)]. albumin levels were higher in the dex group (range, 2.3–2.6 g/dl) than in the non-dex group (range, 2.1–2.7 g/dl; p = 0.01). the percentage of patients with dic did not significantly differ between the groups (range, 21–59% and 17–56% for the dex and non-dex groups, respectively; p = 0.49). the 14-day mortality rates in the dex and non-dex groups were 13 and 21%, respectively (p = 0.16). conclusion: sedation using dexmedetomidine reduced inflammation in patients with sepsis requiring mechanical ventilation. trial registration: clinicaltrials.gov, nct01760967. registered on 4 january 2013. the inflammatory response has catastrophic consequences in patients with sepsis, including multiple organ failure and death [1] . leukocytes secrete inflammatory mediators such as interleukin (il)-6 and tumor necrosis factor (tnf)-α during critical illness. these mediators can cause endothelial dysfunction, which affects vascular permeability, as well as thrombin activation, leading to hypotension, metabolic acidosis, tissue damage, and eventual organ failure [1, 2] . il-6 and tnf-α concurrently stimulate the production of c-reactive protein (crp) and procalcitonin (pct), which are the most widely used inflammatory biomarkers in patients with sepsis in clinical practice [3, 4] . although crp is a marker of the acute inflammatory response, rather than of the infection that caused the sepsis, it is used to assess the severity and progression of sepsis-induced inflammation [3] . pct levels rise in response to a variety of proinflammatory stimuli, especially those of bacterial origin. they closely correlate with the severity of systemic inflammation and can be used to monitor the course of sepsis [4, 5] . dexmedetomidine is a highly selective α 2 -adrenergic agonist widely used for sedation of patients during mechanical ventilation [6] . several studies have shown that it also suppresses the inflammatory response [7] [8] [9] . administration of dexmedetomidine decreases il-6 and tnf-α levels in animals with severe inflammation [7, 8] and il-6, tnf-α, and crp levels in humans undergoing surgery [9] . whether it also reduces inflammation in patients with sepsis is not known. to investigate the effect of administering dexmedetomidine on sepsis-induced inflammation, we compared the outcomes of patients with sepsis who were treated with or without dexmedetomidine for 14 days as part of the desire clinical trial [10] . this analysis was prespecified in the study protocol for the desire trial before patient enrollment began. the desire trial was a multicenter, open-label, randomized clinical trial that compared the sedation strategies of administering dexmedetomidine (dex group) versus not administering dexmedetomidine (non-dex group) in terms of mortality and ventilator-free days during a 28day period [10] . the trial was registered at clinical-trials.gov (identifier: nct 01760967). a total of 201 patients were enrolled from eight intensive care units (icus) in japan between february 2013 and january 2016, all of whom had sepsis requiring mechanical ventilation for more than 24 h [10] . the flow of participants through the trial is shown in the supplemental figure ( see additional file 1). in the trial, sepsis was defined as systemic inflammatory response syndrome (sirs) criteria due to infection [11] . the enrolled patients satisfied the sepsis-iii criteria due to having received mechanical ventilation and having a sequential organ failure assessment (sofa) score of 2 or more [12] . patients in the dex and non-dex groups received other sedatives as needed to achieve the sedation target and analgesics if necessary. in both groups, the targets of sedation depth were a richmond agitation-sedation scale score of 0 (calm) during the day and − 2 (lightly sedated) during the night [13] . the treatment protocol for sepsis was based on the guidelines developed by the japanese society of intensive care medicine for sepsis management [14] . the present study was approved by the institutional review boards at each participating center. additional study protocols, inclusion and exclusion criteria, and informed consent are described in the supplemental methods (see additional file 1). to evaluate the acute phase of inflammation, this sub-analysis compared the inflammatory status of the dex and non-dex groups during the first 14 days after the randomization. the primary outcome in this analysis was inflammation as indicated by crp and pct levels. the secondary outcomes were 14-day mortality, albumin (alb) level, and sepsis-associated coagulopathy. the alb level served as a marker of vascular permeability [15] . the disseminated intravascular coagulation (dic) score, as defined by the japanese association for acute medicine, was used to assess sepsis-associated coagulopathy [16] . the dic score comprises platelet (plt) counts, the patient/normal prothrombin time (pt) ratio, the levels of fibrin/fibrinogen degradation products (fdps), and the number of sirs characteristics. the scoring system for dic is summarized in the supplemental table 1 (see additional file 1). crp, pct, alb, and fdp levels, plt counts, and pt ratios were measured throughout the 14-day observation period. we also determined the number of patients with three or more sirs characteristics and/or dic (as based on the dic score) on days 1, 2, 4, 6, 8, 10, 12, and 14. primary and secondary outcomes were analyzed according to the intention-to-treat principle. continuous variables were presented as means with standard deviations (sds) or medians with interquartile ranges, and categorical variables were presented as numbers and percentages. to compare patient characteristics between the groups, we used t tests or wilcoxon rank sum tests for continuous variables and chi-square tests or fisher's exact tests for categorical variables. we used a generalized linear model (the genmod procedure) to examine the effect of administering dexmedetomidine on crp, pct, alb, and fdp levels, plt counts, and pt ratios and to account for repeated measurements in the same patient. we used a generalized linear model (the genmod procedure with logit) to determine the effect of administering dexmedetomidine on the number of patients with three or more sirs characteristics and/or dic. the variables describing patient status were the dependent variables, and treatment allocation was the independent variable with a repeated variable of patient. the cumulative incidence of mortality over the 14-day treatment period was estimated via the kaplan-meier method, and differences between the groups were assessed using the log-rank test. all statistical analyses were performed using jmp version 11.2.0 (sas institute inc.), and sas version 9.4 (sas institute inc.) software. a two-sided p value < 0.05 was considered statistically significant. among the 201 patients in our study, 127 (63%) were men, and the mean age was 69 years (sd, 14 years) ( table 1 ). the median acute physiology and chronic health evaluation ii score was 23, and the median sofa score was 9. there were 100 patients in the dex group and 101 in the non-dex group; the characteristics of the groups were well balanced. on the first day after randomization, the median and highest crp levels were 13.8 and 48.3 mg/dl in the dex group and 16.8 and 44.0 mg/dl in the non-dex group, respectively. the number of patients with a pct level of more than 0.5 ng/ml was 88 (89%) in the dex group and 88 (90%) in the non-dex group. the mean alb level was 2.6 g/dl in the dex group and 2.7 g/dl in the non-dex group; the number of patients with hypoalbuminemia (alb of 3.5 mg/dl or less) was 90 (90%) in the dex group and 89 (88%) in the non-dex group. forty (40%) patients in the dex group and 42 (42%) in the non-dex group had dic on day 1. crp and pct levels in the dex and non-dex groups during the 14-day observation period are shown in fig. 1a and b . the crp level was highest on day 2 in both the dex (20.3 mg/dl) and the non-dex (21.1 mg/ dl) groups (fig. 1a) . it was significantly lower in the dex group (range, 5.6-20.3 mg/dl) than in the non-dex group (range, 8.3-21.1 mg/dl) over the 14-day observation period (p = 0.03). pct levels were measured on days 1, 4, 8, and 14 and were highest on day 1 in both the dex (37.4 ng/ml) and non-dex (52.9 ng/ml) groups (fig. 1b) . the pct level was significantly lower in the dex group (range, 1.2-37.4 ng/ml) than in the non-dex group (range, 1.7-52.9 ng/ml) over the 14-day observation period (p = 0.04). the alb levels in the dex and non-dex groups during the 14 days after randomization are shown in fig. 1c . the alb level was lowest on days 4-12 in the dex group and on days 4-14 in the non-dex group. alb levels were reduced to a lesser extent in the dex group (difference, − 0.3 g/dl) than in the non-dex group (difference, − 0.6 g/dl). the alb level was significantly higher in the dex group (range, 2.3-2.6 g/dl) than in the non-dex group (2.1-2.7 g/dl) over the 14-day treatment period (p = 0.01). the levels of the coagulation biomarkers and the number of patients with three or more sirs characteristics during the 14-day observation period are shown in the supplement table 2 (see additional file 1). plt counts were lowest on day 4 in both groups and overall did not differ significantly between groups (range, 116-317 × 10 9 /l in the dex group and 104-299 × 10 9 /l in the non-dex group; p = 0.72). fdp levels were also similar in both groups (range, 22.9-34.3 mcg/ml in the dex group and 19.1-51.7 mcg/ml in the non-dex group; p = 0.40). the pt ratio was highest in both groups on day 2 but overall was lower in the dex group (range, 1.13-1.38) than in the non-dex group (1.21-1.48; p = 0.03). the percentage of patients with three or more sirs characteristics did not differ significantly between the dex vs. non-dex group (range, 12-71 vs. 19-74%; p = 0.15). the levels of the dic-associated variables were similar in both groups with the exception of the pt ratio (supplement table 2 ). the percentage of patients with dic was also similar in both groups (range, 21-59% in the dex group and 17-59% in the non-dex group; p = 0.49). among the 201 patients in our study, 34 (17%) died during the 14 days after randomization. the mortality rates in the dex and non-dex groups were 13% (13 patients) and 21% (21 patients), respectively (p = 0.16) (fig. 2 ). we analyzed data derived from a randomized clinical trial and found that the administration of dexmedetomidine to patients with sepsis on ventilators improved crp and pct levels during the first 14 days in the icu. it also reduced the incidence of hypoalbuminemia, but not of dic. the 14-day mortality rate was also 8% lower in the dex group than in the non-dex group, but this reduction was not significant. the original desire trial did not find statistically significant superiority of administering dexmedetomidine in terms of mortality, but the findings implied an 8% reduction in the 28-day mortality rate in patients with sepsis [10] . because the different use of sedatives did not account for the reduction of mortality, the mechanism of the effect of administering dexmedetomidine on mortality should be explored. dexmedetomidine is a unique sedative: unlike aminobutyric acid receptor agonists, it has analgesic [6] and anti-inflammatory [7] [8] [9] effects. the latter may reflect its ability to inhibit the expression of inflammatory molecules when bound to α 2 -adrenergic receptors on macrophages [17] and/or to increase the concentration of norepihephrine (which suppresses the immune response) when bound to synaptic α 2 -adrenergic receptors in the central nervous system [18] [19] [20] . other possible mechanisms include the modulation of cytokine production by macrophages and monocytes; the inhibition of apoptosis and the toll-like receptor 4 and myeloid differentiation factor 88/mitogen-activated protein kinase/nuclear factor-κb signaling pathways; and the stimulation of the cholinergic anti-inflammatory pathway [19] [20] [21] [22] [23] [24] . although the anti-inflammatory mechanisms through which the administration of dexmedetomidine suppresses inflammation remain to be fully elucidated, previous studies suggest that administration of dexmedetomidine decreases the levels of pro-inflammatory cytokines such as il-6 and tnf-α in patients with sepsis [25] , as well as the levels of pro-inflammatory cytokines and crp in patients undergoing surgery while under anesthesia [9] . in the present study, the use of dexmedetomidine for sedation reduced both crp and pct levels in patients with sepsis. this result indicates that the administration of dexmedetomidine alleviates infection-induced inflammation. we also aimed to determine whether administration of dexmedetomidine improved hypoalbuminemia and sepsis-associated coagulopathy, both of which are associated with severe inflammation. systemic inflammation increases vascular permeability, which is a major cause of hypoalbuminemia in patients with sepsis [2] . most of the patients in our study had low albumin levels on the first day after randomization. thereafter, however, albumin levels were higher in patients treated with versus without dexmedetomidine. this finding presumably reflects reduced inflammation rather than improved nutrition: during the acute phase of inflammation, levels of albumin, which has a half-life of 21 days, are more influenced by vascular permeabilization caused by inflammation-induced injuries to the endothelium than by nutrition [26, 27] . sepsis-associated coagulopathy, which can lead to dic, is thought to result from crosstalk between the inflammation and coagulation systems; inflammation triggers coagulation, which in turn promotes inflammation [28, 29] . in this study, the administration of dexmedetomidine did not affect the incidence of coagulation or dic. suppression of inflammation by administering dexmedetomidine might be insufficient for preventing coagulopathy. the administration of dexmedetomidine has been shown to reduce not only plasma inflammatory cytokine concentrations but also mortality in rats with endotoxininduced shock, and these effects were reported to be dose-dependent [30] . a recent database study reported that mortality differed according to the time after diagnosis of sepsis; phases were categorized in that study as phase 1 (days 1 to 5), phase 2 (days 6 to 15), and phase 3 (days 16 to 150) [31] . deaths during phase 1 and phase 2 accounted for 67.5% of mortality in patients with sepsis or septic shock [31] , and one cause of the early peak in mortality was severe inflammation [1] . therefore, we focused on both inflammation status and mortality in a 14-day period. crp levels correlate positively with the risk of organ failure and mortality; hence, monitoring these levels may aid in assessing the response to therapy in patients with sepsis [32, 33] . pct has greater diagnostic accuracy than does crp because it differentiates infectious versus non-infectious causes of inflammation [34] . crp is a risk factor for mortality in patients with sepsis when levels are elevated and the clearance rate is low [35] . hypoalbuminemia has been shown to predict 30-day mortality in critically ill patients [36] . the doses of dexmedetomidine ranged from 0.1 to 0.7 mcg/kg/h in this study; these are the standard approved doses in japan. although these doses are lower than those typically administered in western countries, the administration of dexmedetomidine at these lower doses successfully decreased crp and pct levels and increased albumin levels when administered to patients with sepsis for 14 days. these changes were considered to reflect the improvement of inflammation in the first 14 days after sepsis onset; hence, it might be associated with decreased mortality. as noted above, a point estimate of 8% reduction in mortality at 14 day was observed in our study, although a level of statistical significance was not reached. one possible reason for this non-significant reduction in mortality could be due to the relatively small sample size or the lower doses of dexmedetomidine. as the anti-inflammatory effects of administering dexmedetomidine are reportedly dosedependent [30] , a greater reduction in mortality might be observed if higher doses are used. further research should clarify the effect of administering dexmedetomidine with higher doses on patient mortality and potential adverse effects in patients with sepsis. there are two limitations in this study. first, it was an open-label study, and the endpoints were assessed by a physician at discharge. awareness of the treatment assignment (dexmedetomidine or no dexmedetomidine) may have influenced some of the management protocols. however, crp, pct, and alb levels, 14-day mortality rates, and sepsis-associated coagulopathy would not be affected by the judgments of physicians. although preparations containing alb can increase albumin levels, the physicians in charge followed the guidelines regarding such preparations when treating patients with sepsisassociated hypoalbuminemia [14] . second, because our study was a subcomponent of the desire trial, sample sizes with sufficient power to detect clinically meaningful differences were not calculated and thus may have been inadequate in some cases, especially in those involving sepsis-associated coagulopathy. moreover, multiple endpoints in sub-analyses should be treated with caution owing to inflated alpha errors. however, the consistency of our findings (lower crp and pct levels and higher alb level in the dex group) attest to their validity. the administration of dexmedetomidine significantly improved crp, pct, and alb levels in patients with sepsis requiring mechanical ventilation. because the anti-inflammatory effects of administering dexmedetomidine were not associated with the reduction of mortality in patients with sepsis at 14 days, further studies with larger sample sizes or administering higher doses of dexmedetomidine are warranted. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03207-8. additional file 1: supplemental methods. table s1. scoring system for dic. table s2 . changes in dic and dic-associated variables. figure s1 . flow of participants in the desire trial. the immune system's role in sepsis progression, resolution, and long-term outcome treating patients with severe sepsis c-reactive protein: a valuable marker of sepsis procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis preliminary uk experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats effect of dexmedetomidine on early postoperative cognitive dysfunction and peri-operative inflammation in elderly patients undergoing laparoscopic cholecystectomy effect of dexmedetomidine on mortality and ventilator-free days in patients requiring mechanical ventilation with sepsis: a randomized clinical trial definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis the third international consensus definitions for sepsis and septic shock the richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients the japanese guidelines for the management of sepsis reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort clinical course and outcome of disseminated intravascular coagulation diagnosed by japanese association for acute medicine criteria. comparison between sepsis and trauma differential involvement of sympathetic nervous system and immune system in the modulation of tnf-α production by α 2 -and β-adrenoceptors in mice intrathecal α 2 -adrenergic agonists stimulate acetylcholine and norepinephrine release from the spinal cord dorsal horn in sheep. an in vivo microdialysis study the effects of noradrenaline and alpha-2 adrenoceptor agents on the production of monocytic products effects of dexmedetomidine on regulating endotoxin-induced up-regulation of inflammatory molecules in murine macrophages the effect of dexmedetomidine on inflammatory response of septic rats dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing tlr4/nf-κb pathway sedation improves early outcome in severely septic sprague dawley rats dexmedetomidine controls systemic cytokine levels through the cholinergic anti-inflammatory pathway survival benefits of dexmedetomidine used for sedating septic patients in intensive care setting: a systematic review glycocalyx and sepsis-induced alterations in vascular permeability coagulation and sepsis markers of inflammation and infection in sepsis and disseminated intravascular coagulation dose-and timerelated effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats the late phase of sepsis is characterized by an increased microbiological burden and death rate c-reactive protein levels correlate with mortality and organ failure in critically ill patients failure to reduce creactive protein levels more than 25% in the last 24 hours before intensive care unit discharge predicts higher in-hospital mortality: a cohort study serum procalcitonin and c-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis serum procalcitonin and procalcitonin clearance as a prognostic biomarker in patients with severe sepsis and septic shock clinical usefulness of c-reactive protein to albumin ratio in predicting 30-day mortality in critically ill patients: a retrospective analysis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank the following investigators in the desire trial: tomonori yamamoto, md (osaka city university, osaka, japan); akihiro fuke, md (osaka city general hospital, osaka, japan); atsunori hashimoto, md (hyogo college of medicine, nishinomiya, japan); hiroyuki koami, md (saga university hospital, saga, japan); satoru beppu, md (national hospital organization kyoto medical center, kyoto, japan), and makoto itoh, md (yamaguchi grand medical center, yamaguchi, japan). authors' contributions yo and tm had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. all authors read and approved the final manuscript. this multicenter randomized clinical trial was supported in part by a noncontractual research grant to wakayama medical university from hospira japan. the present study was supported by jsps kakenhi grants to yo (jp20k07839, jp17k09252, jp25860484, and jp15k21535) and tm (jp17689022, jp21659130, jp22390103, jp23659256, and jp26293159). the funding sources had no role in the study design; collection, analysis, or interpretation of data; writing of the report; or decision to submit the manuscript for publication. the data that support the findings of this study are available from the corresponding author upon reasonable request.ethics approval and consent to participate this study was approved by the institutional review boards of wakayama medical university and each participating institution. written informed consent was obtained from the patient or patient's family before randomization. not applicable. dr. ohta has no conflicts of interest. dr. miyamoto received lecture fees from becton dickinson and pfizer japan. dr. kawazoe received lecture fees from hospira japan and pfizer japan and a scholarship from hospira japan. dr. yamamura received lecture fees from hospira japan, nipro, and asahi kasei and educational consulting fees from toray industries, csl behring, teijin pharma, and nihon pharmaceutical. dr. morimoto received lecture fees from bayer, daiichi sankyo, japan lifeline, kyocera, mitsubishi tanabe, novartis, and pfizer japan; a manuscript fee from pfizer japan; and consulting fees from asahi kasei, bristol-myers squibb, and boston scientific. key: cord-001894-ptuelrqj authors: ferrer, miquel; difrancesco, leonardo filippo; liapikou, adamantia; rinaudo, mariano; carbonara, marco; li bassi, gianluigi; gabarrus, albert; torres, antoni title: polymicrobial intensive care unit-acquired pneumonia: prevalence, microbiology and outcome date: 2015-12-23 journal: crit care doi: 10.1186/s13054-015-1165-5 sha: doc_id: 1894 cord_uid: ptuelrqj background: microbial aetiology of intensive care unit (icu)-acquired pneumonia (icuap) determines antibiotic treatment and outcomes. the impact of polymicrobial icuap is not extensively known. we therefore investigated the characteristics and outcomes of polymicrobial aetiology of icuap. method: patients with icuap confirmed microbiologically were prospectively compared according to identification of 1 (monomicrobial) or more (polymicrobial) potentially-pathogenic microorganisms. microbes usually considered as non-pathogenic were not considered for the etiologic diagnosis. we assessed clinical characteristics, microbiology, inflammatory biomarkers and outcome variables. results: among 441 consecutive patients with icuap, 256 (58 %) had microbiologic confirmation, and 41 (16 %) of them polymicrobial pneumonia. methicillin-sensitive staphylococcus aureus, haemophilus influenzae, and several enterobacteriaceae were more frequent in polymicrobial pneumonia. multi-drug and extensive-drug resistance was similarly frequent in both groups. compared with monomicrobial, patients with polymicrobial pneumonia had less frequently chronic heart disease (6, 15 % vs. 71, 33 %, p = 0.019), and more frequently pleural effusion (18, 50 %, vs. 54, 25 %, p = 0.008), without any other significant difference. appropriate empiric antimicrobial treatment was similarly frequent in the monomicrobial (185, 86 %) and the polymicrobial group (39, 95 %), as were the initial response to the empiric treatment, length of stay and mortality. systemic inflammatory response was similar comparing monomicrobial with polymicrobial icuap. conclusion: the aetiology of icuap confirmed microbiologically was polymicrobial in 16 % cases. pleural effusion and absence of chronic heart disease are associated with polymicrobial pneumonia. when empiric treatment is frequently appropriate, polymicrobial aetiology does not influence the outcome of icuap. intensive care unit (icu)-acquired pneumonia (icuap) is the leading infection in critically-ill patients, accounting for prolonged mechanical ventilation and length of stay, and poor outcome [1] [2] [3] [4] . the use of inappropriate initial antibiotic therapy is a major determinant of mortality in patients with icuap [5] , emphasizing the importance of a timely and accurate therapy for this infection [6] . for this reason, it is often necessary to use a combination of broad-spectrum empiric antibiotics, particularly in patients who are at risk for difficult-to-treat bacteria [7, 8] . recent investigations have shown that multi-drug-resistant (mdr) or high-risk pathogens have been isolated in around half of patients with an episode of ventilator-associated pneumonia (vap) or icuap confirmed microbiologically [9, 10] . icuap, and particularly vap, can be caused by more than one microbial pathogen. multiple etiologic pathogens are potentially an additional challenge for achieving appropriate antimicrobial treatment in these patients. a previous study reported a 48 % rate of polymicrobial etiology in episodes of vap with microbiologic confirmation [11] . these authors concluded that the epidemiology and outcomes of patients with monomicrobial and polymicrobial vap did not differ significantly. however, in this study, a substantial proportion of episodes classified as polymicrobial vap had positive isolation of bacteria usually considered as non-pathogenic microorganisms. moreover, between 15 % and 73 % patients with an episode of icuap are not previously intubated [2, 12, 13] , namely non-ventilator icuap (nv-icuap). to our knowledge, no previous studies have comprehensively assessed polymicrobial icuap strictly considering the identification of potentially pathogenic microorganisms (ppm). we have recently shown that positive microbiology is associated with worse outcomes in patients with clinical diagnosis of icuap [14] . therefore, whether patients with polymicrobial etiology of icuap have different characteristics and outcomes to those with monomicrobial etiology is unknown. we therefore investigated the incidence, characteristics, risk factors, systemic inflammatory response and outcomes of polymicrobial, compared with monomicrobial, etiology of icuap. the study was conducted between october 2004 and september 2013 in six medical and surgical icus, comprising 45 beds, at hospital clinic, barcelona, spain, an 800-bed university hospital. the investigators made daily rounds in each icu. patients older than 18 years, admitted to these icus for 48 h or more, with clinical diagnosis of icuap were consecutively enrolled in the study, and this being only the first episode, were analyzed. exclusion criteria were: 1) severe immune suppression (neutropenia after chemotherapy or hematopoietic transplant, druginduced immune suppression in solid-organ transplant or cytotoxic therapy, and patients with human immunodeficiency virus) and 2) absence of microbiologic confirmation. the institution's internal review board approved the study (comite etic d'investigacio clinica, registry number 2009/5427) and written informed consent was obtained from patients or their next of kin. definition of pneumonia, microbiologic processing, and antimicrobial treatment clinical diagnosis of icuap was based on clinical criteria: new or progressive radiological pulmonary infiltrate together with at least two of the following: temperature >38°c or <36°c, leukocytosis >12,000/ mm 3 or leukopenia <4,000/mm 3 , and purulent respiratory secretions [1, 15, 16] . non-ventilated icuap was defined when patients acquired pneumonia after more than 48 h of icu admission and without previous mechanical ventilation [2] . we considered vap in patients with previous invasive mechanical ventilation for 48 h or more. early-onset pneumonia was defined as occurring within the first 4 days of hospitalization [1] . the microbiologic evaluation included the collection of at least one lower respiratory tract sample: sputum in non-ventilated patients, tracheobronchial aspirates (tbas) in intubated patients, and/or bronchoscopic [17] or blind bronchoalveolar lavage (bal) [18] , whenever possible, within the first 24 h of inclusion [19] . bronchoscopic bal and blind bal were performed as previously described [19] . the same sampling method was performed on the third day if clinically indicated. blood cultures and cultures from pleural fluid, if puncture was indicated, were also taken. urinary antigens of legionella pneumophila and streptococcus pneumoniae were systematically collected. microbiologic confirmation of pneumonia was defined by the presence of at least one ppm in respiratory samples above predefined thresholds (bal >10 4 , sputum or tbas >10 5 colony-forming units/ml, respectively), in pleural fluid or in blood cultures if an alternative cause of bacteremia was ruled out [20, 21] . drug resistance of pathogens was defined according to a recent report [22] . mdr pathogens were defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories. extensive drug resistance (xdr) was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories). pan drug resistance (pdr) was defined as non-susceptibility to all agents in all antimicrobial categories. we considered methicillin-resistant staphylococcus aureus (mrsa), and enterobacteriaceae producing extended-spectrum β-lactamase as mdr pathogens [9] . monomicrobial and polymicrobial pneumonia were defined when one and more than one ppm, respectively, were identified as etiologic agents at onset of pneumonia. isolation of candida spp, streptococcus viridans, staphylococcus epidermidis, neisseria spp, enterococcus spp, and corynebacterium spp in lower respiratory tract samples were not considered etiologic agents. the initial empiric antimicrobial treatment was administered according to local adaptation of the american thoracic society/infectious disease society of america guidelines [1] , based on the most frequently isolated ppm and their patterns of antimicrobial sensitivity in our institution, and subsequently revised according to the microbiologic results. the empirical antimicrobial treatment was considered appropriate when the isolated pathogens were susceptible in vitro to at least one of the antimicrobials administered at an adequate dose [8] . we assessed the initial response to treatment after 72 to 96 h of antimicrobial treatment, as previously described [23, 24] . non-response was considered when at least one of the following criteria were present: 1) no improvement of the arterial o 2 tension to inspired o 2 fraction ratio or need for intubation because of pneumonia (defined as need for intubation after 24 h from the beginning of antibiotics); 2) persistence of fever (temperature ≥38°c) or hypothermia (<35.5°c) together with purulent respiratory secretions; 3) increase in the pulmonary infiltrates on chest radiograph ≥50 %; or 4) occurrence of septic shock or multiple organ dysfunction syndrome, defined as three or more organ system failures not present on day 1. we evaluated the serum levels of interleukin (il)-6, il-8, tumor necrosis factor-alpha (tnf-alpha), c-reactive protein, procalcitonin and mid-regional pro-adrenomedullin within the first 24 h after the diagnosis of pneumonia. all methods of these analyses have been recently described in detail [25, 26] . all relevant data were collected at admission and at onset of pneumonia from the medical records and bedside flow charts, including laboratory, radiologic and microbiologic information. we calculated the acute physiology and chronic health evaluation (apache)-ii score [27] and the simplified acute physiology score (saps)-ii [28] on icu admission. the simplified clinical pulmonary infectious score (cpis) [29] and the sepsis-related organ failure assessment (sofa) [30] scores were also evaluated on icu admission and up to 9 days after the onset of pneumonia. septic shock [31] and acute respiratory distress syndrome (ards) [32] were defined according to previously described criteria. patients were followed until death or up to 90 days after the diagnosis of pneumonia. the outcomes of patients with monomicrobial pneumonia were compared to those with polymicrobial pneumonia. the primary outcome variable was mortality at 90 days after the diagnosis of icuap. secondary outcomes included initial non-response to treatment, length of icu and hospital stay, ventilator-free days at day 28 [33] , and mortality at 28 days. categorical and continuous data are presented as number (percentage) and as mean ± sd (or median (inter-quartile range)), respectively. categorical variables were compared with the chi square (χ 2 ) test or the fisher exact test. quantitative continuous variables were compared using the t test or the mann-whitney test for normally and non-normally distributed variables, respectively. survival curves for patients with monomicrobial and polymicrobial pneumonia were obtained using the kaplan-meier method and compared using the log-rank test. the association between polymicrobial or monomicrobial etiology and patients' outcomes was adjusted for variables potentially related to mortality, such as age, apache-ii and saps scores at icu admission, sofa score, cpis and arterial partial pressure of oxygen/inspired oxygen fraction (pao 2 /fio 2 ) ratio at onset of pneumonia, vap or nv-icuap, and unilateral or bilateral chest x-ray infiltrates. we used cox proportional hazard regression analysis for 28-day and 90-day mortality. all reported p values are two-sided and not adjusted for multiple comparisons. a p value <0.05 was considered significant. all statistical analyses were performed using ibm spss statistics version 20 (armonk, ny, usa). we prospectively identified 441 consecutive patients with icuap; 185 (42 %) were excluded because a positive microbiological diagnosis could not be made. therefore, we included 256 patients: 215 (84 %) with monomicrobial, and 41 (16 %) with polymicrobial icuap (fig. 1) . the characteristics of patients at icu admission and at onset of pneumonia are summarized in tables 1 and 2. the rate of chronic heart disease was lower, and the rate of pleural effusion was higher, in patients with polymicrobial, compared to monomicrobial pneumonia. no other significant differences were found between the two groups in the remaining baseline characteristics, comorbidities, reasons for icu admission, disease severity, and laboratory variables at the onset of pneumonia. the proportions of lower respiratory tract samples processed for microbiology were similar in the two groups (table 3) . however, blood and pleural fluid culture were performed more often in patients with polymicrobial pneumonia, in case of pleural fluid, owing to the higher incidence of pleural effusion in this group. there were 2 patients (5 %) in the polymicrobial pneumonia group with methicillin-sensitive staphylococcus aureus (mssa) isolated in pleural fluid. in the monomicrobial pneumonia group, 8 patients (4 %) had positive pleural fluid cultures: mssa and pseudomonas aeruginosa in 3 patients, and mrsa in 2 patients. there were 5 patients (12 %) in the polymicrobial pneumonia group with positive blood cultures: serratia table 4 . all patients with polymicrobial pneumonia had two different pathogens identified, except two who had three different pathogens identified ( table 5 ). the most frequently isolated pathogens were p. aeruginosa, enterobacteriaceae, and mssa. several bacteria, such as mssa, haemophilus influenzae, klebsiella spp., e. coli, enterobacter spp., citrobacter spp., and serratia spp., were more frequently isolated in patients with polymicrobial pneumonia. the remaining pathogens were isolated at similar rates in both groups. these findings were similar when we analyzed patients with vap and non-ventilator icuap separately. the proportion of patients with mdr and xdr pathogens isolated were similar in both groups (table 4 ). there were no patients with pdr microorganisms. patients treated with antibiotics before the onset of icuap more frequently had mdr or xdr pathogens than those not treated previously with antibiotics (59 (30 %) vs. 9 (15 %), respectively, p = 0.014). a new microbiologic evaluation was done on the third day of evolution in 169 patients (79 %) and 33 patients (80 %) from the monomicrobial and polymicrobial groups, respectively. the microbiologic evolution is shown in table 4 . the serum levels of all inflammatory biomarkers were similar in patients from the two groups (table 6 ). the appropriateness of the empirical antimicrobial treatment, the initial non-response to treatment, the length of stay, the ventilator-free days, and mortality at 28 and 90 days were similar in both groups (table 7 and fig. 2) . mortality of patients adjusted for initial non-response to treatment did not differ between groups (28 days: p = 0.71; 90 days: p = 0.49). the most frequent cause of death was shock-multiple organ failure. even when adjusted for variables potentially related to mortality, the polymicrobial etiology of icuap was not associated with 28-day mortality (adjusted hazard ratio 0.86, 95 % confidence interval 0.44-1.58, p = 0.65) or 90-day mortality (adjusted hazard ratio 1.16, 95 % confidence interval 0.57-2.39, p = 0.69). polymicrobial etiology accounted for 16 % cases of icuap with positive microbiology. except for less frequent chronic heart disease and more frequent pleural effusion in polymicrobial pneumonia, there were no other significant differences between patients with monomicrobial and polymicrobial pneumonia in their baseline characteristics, inflammatory response or outcomes. information about the polymicrobial etiology of icuap is limited. the only study that specifically addressed this issue in vap, published in 2002 [11] , found a substantially higher proportion of polymicrobial etiology (48 %) compared to the present one. unlike our study, those authors included some bacteria that are considered nonpathogenic for the lung in non-immunosuppressed patients, such as several streptococcus species, neisseria spp, enterococcus spp, and coagulase-negative staphylococci. indeed, a substantial proportion of microbial isolates reported in polymicrobial vap in that study (42 %) represented these types of microbes [11] . similarly, previous observational studies reported rates of polymicrobial etiology of vap that ranged between 28 % and 50 % when ppms and non-pathogenic microbes were analyszed [34] [35] [36] [37] . having included non-pathogenic microbes would have increased the rate of polymicrobial pneumonia to 30 % in our population. conversely, we report in our study that 16 % of patients with icuap had polymicrobial etiology when we restricted the analysis to ppms. a previous study that used the same criteria reported a similar rate (10 %) for vap of polymicrobial etiology [38] . a relevant issue in the polymicrobial etiology of icuap is the potential prognostic implications. for that reason, finding predictors of polymicrobial pneumonia reported values are median (interquartile range). a number of patients with samples processed for each inflammatory biomarker in each group. il interleukin, mr-proadm mid-regional pro-adrenomedullin, tnf tumor necrosis factor could hypothetically be of potential interest. however, in a clinical setting of highly appropriate initial antibiotic treatment, as reported in the present study for both groups, all the outcomes, including length of stay, ventilator-free days and mortality, were similar in the two groups. indeed, in our study the numbers of patients with mdr or xdr pathogens in our study did not differ with pneumonia of polymicrobial etiology. in addition, when patients were clustered into non-ventilated icuap and vap, there were also no statistically significant differences in these outcomes. in our study, the only variables associated with polymicrobial etiology were absence of chronic heart disease and prior hospital admission, and the presence of pleural effusion, which was twice as high in the polymicrobial group. we have previously reported that patients with clinical diagnosis of both community-acquired pneumonia and icuap and negative microbiology more frequently have chronic heart disease [14, 39] . both studies suggested that some of these cases might also represent, at least in part, fluid overload due to congestive heart failure added to the underlying inflammatory process potentially mimicking pneumonia. similarly, underlying chronic heart disease might hypothetically have contributed to the development of pulmonary congestion in patients with presumably lower bacterial burden, such as those with pneumonia of monomicrobial etiology. we do not have a clear explanation for the association between a higher rate of pleural effusion and polymicrobial pneumonia. the isolation of mssa in pleural fluid culture from two patients was not sufficiently decisive to allocate them to the polymicrobial pneumonia group; in one patient, this pathogen was concomitantly identified in blood and tracheal aspirate cultures, while in the other, both h. influenzae and klebsiella spp were isolated in a tracheal aspirate culture. the association between pleural effusion and icuap of polymicrobial etiology needs to be confirmed in future prospective studies. neither prior antibiotic treatment nor late-onset pneumonia, as in the previous french study [11] , were predictors of polymicrobial pneumonia in our study. however, prior antibiotic treatment was associated with the presence of mdr or xdr pathogens in our study. in addition we found no association between the severity of presentation and polymicrobial etiology. this finding complements a previous study in 343 patients with icuap that concluded that severity of illness seems not to affect etiology [9] . we also found no differences in the serum levels of any inflammatory biomarkers that we measured at the onset of pneumonia. in relation to the etiology of icuap, we have recently reported that inflammatory biomarkers were unable to differentiate between patients with positive and negative microbiology [14] , or patients with or without mdr pathogens [9] . all these studies confirm that inflammatory biomarkers are not useful in predicting the etiology of icuap. the main strengths of our study are the prospective design, the detailed description of microbiology in icuap, the inclusion of both vap and non-ventilator icuap, the exclusion of non-potentially pathogenic microorganisms from the analysis, the assessment of several inflammatory biomarkers, and the follow up of patients up to 90 days. however, in our study we excluded immunosuppressed patients. consequently, we cannot extrapolate our results to this population. this study has some limitations. first, it was conducted in a single center, so the extrapolation of these findings to other settings must be done cautiously. second, we did not use molecular microbiological techniques that are potentially more sensitive. however, the experience of using these techniques in icuap, and in non-ventilator icuap and vap, is still scarce. third, the sample size of our study is not enough large to make a robust analysis of all related questions; when comparing several characteristics between the two groups of patients the current study was underpowered. it is important to outline that this is a non-interventional study and our purpose was only to describe clinical findings. fourth, there were no adjustments made for multiple comparisons. the etiology of icuap with microbiologic confirmation was polymicrobial in 16 % of patients. pleural effusion and absence of chronic heart disease are associated with polymicrobial pneumonia. when empiric antibiotic treatment is frequently appropriate, polymicrobial etiology does not influence the outcome of icuap. polymicrobial etiology of icu-acquired pneumonia accounted for 16 % cases with microbiologic confirmation polymicrobial etiology of icu-acquired pneumonia was associated with pleural effusion and absence of chronic heart disease polymicrobial etiology did not result in higher incidence of multi-drug-and extensive-drugresistant pathogens when empiric treatment is appropriate, polymicrobial etiology does not influence the outcome of icu-acquired pneumonia abbreviations apache: acute physiology and chronic health evaluation; ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage; cpis: clinical pulmonary infectious score; icu: intensive care unit; icuap: icu-acquired pneumonia; il: interleukin; mdr: multi-drug-resistant; mrsa: methicillin-resistant staphylococcus aureus; mssa: methicillin-sensitive staphylococcus aureus; pao 2 /fio 2 : arterial partial pressure of oxygen/inspired oxygen fraction; pdr: pan-drug resistance; ppm: potentially pathogenic microorganism; saps: simplified acute physiology score; sofa: sepsis-related organ failure assessment; tbas: tracheobronchial aspirates; tnf: tumor necrosis factor; vap: ventilator-associated pneumonia; xdr: extensive-drug-resistant. infectious diseases society of america. guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia nosocomial pneumonia in the intensive care unit acquired during mechanical ventilation or not impact of nosocomial infections on clinical outcome and resource consumption in critically ill patients attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. icu-acquired pneumonia study group de-escalation therapy: is it valuable for the management of ventilator-associated pneumonia? early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia assessment of severity of icu-acquired pneumonia and association with etiology prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients* incidence and outcome of polymicrobial ventilator-associated pneumonia pneumonia associated with invasive and noninvasive ventilation: an analysis of the german nosocomial infection surveillance system database hospital and long-term outcomes of icu-treated severe community-and hospitalacquired, and ventilator-associated pneumonia patients icu-acquired pneumonia with or without etiologic diagnosis: a comparison of outcomes clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies definition and classification of community-acquired and nosocomial pneumonias the standardization of bronchoscopic techniques for ventilator-associated pneumonia the safety and diagnosis accuracy of minibronchoalveolar lavage in patients with suspected ventilator associated pneumonia noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome hospital-acquired pneumonia: coverage and treatment adequacy of current guidelines diagnostic value of quantitative cultures of endotracheal aspirate in ventilator-associated pneumonia: a multicenter study resistance patterns and outcomes in intensive care unit (icu)-acquired pneumonia. validation of european centre for disease prevention and control (ecdc) and the centers for disease control and prevention (cdc) classification of multidrug resistant organisms causes and predictors of non-response to treatment of the icu-acquired pneumonia validation of predictors of adverse outcomes in hospital-acquired pneumonia in the icu* inflammatory biomarkers and prediction for intensive care unit admission in severe community-acquired pneumonia prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology apache ii: a severity of disease classification system a new simplified acute physiology score (saps ii) based on a european/north american multicenter study resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock acute respiratory distress syndrome: the berlin definition statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome nosocomial pneumonia in patients receiving continuous mechanical ventilation. prospective analysis of 52 episodes with use of a protected specimen brush and quantitative culture techniques nosocomial bronchopneumonia in the critically ill: histologic and bacteriologic aspects incidence and etiology of pneumonia acquired during mechanical ventilation ventilator-associated pneumonia caused by potentially drug-resistant bacteria effect of ventilator-associated pneumonia on mortality and morbidity factors associated with unknown aetiology in patients with community-acquired pneumonia the authors declare that they have no competing interests.authors' contributions mf participated in the study design, recruitment of patients, data analysis and writing of the manuscript. lfd participated in the study design, recruitment of patients and writing of the manuscript. al participated in the study design, recruitment of patients and writing of the manuscript. mr participated in recruitment of patients, interpretation of data and critical review of the manuscript. mc participated in recruitment of patients, interpretation of data and critical review of the manuscript. glb participated in interpretation of data, critical review and writing of the manuscript. ag participated in the data analysis, management of database and, drafting of the manuscript. at participated in the study design, interpretation of date and critical review and writing of the manuscript. all the authors have read and approved the final version of the manuscript.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord-000891-5r2in1gw authors: giannella, maddalena; rodríguez-sánchez, belen; roa, paula lópez; catalán, pilar; muñoz, patricia; de viedma, darío garcía; bouza, emilio title: should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season? date: 2012-06-14 journal: crit care doi: 10.1186/cc11387 sha: doc_id: 891 cord_uid: 5r2in1gw introduction: influenza is easily overlooked in intensive care units (icus), particularly in patients with alternative causes of respiratory failure or in those who acquire influenza during their icu stay. methods: we performed a prospective study of patients admitted to three adult icus of our hospital from december 2010 to february 2011. all tracheal aspirate (ta) samples sent to the microbiology department were systematically screened for influenza. we defined influenza as unsuspected if testing was not requested and the patient was not receiving empirical antiviral therapy after sample collection. results: we received ta samples from 105 patients. influenza was detected in 31 patients and was classified as unsuspected in 15 (48.4%) patients, and as hospital acquired in 13 (42%) patients. suspected and unsuspected cases were compared, and significant differences were found for age (53 versus 69 median years), severe respiratory failure (68.8% versus 20%), surgery (6.3% versus 60%), median days of icu stay before diagnosis (1 versus 4), nosocomial infection (18.8% versus 66.7%), cough (93.8% versus 53.3%), localized infiltrate on chest radiograph (6.3% versus 40%), median days to antiviral treatment (2 versus 9), pneumonia (93.8% versus 53.3%), and acute respiratory distress syndrome (75% versus 26.7%). multivariate analysis showed admission to the surgical icu (odds ratio (or), 37.1; 95% confidence interval (ci), 2.1 to 666.6; p = 0.01) and localized infiltrate on chest radiograph (or, 27.8; 95% ci, 1.3 to 584.1; p = 0.03) to be independent risk factors for unsuspected influenza. overall mortality at 30 days was 29%. icu admission for severe respiratory failure was an independent risk factor for poor outcome. conclusion: during the influenza season, almost one third of critical patients with suspected lower respiratory tract infection had influenza, and in 48.4%, the influenza was unsuspected. lower respiratory samples from adult icus should be systematically screened for influenza during seasonal epidemics. influenza is a common cause of admission to the intensive care unit (icu) during the influenza season and influenza pandemics [1] [2] [3] [4] . however, it may be overlooked, particularly in patients with clinical manifestations that can be explained by alternative infectious or noninfectious causes [5] . furthermore, influenza may not be suspected when respiratory function deteriorates or fails in patients already admitted to the icu. at present, information on influenza acquired during icu stay is scarce and incomplete [5] . timely knowledge of the presence of influenza virus in patients admitted to the icu has obvious epidemiologic, diagnostic, and therapeutic advantages [4] . we assessed the burden of influenza in adult icus and the number of overlooked cases when the routine diagnostic workup was applied during the influenza season. we screened all tracheal aspirates sent to the microbiology department for the diagnosis of lower respiratory tract infection, even when not requested by the attending physician. our hospital is a 1,550-bed tertiary referral teaching institution caring for a population of approximately 750,000 inhabitants. it has three different adult icus (medical, surgical, and cardiac surgery) with a total of 42 beds. from december 15, 2010, through february 28, 2011, all tracheal aspirate (ta) samples obtained from adult patients (≥18 years) admitted to our icus and sent to the microbiology department were systematically screened for influenza virus. icu admission criteria and management for all patients, including the need for intubation and for obtaining ta samples, were not standardized, and decisions were made at the discretion of the attending physician. patients with laboratory-confirmed influenza, by realtime reverse transcriptase polymerase chain reaction (rt-pcr) on ta and nasopharyngeal samples, were prospectively followed up by an infectious diseases specialist and treated with oseltamivir, 150 mg/day, for 5 to 10 days. clinical and microbiology data were recorded in a preestablished protocol and entered into a database. the study was approved by the ethics committee of the "fundación para la investigación biomédica del hospital gregorio marañón." the requirement for informed consent was waived because we applied an excellent diagnostic technique to improve the quality of patient care without any negative impact. our objectives were to determine the incidence of influenza among adult icu patients with a ta sample obtained during the influenza season, and to demonstrate the frequency of unsuspected cases and the rate of hospital-acquired episodes. the variables recorded were age, sex, classification of the severity of underlying conditions according to the charlson comorbidity index [6] , type of icu, date and cause of icu admission, apache ii score [7] on admission to the icu, date of onset of influenza symptoms, clinical manifestations and radiologic findings at diagnosis, date of ta sample collection, other samples tested for influenza and result, date of initiation of antiviral treatment, complications (septic shock, acute respiratory distress syndrome (ards)), outcome including mortality within 30 days after influenza diagnosis, and length of icu and hospital stay. we defined the diagnosis of influenza as unsuspected when influenza testing was not explicitly requested or had not been previously requested in other samples, such as nasopharyngeal swabs, and the patient was not receiving empirical antiviral treatment immediately after sample collection. influenza was classified as community acquired if the flu syndrome (fever, chills, malaise, sore throat, rhinorrhea, cough, dyspnea, myalgia, nausea, and diarrhea) began before or during the first 72 hours of hospital admission. the infection was classified as hospitalacquired, if symptoms started after the first 72 hours [8] . as for causes of icu admissions, severe respiratory failure was defined as severe hypoxemia (pao 2 < 60 mm hg) refractory to high-flow oxygen therapy (fio 2 , 50%) with a venturi mask. as for underlying conditions, chronic obstructive pulmonary disease was defined according to the criteria of the 2007 global initiative for chronic obstructive lung disease [9] . immunosuppressed patients were those with hematologic malignancy (with or without bone marrow transplantation), hiv infection, inflammatory diseases under biologic or immunosuppressive treatment and solid organ transplant. as for influenza vaccination, we considered patients who had been vaccinated against influenza within 6 months before admission. pneumonia was defined according to the current idsa/ats guidelines [10] . ards and septic shock were defined by using standard criteria [11, 12] . samples for microbiologic diagnosis were taken by endotracheal aspiration with a 14f sterile probe to a depth of 2 cm from the distal end of the endotracheal tube. the secretions obtained were collected in a sterile container (lukens specimen container; sherwood medical, tullamore, ireland) and transported in sterile packages to the microbiology laboratory for gram staining and bacterial and viral procedures. standard bacterial procedures included quantitative culture performed on blood agar, chocolate agar, mcconkey agar, and, when required, legionella agar (bcye) [13] . positive samples were defined as those with bacterial counts ≥10 5 cfu/ml of each significant microorganism. the microorganisms were identified and antimicrobial susceptibility testing performed by using an automatic system (microscan; dade behring, sacramento, ca, usa). breakpoints were determined after the clinical and laboratory standards institute (clsi) guidelines [14] . unless proven otherwise, we considered as nonpathogenic the isolation (at any concentration) of the following microorganisms: viridans-group streptococci, enterococcus spp., coagulase-negative staphylococcus, neisseria spp., corynebacterium spp., and candida spp. samples were collected in viral-transport medium (copan 305c; copan innovation, brescia, italy). a 200μl aliquot was stored at 4°c for no longer than 48 hours until analysis. the rest of the sample was stored at -80°c for further amplification and sequencing. rna was extracted in a nuclisens easymag system (biomérieux, boxtel, the netherlands) by following the manufacturer's instructions. pandemic influenza a ph1n1 was detected by real-time reverse transcriptase polymerase chain reaction (rt-pcr) by following the who/cdc protocol in a stratagene mx3000 thermocycler (stratagene, la jolla, ca, usa). those samples rendering indeterminate results (low-fluorescence signal or high ct values) were tested again with the realtime ready inf a/h1n1 detection set (roche diagnostics, mannheim, germany). influenza b was detected by using the realtime ready influenza b detection set (roche diagnostics). h3n2 and seasonal h1n1 strains were detected as described elsewhere [15] . relative dna was quantified by combining the rt-pcr methods described with the detection of a housekeeping gene with real-time rt-pcr, as described by the cdc. this method allowed normalization of the initial amount of rna present in each sample [16] . categoric variables appear with their frequency distribution. nonnormally distributed continuous variables are expressed as the median and interquartile range (iqr). the association between categoric variables was evaluated by using the χ 2 test or fisher exact test; the association between continuous variables was evaluated by using the mann-whitney u test. a logistic binary model was used to analyze the independent risk factors for unsuspected influenza and 30-day mortality. variables with p ≤ 0.1 in the univariate analysis were entered into the multivariate model. the level of significance was set at p < 0.05 for all the tests. the statistical analysis was performed by using spss 13.0. during the study period, 618 patients were admitted to our adult icus. overall, one or more ta samples were obtained from 105 patients, and a microbiologic diagnosis was made in 65 of them (see figure 1 ). bacterial infection was diagnosed in 29 patients, and the frequencies of the pathogens isolated were as follows: staphylococcus aureus, 37.9%; enterobacteriaceae, 24.1%; pseudomonas aeruginosa, 17.2%; streptococcus pneumoniae, 13.7%; and acinetobacter baumannii, 6.8%. a diagnosis of viral infection only was made in 25 patients: 23 with influenza virus, one with adenovirus, and one with herpes simplex virus. aspergillus fumigatus was the only microorganism isolated in three patients. the remaining eight patients initially had coinfection with influenza virus and the following microorganisms: s. aureus, three; s. pyogenes, one; s. pneumoniae, one; a. baumannii, one; p. aeruginosa, one; and aspergillus fumigatus, one. during the study period, the overall incidence of influenza in the adult icus of our hospital was 5.3 cases per 100 icu admissions. the incidence of influenza among the patients with at least one ta sample sent to the microbiology department was 29.5 cases per 100 icu patients. the reasons for admission to the icu and the characteristics and outcome of the 31 patients with influenza are shown in table 1 . influenza was unsuspected in 15 (48.4%) patients and hospital-acquired in 13 (42%) patients. at the time of influenza diagnosis, all patients but one were intubated. among patients with co-infection, the reasons for admission to the icu were as follows: surgery, five; respiratory failure, one; cardiac arrest, one; and decompensated cirrhosis, one. influenza was classified as hospital acquired in five (62.5%) of them, and pneumonia was diagnosed in seven (87.5%) patients. overall, viral infection was diagnosed in 33 patients, and in 31 (93.9%) of them, influenza was detected. influenza was due to the 2009 pandemic influenza a h1n1 strain in 27 (87%) patients, influenza b in three (9.7%) patients, and influenza a h3n2 in one (3.2%) patient. in 17 of the 31 patients, influenza testing was performed simultaneously in the ta and nasopharyngeal samples. the upper respiratory tract sample failed to detect influenza in 17.6% of cases. overall, the median relative viral load at diagnosis was 1.55 (iqr, 0.68 to 3.16) . this tended to be higher in patients with suspected influenza ( table 2) . patients with suspected influenza were compared with those with unsuspected influenza ( table 2 ). the univariate analysis revealed significant differences for age (53 versus 69 years; p = 0.008), medical icu (93.8% versus 40%; p = 0.002), admission to the icu for severe respiratory failure (68.8% versus 20%; p = 0.002), length of icu stay before the influenza diagnosis (1 (iqr, 0 to 1) versus 4 (iqr, 1 to 17) days; p = 0.01), classification as having hospital-acquired influenza (18.8% versus 66.7%; p = 0.01), cough (93.8% versus 53.3%; p = 0.01), localized pulmonary infiltrate on radiograph (6.3% versus 40%; p = 0.04), median days to initiation of antiviral therapy after onset of symptoms (2 (iqr, 2 to 6) versus 9 (iqr, 4.5 to 18) days; p = 0.02), pneumonia (93.8% versus 53.3%; p = 0.01), and development of ards (75% versus 26.7%; p = 0.01). mortality at 30 days after the influenza diagnosis was 37.5% and 20% (p = 0.43) in patients with suspected and unsuspected influenza, respectively. multivariate analysis showed the independent risk factors associated with unsuspected influenza to be admission to the surgical icu (or, 37.13; 95%ci, 2.06 to 666.60; p = 0.01) and localized pulmonary infiltrate on radiograph (or, 27.78; 95%ci, 1.32 to 584.06; p = 0.03). longer icu stay before the diagnosis of influenza was also associated with unsuspected influenza but was not significant (table 3) . overall mortality at 30 days after influenza diagnosis was 29%. the univariate analysis of the risk factors for mortality is shown in table 4 . nosocomial acquisition of influenza was associated with better outcome (54.5% versus 11.1%; p = 0.04). the only independent risk factor for 30-day mortality in the multivariate analysis was severe respiratory failure as the reason for admission to the icu (or, 7.5; 95%ci, 1.23 to 45.8; p = 0.03). during the influenza season, almost one third of patients hospitalized in our adult icus and with suggestion of lower respiratory tract infection had influenza. influenza was unsuspected in 48.4% and hospital acquired in 42%. patients with unsuspected influenza were more frequently admitted to the icu for surgery, had a localized infiltrate on chest radiograph, and stayed longer in the icu before being diagnosed with influenza. antiviral treatment was initiated later in patients with unsuspected influenza, although mortality was similar in both groups. overall mortality at 30 days after the influenza diagnosis was 29%; however, it was lower in patients with nosocomial influenza. severe respiratory failure as the cause of admission to the icu was the only independent factor associated with poor outcome. acute febrile respiratory illness is a common cause of respiratory failure and admission to the icu [2] [3] [4] . in most cases, the etiology is bacterial, although viruses have been implicated in almost 9% of cases [17] . during the 2009 pandemic, the rate of icu admission for respiratory failure among hospitalized patients with a confirmed diagnosis of influenza a (h1n1v) ranged from 15% to 34% [18] [19] [20] [21] [22] . however, no studies have investigated the rates of bacterial and viral etiologies among patients admitted to the icu with suggestion of lower respiratory tract infection during the 2009 pandemic. here, we demonstrated that, after the pandemic influenza season, the etiology was viral in 31.4% of patients admitted to the icu with suggestion of lower the etiology of acute febrile respiratory illness causing respiratory failure is often unknown at admission to the icu [17] . about half of the cases are diagnosed as bacterial pneumonia shortly after admission, with a small number of cases found to be viral pneumonia when the initial bacterial studies are negative [10] . detection of influenza virus often depends on specific epidemiologic risk factors and clinical suspicion. the combination of fever, malaise, and cough was shown to have a 79% positive predictive value during the pandemic and seasonal epidemics [23, 24] ; however, these criteria may be not accurate in icu patients, because other etiologies, or conditions like as postsurgery sedation, may confound the diagnosis [25] . in our study, influenza was unsuspected in 48.4% of cases. suspicion of influenza was lower in older patients, in those admitted to the icu for surgical conditions, in those who stayed for a longer time in hospital and icu, and in those who did not have a cough and diffuse pulmonary infiltrates. the direct consequence of overlooked influenza was a significant delay in the initiation of antiviral treatment. definitive diagnosis of influenza is by detection of the virus in culture or rt-pcr with a nasopharyngeal aspirate/swab or lower respiratory tract sample [23, 24] . because viral shedding peaks at 48 hours after the onset of illness and declines thereafter, testing of lower respiratory tract samples in patients with compromised lung parenchyma may be more beneficial [23, 26, 27] . accordingly, we found that the upper respiratory tract sample did not reveal influenza in 17.6% of cases. diagnostic viral load tended to be higher in patients with suspected influenza, possibly as a result of the earlier diagnosis of influenza after onset of symptoms in this group compared with patients with unsuspected influenza. hospital-acquired influenza is a well-recognized problem [28, 29] . nosocomial outbreaks of pandemic and seasonal influenza have been documented in various settings, including icus, pediatric wards, transplant units, medical wards, and surgical wards [28] [29] [30] [31] [32] . however, few sporadic cases of hospital-acquired influenza have been reported during surveillance activities [33] . in a study including 1,520 patients hospitalized with the pandemic 2009 influenza a in 75 hospitals in the united kingdom, the authors identified 30 (2%) cases of sporadic nosocomial influenza [33] . these comprised 15 adults and 15 children. most had serious underlying illnesses and were admitted to nonmedical areas, as in our study. unexpectedly, we found that the 30-day mortality rate was lower in patients with hospital-acquired influenza. this figure can be associated with viral factors, such as lower virulence of the influenza strains circulating in the hospital, or with host factors, such as older age and surgical conditions. overall, 30-day mortality was high (29%), and admission to the icu for severe respiratory failure was an independent risk factor for death. these data are consistent with those of martin-loeches et al. [34] , who showed that patients from the postpandemic influenza ph1n1 period had an unexpectedly high mortality rate. early administration of antiviral therapy has been associated with better outcome in critically ill patients [35] . in our study, although the timing to initiation of antiviral treatment was longer among patients with unsuspected influenza, a trend to lower mortality was seen in this group compared with patients with suspected influenza. a possible explanation of this finding could be that: suspected and unsuspected groups were epidemiologically very different, and the median relative viral load was lower in the unsuspected group; thus, epidemiologic and viral factors could influence the outcome in the two groups independently of the timing of antiviral treatment. conversely, the benefit of testing will not be necessarily to the patient in terms of improved outcome due to early therapy, but more likely to preventing the nosocomial transmission of influenza. our study is limited in that the small number and heterogeneity of patients diminishes the power of our data analysis. we performed the study during the postpandemic period (2010 to 2011), when the prevalence of the pandemic influenza a h1n1 strain was still high. findings could vary between one influenza season and another, depending on the characteristics of the prevalent influenza virus stain. we did not perform a costeffectiveness analysis, although the finding of a longer icu and hospital stay in patients with unsuspected influenza suggests a potential favorable impact on care management. we could not perform an analysis of the possible routes of transmission of the nosocomial cases. however, we can exclude with sufficient certainty the occurrence of an outbreak for the following reasons: (a) the cases of hospital-acquired influenza were distributed uniformly between the three icus (postsurgery icu, six; medical icu, five; and postcardiosurgery icu, two); (b) no case of influenza was recognized among the healthcare staff during the study period; (c) the preventive measures included vaccination of staff, respiratory isolation, and droplet-contact precautions, as recommended by the centers for disease control and prevention [36] . we showed that influenza is a common cause of acute respiratory illness among patients admitted to the icu during seasonal epidemics, and that it is often overlooked, and it could lead to a delay in the initiation of antiviral treatment and possible nosocomial transmission of influenza. microbiology departments should systematically investigate the presence of influenza in respiratory samples obtained from icu patients during the seasonal epidemic. • the incidence of influenza in the adult icu during the influenza season is high. • the diagnosis of influenza is often overlooked in icu patients. among patients with unsuspected influenza, the timing to initiation of antiviral treatment was longer, and the rate of hospital-acquired influenza was higher compared with that of patients with suspected influenza. • microbiology departments should systematically investigate the presence of influenza in respiratory samples obtained from icu patients during the seasonal epidemic. abbreviations apache: acute physiology and chronic health evaluation; ards: acute respiratory distress syndrome; ats: american thoracic society; cdc: centers for disease control; copd: chronic obstructive pulmonary disease; icu: intensive care unit; idsa: infectious diseases society of america; iqr: interquartile range; rt-pcr: reverse transcriptase-polymerase chain reaction; ta: tracheal aspirate; who: world health organization. case mix, outcome and length of stay for admissions to adult, general critical care units in england, wales and northern ireland: the intensive care national audit & research centre case mix programme database febrile respiratory illness in the intensive care unit setting: an infection control perspective acute febrile respiratory illness in the icu: reducing disease transmission severe febrile respiratory illnesses as a cause of mass critical care nosocomial influenza: new concepts and practice morbidity during hospitalization: can we predict it? apache ii: a severity of disease classification system incubation periods of acute respiratory viral infections: a systematic review the 2007 gold guidelines: a comprehensive care framework infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock guidelines for performance of respiratory tract cultures performance standards for antimicrobial susceptibility testing: fifteenth informational supplement typing (a/b) and subtyping (h1/h3/h5) of influenza a viruses by multiplex real-time rt-pcr assays prolonged viral shedding in pandemic influenza a h1n1: clinical significance and viral load analysis in hospitalized patients acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data critically ill children with pandemic influenza (h1n1) in pediatric intensive care units in turkey outcomes from pandemic influenza a h1n1 infection in recipients of solid-organ transplants: a multicentre cohort study hospitalized children with 2009 pandemic influenza a (h1n1): comparison to seasonal influenza and risk factors for admission to the icu pandemic influenza a (h1n1) virus hospitalizations investigation team: hospitalized patients with 2009 h1n1 influenza in the united states hospitalized patients with 2009 pandemic influenza a (h1n1) virus infection in the united states efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial neuraminidase inhibitor flu treatment investigator group does this patient have influenza? when should a diagnosis of influenza be considered in adults requiring intensive care unit admission? results of population-based active surveillance in toronto implications of antiviral resistance of influenza viruses intensive care adult patients with severe respiratory failure caused by influenza a (h1n1)v in spain nosocomial influenza in children influenza in the acute hospital setting nosocomial outbreak of influenza virus a (h3n2) infection in a solid organ transplant department a nosocomial outbreak of 2009 pandemic influenza a(h1n1) in a paediatric oncology ward in italy outbreak of novel influenza a (h1n1) in an adult haematology department and haematopoietic cell transplantation unit: clinical presentation and outcome nosocomial pandemic (h1n1) 2009 pandemic and post-pandemic influenza a (h1n1) infection in critically ill patients impact of early oseltamivir treatment on outcome in critically ill patients with 2009 pandemic influenza a should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season? critical care 2012 16:r104. submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution we thank thomas o'boyle for his help with the preparation of the manuscript. this study was partially financed by the programa de centros de investigación biomédica en red (ciber) de enfermedades respiratorias cb06/06/0058. maddalena giannella (cm08/00279) is contracted by the fis. all the authors made a substantial contribution. eb, dgdv, pc, and pm assisted in the conception and design of the study, revised the manuscript critically, and gave the final approval of the version to be published. mg, br, and plr were responsible for data acquisition, analysis, and interpretation. mg drafted the manuscript. members of gang study group revised and approved the study design and assisted in the data acquisition. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord-004147-9bcq3jnm authors: fernando, shannon m.; mathew, rebecca; hibbert, benjamin; rochwerg, bram; munshi, laveena; walkey, allan j.; møller, morten hylander; simard, trevor; di santo, pietro; ramirez, f. daniel; tanuseputro, peter; kyeremanteng, kwadwo title: new-onset atrial fibrillation and associated outcomes and resource use among critically ill adults—a multicenter retrospective cohort study date: 2020-01-13 journal: crit care doi: 10.1186/s13054-020-2730-0 sha: doc_id: 4147 cord_uid: 9bcq3jnm background: new-onset atrial fibrillation (noaf) is commonly encountered in critically ill adults. evidence evaluating the association between noaf and patient-important outcomes in this population is conflicting. furthermore, little is known regarding the association between noaf and resource use or hospital costs. methods: retrospective analysis (2011–2016) of a prospectively collected registry from two canadian hospitals of consecutive icu patients aged ≥ 18 years. we excluded patients with a known history of af prior to hospital admission. any occurrence of atrial fibrillation (af) was prospectively recorded by bedside nurses. the primary outcome was hospital mortality, and we used multivariable logistic regression to adjust for confounders. we used a generalized linear model to evaluate contributors to total cost. results: we included 15,014 patients, and 1541 (10.3%) had noaf during their icu admission. while noaf was not associated with increased odds of hospital death among the entire cohort (adjusted odds ratio [aor] 1.02 [95% confidence interval [ci] 0.97–1.08]), an interaction was noted between noaf and sepsis, and the presence of both was associated with higher odds of hospital mortality (aor 1.28 [95% ci 1.09–1.36]) than either alone. patients with noaf had higher total costs (cost ratio [cr] 1.09 [95% ci 1.02–1.20]). among patients with noaf, treatment with a rhythm-control strategy was associated with higher costs (cr 1.24 [95% ci 1.07–1.40]). conclusions: while noaf was not associated with death or requiring discharge to long-term care among critically ill patients, it was associated with increased length of stay in icu and increased total costs. atrial fibrillation (af) is the most common cardiac dysrhythmia, with a lifetime risk of 1 in 4 among older adults [1] . development of af has been associated with stroke, myocardial infarction, heart failure, and death [2] . in the intensive care unit (icu), patients often present with pre-existing af; however, some icu patients may develop new-onset af (noaf) in the context of critical illness [3] . unlike af seen in non-critically ill patients, noaf is often thought to be a consequence of critical illness pathophysiology and treatment, including inflammation, electrolyte disturbances, or proarrhythmic medications, namely vasopressors and inotropes [4] . incidence of noaf in the general icu varies markedly; however, most studies suggest that 10-15% of patients will develop this complication during their icu stay [3] [4] [5] . the clinical importance of critical illness-associated noaf is a matter of ongoing uncertainty [4] . af in and of itself may contribute to clinical decompensation through hemodynamic compromise [6] . alternatively, noaf may simply represent a marker of increased illness severity, and may identify patients at increased risk of death without acting causally to worsen prognosis. some cohort studies have identified an independent association between noaf and mortality [7] [8] [9] , while others have not [5, 10] . whether this relationship is seen among all critically ill patients, or limited to select subgroups, is unknown. furthermore, the factors associated with death among patients with noaf are unknown. equally important is the relationship between noaf, and subsequent icu resource use and costs [11, 12] . since the icu is a major source of hospital expenditure, considerable effort has been dedicated to understand the contributors to cost, in order to drive policy and optimize resource utilization [13] . with regard to noaf, little is known regarding the degree of impact on cost expenditures. we primarily sought to evaluate the association between noaf and outcomes, resource utilization, and costs among critically ill adult patients. given the prognostic importance of noaf among patients with sepsis [14, 15] , we secondarily aimed to evaluate the association between incidence of noaf and associated outcomes and resource utilization among critically ill patients with suspected infection, sepsis, and septic shock. we obtained ethics approval for this study from the ottawa health science network research ethics board (protocol 20160570-01h). we studied icu patients from two hospitals within the ottawa hospital network (ottawa, on). these hospitals have approximately 2500 combined icu admissions per year. these are combined medical and non-cardiac surgical icus. we retrospectively examined prospectively collected data from the ottawa hospital data warehouse, a health administrative database used in previous studies [16] [17] [18] [19] . from hospital admission, data is gathered daily from each patient and stored in the data warehouse. data quality assessments are executed routinely, and quality-assurance initiatives are conducted regularly to ensure completeness and accuracy. we included all consecutive patients ≥ 18 years of age, admitted to one of the two icus between january 2011 and december 2016. sample size was determined pragmatically, on the basis of available patients in the data warehouse. we also examined pre-specified subgroups of patients, including those with suspected infection, sepsis, and septic shock, as based on the third international consensus definitions for sepsis and septic shock (sepsis-3) [20] [21] [22] . "suspected infection" was defined as concomitant administration of oral or parenteral antibiotics, and sampling of body-fluid cultures, as performed previously [16, 23] , and in keeping with the sepsis-3 definitions [20] . "sepsis" was defined as suspected infection and an increase in the sequential organ failure assessment (sofa) score by greater than 2 points [20, 21] . finally, "septic shock" was defined by sepsis in addition to initiation of vasopressors or a serum lactate ≥ 2.0 mmol/l [20, 22] . we obtained all data from the ottawa hospital data warehouse. we abstracted demographic data, comorbidities, elixhauser comorbidity score [24] , and multiple organ dysfunction score (mods) [25] at the time of icu admission. the elixhauser comorbidity score is generated from comorbidities stored in the data warehouse, and the association between this index and hospital mortality has been previously validated in our database [26] . the "most responsible diagnosis" was recorded at death or discharge, based upon international classification of diseases, version 10 (icd-10, july 2015). we also noted whether there was presence of a "no cardiopulmonary resuscitation (cpr)" directive at the time of icu admission. we collected outcome data from admission until either the point of discharge from hospital or hospital death. we determined patient costs using the case-costing system of the ottawa hospital data warehouse, as done previously [17, 23, 27] . total hospital costs include both direct and indirect sources. direct costs refer to all hospital expenses with fee codes linked to the patient identifier. indirect costs refer to any overhead operational fees associated with provided service. the ottawa hospital uses a standardized case-costing methodology, developed by the ontario case costing initiative, and based upon the canadian institute for health information management guidelines [28] . costs were indexed to 2018 canadian dollars using consumer price indices [23, 27] . the primary outcome was hospital mortality. secondary outcomes included discharge directly from hospital to long-term care (among survivors to hospital discharge originally from home), hospital readmission within 30 days of hospital discharge among survivors, icu length of stay (los), hospital los, resource utilization (including invasive and non-invasive mechanical ventilation, and renal replacement therapy), and total hospital costs. for each patient, the occurrence of any af was prospectively recorded by bedside nurses for the purposes of quality assurance. the date and time of af, as captured by the bedside nurse, was stored in the data warehouse. patients identified through this method were then evaluated by a single investigator (smf), to confirm the diagnosis. since there is no consensus definition for noaf [4] , we followed pre-existing definitions from the literature [7, 8] . noaf was defined as either (1) af ≥ 1 h in duration, as noted by bedside telemetry (routinely evaluated in charts where electrocardiograms were not completed); (2) af < 1 h in duration, but captured on electrocardiogram; or (3) af initiating pharmacologic therapy or electrical cardioversion. all bedside ecgs, along with final interpretation by an attending cardiologist are stored in patient records. "sustained" af was defined as failure to convert to sinus rhythm 24 h following the onset of any pharmacological treatment or electrical cardioversion. we excluded patients with a previously documented or known history of af, as determined at the time of hospital admission and stored in the data warehouse. we performed all statistical analyses using r (version 3.3.3) and ibm spss (version 24.0). we present data as mean values, with standard deviation (sd), or medians, with interquartile range (iqr), where appropriate. student's t test (parametric values), mann-whitney test (non-parametric values), and χ 2 (for categorical values) were performed to determine between-group differences. in keeping with existing guidelines, we did not perform pairwise comparisons of baseline characteristics [29] . to adjust for measured confounders in the association between new-onset af and outcomes of interest, we followed recommendations for observational studies in the critically ill [30] . as per these recommendations, confounders were determined a priori, on the basis of their likelihood of influencing both the presence of noaf and mortality and not acting as mediators or colliders in the association between af and mortality, as based upon existing clinical knowledge evaluating the association between noaf and mortality in critically ill patients [3, 4] . in accordance with these recommendations [30] , we used multivariable logistic regression modeling to adjust for important continuous (age, mods at icu admission, elixhauser comorbidity index) and categorical (sex, individual comorbidities, "no-cpr" directive on admission, location prior to icu admission, and most responsible diagnosis) variables. as recommended, variables on the causal pathway and potentially contributing to noaf (e.g., vasoactive medications) were not included [30] . we evaluated for possible synergy between noaf and sepsis through the use of an interaction term in the primary model, as performed previously [23] . if a statistically significant interaction term was found between noaf and sepsis, we then represented this with a four-level categorization. we assessed variation in total hospital costs using a multivariable generalized linear model with gamma distribution and log link [31, 32] . we present adjusted odds ratios (aors) and cost ratios (crs) with 95% confidence intervals. a p value of ≤ 0.05 was considered statistically significant. a total of 17,173 patients were admitted to the participating icus from 2011 to 2016 (fig. 1 ). of these, 2105 patients (12.3%) had a known or documented history of af prior to icu admission, and were excluded. a further 54 patients (0.4%) were excluded because of missing outcome data. we included 15,014 patients in the analyses. of these patients, 1541 (10.3%) had noaf while in the icu. baseline characteristics of patient with and without noaf are shown in table 1 . noaf patients were older (mean age 64.7 years vs. 58.5 years), had higher severity of illness (mean mods 5.3 vs. 4.2), and higher comorbidity burden. patient outcomes are depicted in table 2 . median time from hospitalization to development of noaf was 1 day (iqr 1-3), and 345 (22.4%) of noaf patients had sustained af lasting longer than 24 h. multivariable logistic regression analyses examining in-hospital mortality among the entire cohort, and among subgroups with suspected infection (n = 4837, table 3 ), sepsis (n = 1944, 40.2% of "suspected infection" population), and septic shock (n = 1286, 66.2% of "sepsis" population) are included in additional files 1, 2, and 3: tables s1-s3, respectively). following adjustment for confounding variables, noaf was not associated with higher hospital mortality among all icu patients (aor 1.02 [95% ci 0.97-1.08]). however, noaf was associated with higher hospital mortality among icu patients with suspected infection (aor 1.21 [95% ci 1.08-1.37]), sepsis (aor 1.24 [95% ci 1.10-1.39]), and septic shock (aor 1.28 [95% ci 1.14-1.44]). a statistically significant interaction was seen between noaf and presence of sepsis, and the presence of both was associated with higher odds than either alone (additional file 4: . patients with noaf had prolonged median icu los (7 days vs. 6 days, p < 0.001) and median total hospital los (14 days vs. 12 days, p < 0.001). among patients with noaf, factors associated with increased risk of hospital mortality included increasing age, increased mods score, history of chf (as identified in the data warehouse), and sustained af (additional file 5: table s5 ). comparisons of resources used between patients with and without af are shown in table 4 . no differences were seen in the use of invasive (54.7% in those with noaf vs. 52.8% in those without noaf, p = 0.16) or non-invasive ventilation (16.6% in those with noaf vs. 17.5% in those without noaf, p = 0.38). vasoactive medication use was higher among patients with noaf (64.3% vs. 61.2%, p = 0.02). in terms of treatment strategy for noaf, 747 (48.5%) patients received antiarrhythmic medical therapy (i.e., amiodarone, procainamide, or flecainide), while 644 (41.8%) received therapy with a beta-blocker, calcium channel blocker, or digoxin. a total of 128 patients (8.3%) received a combination of the above therapies. finally, comparisons of patient costs between patients with and without noaf are shown in table 5 table s6 ). among patients with noaf (additional file 7: table s7 ), significant predictors of total hospital costs include total hospital or icu los, use of invasive mechanical ventilation or renal replacement therapy, and use of antiarrhythmic medical therapy (as compared to beta-blocker, calcium channel blocker, or digoxin treatment). we identified noaf in 10.3% of critically ill adults, in keeping with known prevalence rates [4] . we found no association between noaf and increased hospital patients with noaf had prolonged icu and hospital los, and noaf was a predictor of increased total costs. mechanical ventilation, renal replacement therapy, and use of antiarrhythmic therapy were significant predictors of total cost in noaf patients. taken together, our study identifies important novel associations between noaf and outcomes among critically ill patients, and also describes the economic impact of noaf. hospital mortality among critically ill adults is high, and therefore, identification of prognostic factors associated with increased risk can be helpful to clinicians in escalating or tailoring therapy. identification of these factors may also be helpful in discussions with patients and families regarding goals of care. noaf is often thought to be a marker of illness severity [3] ; however, the evidence examining the association between noaf and hospital mortality remains uncertain [4] . in our large cohort of critically ill adults, we did not find such an association. however, evaluation of subgroups of patients with suspected infection, sepsis, and septic shock did find an independent association between noaf and hospital mortality potentially suggesting that the consequences of noaf in the patient with sepsis may differ from other populations. important physiologic changes occur during sepsis that make the atrial substrate vulnerable to noaf [33] , and patients with sepsis have a nearly sixfold risk of developing af, as compared to other populations [14] . our findings identifying an independent association between noaf and mortality from sepsis are supportive of existing literature, and potentially suggest that survival in this population may be improved through the prevention and treatment of noaf [34] . importantly, unlike previous studies, we defined sepsis and septic shock using the most recent sepsis-3 definitions, indicating that noaf has potential implications in these populations, and demonstrate an interaction between the presence of noaf and sepsis. in keeping with the sepsis-3 focus of sepsis as infection with concomitant organ dysfunction, noaf may indeed represent sepsis-defining cardiac dysfunction [35] . as such, noaf during sepsis might mediate mortality and may not simply be a marker of illness severity, as is seen in other disease processes [36] . if noaf does represent a marker of illness severity, then its presence may be considered an important indicator of deterioration among critically ill patients. therefore, identification of factors associated with mortality among icu patients who develop noaf remains an important area of ongoing research [4] . unsurprisingly, a history of heart failure was associated with hospital mortality among patients with noaf in our cohort, suggesting that these patients may be more susceptible to the hemodynamic effects of noaf. our results also found that sustained af following 24 h of treatment was also associated with higher hospital mortality. therefore, sustained af may represent a particular ominous marker of illness severity among critically ill adults, and clinicians should act cautiously in those patients with noaf and persisting af. we additionally evaluated the association between noaf and hospital resource use and cost. identification of factors associated with such outcomes remains an important focus in critical care research [11] . few differences were found with regard to resource utilization between patients with and without noaf. however, patients with noaf did have prolonged icu and hospital los, which translated into higher costs. the presence of noaf was also a significant predictor of costs among our cohort, and this was independent of other important factors more commonly associated with cost, including renal replacement therapy and mechanical ventilation [37] . this prolonged los was also manifested in increased laboratory, pharmacy, and nursing costs. despite higher costs, patients with noaf had higher unadjusted mortality, which translated into significant differences in cost per survivor (a proxy indicator of cost-effectiveness). among patients with noaf, treatment with antiarrhythmic medication (as compared to beta-blockers, calcium channel blockers, or digoxin) was associated with higher cost, but decrease in mortality. while this study was not designed to test the efficacy of therapeutic agents for noaf, the little evidence that exists on this topic seems to suggest no beneficial effect of any particular agent [3, 4] . this is in keeping with our results. we did not find evidence of difference in mortality associated with antiarrhythmic agents, but did note increased cost. this is likely attributable to the expense of these drugs [38] , and the fact that they often cannot be administered outside of a monitored setting and therefore may prolong icu los. however, it must be stressed that the efficacy of these agents can only be appropriately tested in a randomized trial, and while equipoise exists, decisions related to agents for treatment of noaf must be made on a case-by-case basis. we used a large multicenter database of patients with prospective identification of noaf, and provide novel data related to hospital mortality, resource utilization, and cost. we also closely followed recommendations for control of confounding in observational studies [30] . however, our study has important limitations. most importantly, our database lacks the granularity to investigate other potential factors that may influence outcome from noaf, such as underlying cardiac function, pulmonary artery catheterization, rate of af, timing of af (particularly in relation to onset of critical illness), use of anticoagulation, and incidence of other arrhythmias. some outcome data, such as incidence of stroke, were not available. we additionally excluded patients with existing af on the basis of known or documented af, but it is possible that patients may have had pre-existing af and not known, due to absence of symptoms [39] . overall, this lack of granularity represents an important limitation in our study. second, patients were included on the basis of prospective identification by nursing staff. while similar methods have been used at other institutions [40] , it is possible that cases of noaf were missed using this methodology, particularly if af was brief and transiently lifetime risk for development of atrial fibrillation: the framingham heart study impact of atrial fibrillation on the risk of death: the framingham heart study atrial fibrillation in the icu new-onset atrial fibrillation in adult critically ill patients: a scoping review incidence and prognosis of sustained arrhythmias in critically ill patients epidemiology and management of atrial fibrillation in medical and noncardiac surgical adult intensive care unit patients incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis. a cohort study new-onset atrial fibrillation in the critically ill atrial fibrillation is an independent predictor of mortality in 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observational study strengthening the reporting of genetic association studies (strega): an extension of the strengthening the reporting of observational studies in epidemiology (strobe) statement control of confounding and reporting of results in causal inference studies. guidance for authors from editors of respiratory, sleep, and critical care journals using generalized linear models to assess medical care costs regression models for analyzing costs and their determinants in health care: an introductory review incidence and prognostic impact of newonset atrial fibrillation in patients with septic shock: a prospective observational study when rhythm changes cause the blues: new-onset atrial fibrillation during sepsis new-onset atrial fibrillation as a sepsis defining organ failure mediation analysis of high blood pressure targets, arrhythmias, and shock mortality daily cost of an intensive care unit day: the contribution of mechanical ventilation costeffectiveness of defibrillator therapy or amiodarone in chronic stable heart failure: results from the sudden cardiac death in heart failure trial (scd-heft) asymptomatic or "silent" atrial fibrillation: frequency in untreated patients and patients receiving azimilide novel method of atrial fibrillation case identification and burden estimation using the mimic-iii electronic health data set long-term impact of newly diagnosed atrial fibrillation during critical care: a south korean nationwide cohort study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations resolved. third, we only had data related to outcomes prior to hospital death or discharge. existing data suggest deleterious long-term outcomes in patients who develop noaf during critical illness [15, 41] . unfortunately, we were unable to evaluate this in our cohort. finally, while our data are derived from two hospitals, they exist within the same city and therefore are susceptible to bias from local practices. while noaf was not associated with hospital mortality among all critically ill patients, it was associated with mortality in subgroups of patients with suspected infection, sepsis, and septic shock. among patients with noaf, sustained af was associated with higher risk of hospital mortality. finally, patients with noaf had higher costs than patients without noaf, and noaf was a predictor of increased total costs among all icu patients. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-2730-0.additional file 1 : table s6 . generalized linear model with gamma distribution and log link for total cost for entire study cohort (n = 15,014). generalized linear model with gamma distribution and log link for total cost for entire study cohort (n = 15,014). additional file 7 : table s7 . generalized linear model with gamma distribution and log link for total cost for patients with new-onset atrial fibrillation (n = 15,014). generalized linear model with gamma distribution and log link for total cost for patients with new-onset atrial fibrillation (n = 15,014). authors' contributions smf, rm, bh, br, and kk designed the study. smf and kk gathered the data. smf, rm, bh, br, lm, ajw, mhm, ts, pd, fdr, pt, and kk analyzed the data, interpreted the data, and wrote the manuscript. all authors read and approved the final manuscript. none received. the datasets generated and analyzed are not publicly available due to patient privacy considerations, but are available from the corresponding author on reasonable request.ethics approval and consent to participate ethics approval for this study was obtained from the ottawa health sciences research ethics board. not applicable. the authors declare that they have no competing interests.author details key: cord-001661-dj9bxhwb authors: kao, kuo-chin; hu, han-chung; chang, chih-hao; hung, chen-yiu; chiu, li-chung; li, shih-hong; lin, shih-wei; chuang, li-pang; wang, chih-wei; li, li-fu; chen, ning-hung; yang, cheng-ta; huang, chung-chi; tsai, ying-huang title: diffuse alveolar damage associated mortality in selected acute respiratory distress syndrome patients with open lung biopsy date: 2015-05-15 journal: crit care doi: 10.1186/s13054-015-0949-y sha: doc_id: 1661 cord_uid: dj9bxhwb introduction: diffuse alveolar damage (dad) is the pathological hallmark of acute respiratory distress syndrome (ards), however, the presence of dad in the clinical criteria of ards patients by berlin definition is little known. this study is designed to investigate the role of dad in ards patients who underwent open lung biopsy. methods: we retrospectively reviewed all ards patients who met the berlin definition and underwent open lung biopsy from january 1999 to january 2014 in a referred medical center. dad is characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury. clinical data including baseline characteristics, severity of ards, clinical and pathological diagnoses, and survival outcomes were analyzed. results: a total of 1838 patients with ards were identified and open lung biopsies were performed on 101 patients (5.5 %) during the study period. of these 101 patients, the severity of ards on diagnosis was mild of 16.8 %, moderate of 56.5 % and severe of 26.7 %. the hospital mortality rate was not significant difference between the three groups (64.7 % vs 61.4 % vs 55.6 %, p = 0.81). of the 101 clinical ards patients with open lung biopsies, 56.4 % (57/101) patients had dad according to biopsy results. the proportion of dad were 76.5 % (13/17) in mild, 56.1 % (32/57) in moderate and 44.4 % (12/27) in severe ards and there is no significant difference between the three groups (p = 0.113). pathological findings of dad patients had a higher hospital mortality rate than non-dad patients (71.9 % vs 45.5 %, p = 0.007). pathological findings of dad (odds ratio: 3.554, 95 % ci, 1.385–9.12; p = 0.008) and sequential organ failure assessment score on the biopsy day (odds ratio: 1.424, 95 % ci, 1.187–1.707; p<0.001) were significantly and independently associated with hospital mortality. the baseline demographics and clinical characteristics were not significantly different between dad and non-dad patients. conclusions: the correlation of pathological findings of dad and ards diagnosed by berlin definition is modest. a pathological finding of dad in ards patients is associated with hospital mortality and there are no clinical characteristics that could identify dad patients before open lung biopsy. in 1994 the american-european consensus conference (aecc) released its definitions of acute lung injury (ali) and acute respiratory distress syndrome (ards) [1] . several studies had challenged the aecc criteria for the diagnosis of ards because of its many limitations [2] [3] [4] [5] [6] [7] . to provide a more reliable definition of ards, an expert panel revisited the aecc definition and released the berlin definition of ards [8] . however, the pathological diagnosis of ards using lung biopsy was not included in the berlin definition because of the controversial definition of the pathology and concern about surgical complications [9] . it is essential to clarify the diagnosis of ards and to initiate effective treatments such as low tidal volume and prone positioning to improve clinical outcome [10] [11] [12] . the current clinical definition of ards reflects only nonspecific functional or physiological abnormalities rather than pathological abnormality. since ards may occur with other pathologic findings, it is uncertain if the same management should be applied to all patients. the heterogeneity of patients with ards included in therapeutic trials remains a challenge when interpreting results from such trials [13] . therefore, open lung biopsy sometimes has been performed to better define the pathology and to guide therapeutic management of selected patients with ards [14] [15] [16] [17] . ards is a form of ali characterized by severe inflammation with increasing epithelial and endothelial permeability [18] . the pathologic hallmark of ards is diffuse alveolar damage (dad) characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury [19, 20] . a post mortem study showed that 66 % of 127 patients who met the aecc definition of ards had typical dad findings [21] . another study reported that of the 64 patients diagnosed as having ards using aecc criteria, 50 % (32/64) had dad findings at autopsy [22] . a large retrospective study in spain revealed that among 356 patients who met the berlin definition of ards, 45 % had dad at autopsy [23, 24] . however, autopsy results are based on results of analysis of samples from deceased patients and thus, there might be differences to results of analysis in the living. the purpose of this study was to investigate the role of dad in patients with ards defined by the berlin definition on open lung biopsy. our study was approved by the institutional review board of chang gung memorial hospital which waived the need for informed consent due to the retrospective nature of the study. chang gung memorial hospital is a tertiary care referral center with a 3700-bed general ward, and a 278-bed adult icu. the hospital charts of all patients with ards who underwent open lung biopsy from january 1999 to january 2014 were reviewed. all patients who were given a discharge diagnosis code of 518.82 (according to the international classification of diseases, ninth revision, clinical modification) were reviewed for possible inclusion in this study. using the berlin definition, ards was characterized as mild if the arterial partial pressure of oxygen/inspired oxygen fraction (pao 2 /fio 2 ) was between 201 and 300 mm hg, moderate if pao 2 /fio 2 was between 101 and 200 mm hg, and severe if pao 2 /fio 2 was less than or equal to 100 mm hg, in all cases using either continuous positive airway pressure (cpap) or positive end-expiratory pressure (peep) of at least 5 cm h 2 o [8] . a total of 1,838 patients with ards were identified by the chart sheets and open lung biopsies were performed on 101 patients (5.5 %). those patients with a pao 2 /fio 2 <200 while on cpap, or those treated with another noninvasive ventilation approach classified as as having moderate or severe ards were excluded. the ards severity was characterized at the time of diagnosis. these 101 patients included patients previously identified using the aecc definition of ards, but reanalyzed in this study according to the berlin definition of ards [16, 25] . the results of cultures from blood, sputum, transtracheal aspiration, and pleural effusion were recorded. the location for bronchoalveolar lavage (bal) sampling was decided on the basis of findings from high-resolution computed tomography (hrct) of the chest or chest x-ray (cxr), if hrct was not available. each specimen was examined for bacteria including legionella, mycoplasma pneumoniae, pneumocystis jiroveci, and mycobacteria, and for fungi and viruses (including cytomegalovirus, influenza virus, parainfluenza virus, adenovirus, herpes simplex virus, respiratory syncytial virus, and coxsackie virus). specimens were also sent for cytology and iron stain analysis. bal results were deemed positive when at the minimum one microorganism had grown to a concentration greater than 10 4 colony-forming units/ml. all specimen examinations were performed within 24 hours of open lung biopsy. open lung biopsy was indicated when ards was suspected to be noninfectious, there was no obvious risk factor, and if there was a possible indication for corticosteroid therapy based on clinical presentation with rapid progression, relative symmetric distribution of infiltrates on cxr, and predominant ground-glass attenuation on hrct of the chest. informed consent for surgical lung biopsy was obtained from each patient's family before surgery. open lung biopsy was performed in an operating room or at the bedside in the icu. the lobe of the lung biopsy was chosen based on the presence of a new or progressive lesion identified on hrct of the chest or cxr. while under general anesthesia, open lung biopsy was performed using either video-assisted thoracoscopic surgery (vats) or a 5-cm thoracotomy, depending on the patient's tolerance. for vats and thoracotomy, an endoscopic stapler-cutter was used to secure the pulmonary margins. to avoid the risk of transfer to the operating room, the timing of bedside open lung biopsy was considered when the given fio 2 reached 1 with a peep above 12 cm h 2 o. each tissue specimen was cultured and examined by pathologists. pathological criteria for the diagnosis of pneumonia involved severe neutrophil infiltration in the interstitium and intra-alveolar spaces, particularly around terminal bronchioles. the pathological criteria for the diagnosis of ali and dad included the presence of pulmonary inflammatory infiltrates and presence of hyaline membrane formation and at least one of the following: intra-alveolar edema, alveolar type i cell necrosis, alveolar type ii cell proliferation progressively covering the denuded alveolar-capillary membrane, interstitial proliferation of fibroblasts and myofibroblasts, or organizing interstitial fibrosis [19, 20, 26] . our strategy for mechanical ventilation of patients with ards consisted of an initial low tidal volume of 6 to 8 ml/kg of predicted body weight for either volumecontrolled or pressure-controlled ventilation. ventilatory adequacy was monitored by arterial blood gas measurements, with the ventilator settings changed as needed. the peep levels were set according to a lower peep and fio 2 strategy or at least 2 cm h 2 o above the lower inflection point derived from the p-v tool maneuvers of the ventilator [27] . the plateau airway pressure was maintained below 30 cm h 2 o combined the peep setting and low tidal volume strategy. pulse oximeter was used to monitor oxygen saturation and the fio 2 was adjusted to maintain spo 2 above 90 %. the plateau airway pressure was tried to avoid raising above 30 cm h 2 o. the following data were collected from the hospital chart of each patient and analyzed: age, sex, underlying diseases, acute physiology and chronic health evaluation (apache) ii score on the day of icu admission [28] , sequential organ failure assessment (sofa) score on the day of icu admission and the day of open lung biopsy [29] , lung injury score (lis) [30] , pao 2 /fio 2 ratio, peep, tidal volume, diagnostic procedures before open lung biopsy (hrct or bal), complications related to surgery (i.e., postoperative air leak, pneumothorax, subcutaneous emphysema, bleeding, and wound infection), pathological diagnosis, hospital mortality, and therapeutic alterations. postoperative therapeutic alterations indicated that the results of open lung biopsy had led to the addition of a new therapy, or the original therapy had been stopped. immunocompromised patients were defined as follows: presence of hiv infection, recipient of solid organ transplantation, recipient of hematopoietic stem cell transplantation (hsct), recipient of chemotherapy, and recipient of long-term systemic corticosteroids for more than 2 weeks. all statistical analyses were performed using the spss statistical package (spss for windows, spss inc., chicago, il, usa). all values are reported as means ± sd. categorical data were tested using the chi-square test (or fisher's exact test when the expected number of events was fewer than five). risk factors for hospital mortality were analyzed by univariate analysis, and the variables statistically significant (p <0.05) in the univariate analysis were included in the multivariate analysis by applying multiple logistic regression based on backward elimination of data. the hosmer-lemeshow goodness-of-fit test was used for calibration when evaluating the number of observed and predicted deaths in risk groups for the entire range of death probabilities. a p value <0.05 was considered statistically significant. from 1 january 1999 to 31 january 2014, 1838 patients were admitted to our icus with a diagnosis of ards, of whom 101 had undergone open lung biopsy, and the overall hospital mortality rate was 60.4 % (fig. 1 ). of the 1838 screened patients, 30 patients were excluded because the symptom onset was more than 1 week ago and had not met berlin criteria. among the 101 patients who met the berlin definition for ards, most patients were classified as having moderate ards (n = 57, 56.5 %), followed by severe ards (n = 27, 26.7 %), and mild ards (n = 17, 16.8 %). the proportions of dad were 76.5 % (13/17) in mild, 56.1 % (32/57) in moderate and 44.4 % (12/27) in severe ards and there were no significant differences among these three groups (p = 0.113). according to the severity on the biopsy day, the proportions of dad were 72 % (13/18) in mild, 56.9 % (33/58) in moderate and 44 % (11/25) in severe ards and there were no significant differences among these three groups (p = 0.113). figure 2 shows the pathological findings of diffuse alveolar damage in the acute phase and organizing phase. baseline characteristics of these patients are shown in table 1 pneumonia, 3 with invasive fungal infection, 2 with staphyloccus aureus, 1 with a viral infection and 1 with mycobacterium tuberculosis), 2 as having an interstitial lung pattern (both patients having organizing pneumonia) and 3 were classified as having miscellaneous infection (2 patients with metastatic adenocarcinoma and 1 with vasculitis). forty-four patients did not have dad and 10 of these patients were classified as having infection (1 patient with pneumocystis jiroveci pneumonia and cytomegalovirus pneumonia, 2 with pneumocystis jiroveci pneumonia, 2 with viral pneumonia, 2 with invasive fungal infection, 2 with bacterial pneumonia and 1 with mycobacterium tuberculosis), 18 patients had interstitial lung patterns (5 patients with usual interstitial pneumonia, 4 with organizing pneumonia, 2 with nonspecific interstitial pneumonia, 1 with desquamative interstitial pneumonia, 1 with hypersensitive pneumonitis and 5 with unclassified interstitial pneumonitis), and 16 patients were classified as having miscellaneous conditions (7 patients with fibrosis, 3 with leukemic infiltration, 2 with metastatic adenocarcinoma, 2 with vasculitis and 2 with lung edema). there were 21 pneumonia patients including 11 patients with dad and 10 patients without dad. the hospital mortality rate was significantly higher in patients with pneumonia and dad (8/11) than in those with pneumonia without dad (2/10) (72.7 % vs 20 %, p = 0.03). according to the results of open lung biopsy, 49 patients had alterations to their therapy (48.5 %). these alterations included 16 patients who had steroid therapy introduced, 7 patients whose antimicrobial agent was changed, 1 patient who had chemotherapy introduced, and 25 patients in whom certain medications were discontinued, including withdrawal of antibiotics in viral pneumonia and metastatic carcinoma, and withdrawal of corticosteroids in bacterial pneumonia. the hospital mortality rates were 64.7 % in mild ards, 61.4 % in moderate ards, and 55.6 % in severe ards and there was no significant difference between the three groups (p = 0.81). table 3 shows the demographic and clinical characteristics of survivors vs non-survivors hyaline membrane (arrow) is seen lining the alveolar ducts (hematoxylin and eosin stain, ×100). b diffuse alveolar damage in the organizing phase. the interstitium is thickened with organizing connective tissue. prominent type 2 pneumocyte hyperplasia is seen (hematoxylin and eosin stain, ×200) univariate analysis was used to identify variables that have prognostic value for hospital mortality, and multivariate logistic regression analysis was used to identify variables that did not have significant prognostic value ( table 4 ). identification of dad on pathological examination (odds ratio 3.554, 95 % ci 1.385, 9.120; p = 0.008) and sofa score on the biopsy day (odds ratio 1.424, 95 % ci 1.187, 1.707; p <0.001) were significantly and independently associated with hospital mortality. regression coefficients for these variables were used to calculate a natural logarithm of the odds (logit) of the probability of death (p) as follows: demographic and clinical characteristics of patients with ards with dad vs those without dad are shown in table 5 . there were no clinical characteristics that could discriminate patients with dad from those without dad before open lung biopsy. patients with ards and a pathologic diagnosis of dad had a higher mortality rate than those without dad (71.9 % vs 45.5 %, p = 0.007). in our study, dad was found in 56.4 % of patients who had ards diagnosed using the berlin definition and who underwent open lung biopsy. the overall hospital mortality rate was 60.4 %. dad and sofa scores obtained by pathological examination on biopsy day were significantly associated with hospital mortality. demographic and clinical characteristics were not significantly different between patients with and without dad patients before open lung biopsy. the typical pathological finding of ards is dad but the correlation between clinical criteria for ards and dad is not well-understood [1, 9, 20, 21] . in an autopsy series, of the 127 patients who met the aecc criteria for ards, 66 % (84/127) were found to have dad identified on pathological examination [21] . in another study based on autopsy data, dad was documented in 43 % (35/82) of patients who met the aecc criteria for ards [31] [14] . they found that 13.8 % (5/36) of patients had dad. in another study, papazian and coworkers prospectively studied 100 patients with ards who fulfilled aecc criteria and who underwent open lung biopsy; 13 % were identified to have dad on pathological examination [17] . in patel's study of open lung biopsy in patients with ards, 40 % (23/57) of patients had dad on pathologic examination [15] . in our previous study, dad was found in 29.3 % (12/41) of patients with early-stage ards, who were receiving open lung biopsy [16] . a recent study in non-resolving ards showed the dad was found in 57.8 % (48/83) patients who had open lung biopsy [32] . in the present study of open lung biopsy, dad was noted in 56.4 % (57/101) of patients with ards in this study, we demonstrated that a dad identified on pathological examination correlated with increased mortality in patients with ards identified using the berlin definition. in a study by parambil et al., the hospital mortality rate in patients with dad was 58 % in patients with ards compared to 17 % in patients without ards [31] . in a study of patients with ards (papazian et al.) , the factors predicting survival included female gender, organ system failure score on the day of biopsy, and biopsy result leading to the addition of a new drug [17] . another open lung biopsy study was performed in mechanically ventilated patients with undiagnosed diffuse pulmonary infiltrates to determine factors independently associated with survival [33] . they found that the charlson agecomorbidity index score, number of organ dysfunctions, and the pao 2 /fio 2 ratio on the day of biopsy were associated with survival. a study in patients with non-resolving ards, who had open lung biopsy showed that the icu mortality rate was higher in patients with dad than in those without dad (67 % vs 57 %), but this was not significantly different [32] . the present study demonstrated that patients with dad had significantly increased hospital mortality compared to those without dad (71.9 % vs 45.5 %, p = 0.007). the poor survival outcome in patients with dad may imply more severe lung injury in patients with ards with vs without dad. however, no clinical characteristic differentiated between patients with and without dad before open lung biopsy (table 5 ). our study highlights the heterogeneity of patients with ards and discrepancy between the clinical and pathological definitions of ards. a distinct phenotype of patients with ards characterized by dad needs to be further addressed due to it having worse outcomes. a meta-analysis of open lung biopsy in patients with ards summarized that the surgical complication rate was 22 %; the most common complication was prolonged air leak, but mortality resulting from surgery was infrequent [34] . meanwhile, open lung biopsy could offer a specific diagnosis in 84 % of patients and altered management in 73 % of patients. our study revealed that the surgical complication rate was 13.9 % and management alteration rate was 48.5 % in these selected patients with ards. the survival advantage of open lung biopsy in ards is still not approved due to lack of a randomized controlled trial. practically, it is important to assess the balance between the potential risk of surgical complications and diagnosis or treatment benefit in deciding to perform open lung biopsy. there were several limitations of our study. first, it is a retrospective study in one referred medical center, which may limit the generalization to all other icus. given the patients included retrospectively from the charts, some patients with ards may have been missed. in addition, the icd-9 diagnosis code 518.82 excludes ards associated with trauma and surgery and includes all type of hypoxemic acute respiratory failure. some patients with trauma-associated or surgery-associated ards may be missed in our study. however, it is one of the largest studies in patients with ards having open lung biopsy. second, the decision to perform open lung biopsy was highly selective and only 5.5 % of patients with ards were referred for biopsy in this study. the results, therefore, are unlikely to be representative of all patients with ards. however, the potential for selection bias for patients with ards may be lower with open lung biopsy than with autopsy as the patients are alive. third, only 85 % of patients had bal before open lung biopsy. some specific diagnoses may have been missed because their recognition depended on the availability of laboratory facilities. fourth, the lung specimens were assessed by one pulmonary pathologist only and so the possibility of individual interpretation bias should be considered. finally, there was no standard treatment for patients with some specific diagnoses, such as interstitial lung disease, after the biopsy result became available. specific treatments such as corticosteroid therapy might have influenced the survival outcome in these patients. this retrospective study demonstrated that 56.4 % of selected patients with ards based on the berlin definition and who underwent open lung biopsy were identified as having dad. as a result of the moderate agreement between clinical and pathological diagnosis of ards, open lung biopsy may be considered in some patients to exclude or to clarify the diagnosis. according to the results of pathological examination, patients with dad had poorer outcomes than patients without dad. however, there was no clinical characteristic that discriminated between patients with and without dad before open lung biopsy. in future studies of ards, the clinical therapeutic trial may focus on this subgroup owing to the high mortality among these patients. in addition to open lung biopsy, some non-invasive modalities such as serum biomarkers and hrct may be used to identify this distinct type of patient with ards. this retrospective study demonstrated that 56.4 % of selected patients with ards based on berlin definition, and who underwent open lung biopsy were found to have dad. the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination acute lung injury and acute respiratory distress syndrome current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome a high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial an early peep/fio2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome acute respiratory distress syndrome 40 years later: time to revisit its definition are we able to optimize the definition and diagnosis of severe acute respiratory distress syndrome? acute respiratory distress syndrome: the berlin definition the berlin definition of ards: an expanded rationale, justification, and supplementary material year in review in intensive care medicine 2012: iii. noninvasive ventilation, monitoring and patient-ventilator interactions, acute respiratory distress syndrome, sedation, paediatrics and miscellanea the acute respiratory distress syndrome network. ventilation with lower tidal volumes for acute lung injury and the acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome clinical trials in patients with the acute respiratory distress syndrome: burn after reading open-lung biopsy in patients with acute respiratory distress syndrome the role of open-lung biopsy in ards open lung biopsy in early-stage acute respiratory distress syndrome a contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients the acute respiratory distress syndrome diffuse alveolar damage-the role of oxygen, shock, and related factors: a review pulmonary pathology of acute respiratory distress syndrome comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings ards: a clinicopathological confrontation comparison of the berlin definition for the acute respiratory distress syndrome with autopsy chronology of histological lesions in acute respiratory distress syndrome with diff use alveolar damage: a prospective cohort study of clinical autopsies the utility of surgical lung biopsy in cancer patients with acute respiratory distress syndrome ards and diffuse alveolar damage: a pathologist's perspective effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure an expanded definition of adult respiratory distress syndrome causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy open lung biopsy in nonresolving ards frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management usefulness of open lung biopsy in mechanically ventilated patients with undiagnosed diffuse pulmonary infiltrates: influence of comorbidities and organ dysfunction surgical lung biopsy in adult respiratory distress syndrome: a meta-analysis this study was supported by grant cmrpg3d0851 from chang gung memorial hospital. the authors would like to thank chiu-hua wang, shin-wen bai and ya-hui hsu for data management and appreciate the patients and staff of icus at chang gung memorial hospital. patients with dad identified on pathological examination had significantly higher hospital mortality than patients without dad, and there was no clinical characteristic that differentiated between patients with and without dad before open lung biopsy. in future studies, the clinical therapeutic trial may focus on patients with ards and dad and investigate some non-invasive modalities to identify this subgroup of patients with ards. on behalf of all authors, the corresponding author states that there is no competing interest.authors' contributions kck took responsibility for the accuracy of the data analysis and drafting the manuscript. hch, chc, cyh, lcc, shl, swl, lpc were responsible for data collection. lfl, nhc and cty were responsible for primary data analysis. cww reviewed the pathological specimens. cch and yht were responsible for interpretation of the results. all authors contributed to completing the manuscript and have approved the final version.submit your next manuscript to biomed central and take full advantage of: key: cord-009274-32adi3hb authors: hu, bo; chen, joy c. y.; dong, yue; frank, ryan d.; passe, melissa; portner, erica; peng, zhiyong; kashani, kianoush title: effect of initial infusion rates of fluid resuscitation on outcomes in patients with septic shock: a historical cohort study date: 2020-04-07 journal: crit care doi: 10.1186/s13054-020-2819-5 sha: doc_id: 9274 cord_uid: 32adi3hb background: fluid resuscitation has become the cornerstone of early septic shock management, but the optimal fluid rate is still not well studied. the goal of this investigation is to examine the relationship between fluid resuscitation rate and septic shock resolution. method: we retrospectively studied adult (≥ 18 years) patients with septic shock, defined based on sepsis iii definition, from january 1, 2006, through may 31, 2018, in the medical intensive care unit (micu) of mayo clinic rochester. the fluid resuscitation time was defined as the time required to infuse the initial fluid bolus of 30 ml/kg, based on the recommendations of the 2016 surviving sepsis campaign. the cohort was divided into four groups based on the average fluid rate (group 1 ≥ 0.5, group 2 0.25–0.49, group 3 0.17–0.24, and group 4 < 0.17 ml/kg/min). the primary outcome was the time to shock reversal. multivariable regression analyses were conducted to account for potential confounders. result: a total of 1052 patients met eligibility criteria and were included in the analysis. the time-to-shock reversal was significantly different among the groups (p < .001). patients in group 1 who received fluid resuscitation at a faster rate had a shorter time to shock reversal (hr = 0.78; 95% ci 0.66–0.91; p = .01) when compared with group 4 with a median (iqr) time-to-shock reversal of 1.7 (1.5, 2.0) vs. 2.8 (2.6, 3.3) days, respectively. using 0.25 ml/kg/min as cutoff, the higher fluid infusion rate was associated with a shorter time to shock reversal (hr = 1.22; 95% ci 1.06–1.41; p = .004) and with decreased odds of 28-day mortality (hr = 0.71; 95% ci 0.60–0.85; p < .001). conclusion: in septic shock patients, initial fluid resuscitation rate of 0.25–0.50 ml/kg/min (i.e., completion of the initial 30 ml/kg iv fluid resuscitation within the first 2 h), may be associated with early shock reversal and lower 28-day mortality compared with slower rates of infusion. septic shock refers to sepsis with cardiovascular dysfunction. it is prevalent and is associated with a high rate of mortality [1, 2] . it is characterized by systemic vasodilation and increased vascular permeability [2] [3] [4] . these changes result in impaired microcirculatory blood flow and reduced tissue perfusion [5] . the fluid resuscitation for septic shock can restore perfusion before the onset of irreversible tissue damage [4] and prevent cardiovascular collapse and death [6, 7] , and, hence, lower mortality [8] . therefore, appropriate fluid resuscitation within the first 3 h of shock state is strongly recommended by the surviving sepsis campaign (ssc) guidelines [9] as the cornerstone of septic shock treatment [10] . the challenge remains to identify the optimal fluid resuscitation strategy. while the standard of practice is the use of boluses of intravascular (iv) fluid for resuscitation [6, 9] , a few trials have shown increased mortality with fluid resuscitation [11, 12] . also, three recent multi-center randomized controlled trials [13] [14] [15] and a follow-up metaanalysis [16] showed that early goal-directed therapy (egdt) bundles in comparison with usual care were not associated with improved outcomes in septic shock. additionally, fluid boluses could lead to a positive fluid balance and excess fluid in the interstitial space [17, 18] , resulting in tissue edema, decreased oxygen delivery, and increased mortality [19] [20] [21] . these controversies surrounding the optimal strategies of initial bolus-fluid administration during septic shock resuscitation make searching for the optimal dose, type, and rate of fluid resuscitation in septic shock a research priority [22] . the current guidelines recommend at least 30 ml/ kg of intravenous crystalloid fluid to be given within the first 3 h of resuscitation [9, 23] , but the influence may be different based on the time to attainment of this target in fluid resuscitation. so the goal of this study is to examine the relationship between initial fluid resuscitation rate and septic shock resolution in septic shock patients. this is a retrospective cohort study of adult (≥ 18 years of age) medical intensive care unit (micu) patients in mayo clinic, rochester, mn, from january 1, 2006, through may 31, 2018, who had a diagnosis of septic shock and underwent resuscitation with iv fluids. using hospital electronic health records (ehr), we screened micu patients for eligibility. we identified septic shock patients who received fluid resuscitation > 30 ml/kg within the first 24 h and excluded patients with other types of shock [hypovolemic shock, cardiogenic shock, obstructive shock based on the international classification of diseases-10 (icd-10) code of discharge diagnosis], those without minnesota research authorization, vulnerable adults, prisoners, individuals with known pregnancy at the time of index admission, and patients who stayed in the micu for < 48 h. the study was reviewed and approved by the institutional review board (#18-008349) at mayo clinic, rochester. informed consent was waived for patients with minnesota research authorization due to the minimal risk nature of the study. sepsis was defined as an increase in the sequential [sepsis-related] organ failure assessment (sofa) score of 2 points or more, which caused by presumed or confirmed infection (sepsis-3) [2] . to minimize the effect of temporal changes in the care of patients with sepsis during the study period and to confirm the accuracy of the included patients, the septic shock cases had to meet all three following criteria (1) diagnosis of septic shock based on icd-10 code of discharge diagnosis, (2) criteria of sepsis described by sepsis-3, and (3) mean arterial pressure (map) < 65 mmhg with vasopressor use and serum lactate level > 2 mmol/l along with an antibiotic prescription. to minimize the effect of pre-hospital fluid resuscitation, we only included patients whose first recorded mean arterial pressure of < 65 mmhg occurred in micu, and there was no record of vasopressor utilization prior to micu admission. time zero (t 0 ) was defined as the first time that map was < 65 mmhg or serum lactate was > 2 mmol/l. shock reversal time (t r ) was defined as the time in which map was > 65 mmhg without vasopressors and lactate < 2 mmol/l. time to shock reversal was calculated as the duration between t r and t 0. the initial fluid resuscitation rate (ml/kg/min) was calculated as the volume of 30 ml/kg of the actual body weight on admission divided by the time (min) to complete. although the literature in support of the use of 30 ml/kg of crystalloid for initial volume resuscitation among septic shock patients is scarce, it is considered as one of the major recommendations by ssc 2016 . therefore, we chose 30 ml/kg of crystalloid as a cutoff for the inclusion of patients in our study. in a recent study, investigators demonstrated that failure to deliver 30 ml/kg within 3 h of diagnosis of sepsis was associated with increased odds of in-hospital mortality, irrespective of other comorbidities [24] . patients were categorized into four groups based on the resuscitation time: ≤ 1 h, 1.1-2 h, 2.1-3 h, and > 3 h for groups 1 to 4, respectively. the corresponding fluid rate for the groups described above were ≥ 0.5, 0.25-0.49, 0.17-0.24, and < 0.17 ml/ kg/min, respectively (fig. 1) . pre-resuscitation lactate was defined as the lactate level closest (from 48 h before t 0 to 2 h after t 0 ) to t 0 , postresuscitation lactate was defined as the lactate level closest to t 3 (3 h after t 0 ), and lactate clearance was determined by its decline between pre-and post-resuscitation lactate levels. the doses of the vasopressors were described by vasoactive-inotropic score (vis; [vis = dopamine dose (mcg kg −1 min −1 ) + dobutamine dose (mcg kg −1 min −1 ) + 100 × epinephrine dose (mcg kg −1 min −1 ) + 10,000 × vasopressin dose (units kg −1 min −1 ) + 100 × norepinephrine dose (mcg kg −1 min −1 ) + 100 × phenylephrine dose (mcg kg −1 min −1 )]) [25] . fluid balance was defined as the difference of the fluid intake and output and was adjusted based on hospital admission weight. acute physiology and chronic health evaluation (apache) iii and sofa scores were automatically calculated. charlson comorbidity index (cci) was determined at hospital admission. baseline variables including patient demographics, hospital admission weight, hemodynamic variables, sites of infection, apache iii and sofa scores, and cci were collected from the multidisciplinary epidemiology and translational research in intensive care (metric) data-mart [26] . the primary outcome was the time to shock reversal. secondary outcomes included lactate clearance, weight-adjusted fluid balance in the first 3 h of resuscitation and throughout micu stay, weight-adjusted fluid infusion between t 3 and micu discharge, timing of vasopressor initiation, temporal trends of vis in the first 24 h calculated every 3 h, map and heart rate changes within the first 3 h of resuscitation, need and length of mechanical ventilation, sofa day 1 to day 2 score changes, time to alive discharge from micu and hospital, and finally micu, hospital, and 28-day mortality (fig. 1 ). we summarized the data using frequencies and percentages for categorical variables and medians and interquartile fig. 1 schematic representation of the study protocol. time zero (t 0 ) was the starting point of septic shock fluid resuscitation and defined as the first time that map < 65 mmhg or serum lactate > 2 mmol/l during the icu stay. according to the different range of initial fluid resuscitation rate (equal to the slope in the graph), the cohort was divided into four groups: group 1 (≥ 0.5 ml/kg/min), group 2 (0.25-0.5 ml/kg/min), group 3 (0.17-0.25 ml/kg/min), and group 4 (< 0.17 ml/kg/min). the " " on the timeline marked icu admission, shock reversal time (t r ), and icu and hospital discharge; shock reversal time (t r ), icu discharge, and hospital discharge must be after t 0 but had no fixed time relationship with t 0 . the main variables and measurements of the study are shown in the bottom half of the figure. the period of shock reversal was defined as the duration between t r and t 0 (abbreviation: icu = intensive care unit; t 0 = time zero; t 3 = 3 h after t 0 ; t r = shock reversal time; vis = vasoactive-inotropic score; los = length of stay) ranges for continuous variables. we also compared data distributions across fluid resuscitation rate groups using chi-square and kruskal-wallis tests for categorical and continuous data, respectively. associations between fluid resuscitation rate and outcomes were analyzed using the univariable and multivariable models to adjust for age, sex, race, weight, cci, apache iii, and sofa scores. we used logistic regression for binary outcomes (i.e., hospital and 28-day mortality) and linear regression for continuous outcomes (i.e., lactate clearance, fluid balance). the time to shock reversal and alive discharge from micu, hospital, and 28 days were analyzed using cox proportional hazards regression models. associations between fluid resuscitation rate and vis at different time points were analyzed using a multivariable generalized estimated equation model to adjust for the same variables listed previously. the median and interquartile range of vis was plotted at hours 0, 6, 12, and 18 by fluid resuscitation completion time. all analyses were performed using sas version 9.4 (sas institute inc., cary, nc). a 2-sided p value < 0.05 was determined to be significant. table 1 . supplementary figures 1a, b , and c show the average fluid intake, output, and balance, respectively, among all participants during the first 7 days of icu admission. the four groups were similar with respect to demographic characteristics, comorbid conditions, and severity of illness. patients with slower fluid resuscitation rates were heavier at baseline. among the groups, 91, 84, 83, and 87% achieved shock reversal in groups 1 to 4, respectively (p = .2). however, the time to shock reversal was significantly different (p < .001) among the groups. in multivariable analyses after adjustment for a priori independent variables, patients in group 1 achieved shock reversal faster compared to patients in group 4 (hr = 0.78; 95% ci 0.66-0.91) with a median (iqr) time to shock reversal of 1.7 (1.5, 2.0) vs. 2.8 (2.6, 3.3) days, respectively. when we used the year of admission in the multivariable models, it was not a significant predictor of outcomes (results are not shown). time to shock reversal was not different when we compared groups 2 and 3 with group 1 ( days] compared to patients with a lower fluid rate (< 0.25 ml/kg/min) (fig. 3a) . the time of pre-resuscitation reported lactate was 0 (− 3.6, 1.1) h from t 0 , and the time of post-resuscitation reported lactate was 3.8 (1.5, 10.6) h after t 3 . the lactate clearance during initial fluid resuscitation was significantly different among groups (p < .001); group 4 had less lactate reduction compared to group 1 (0.2 vs. 0.5 mg/dl; p < .001). group 4 also had minimal change in map at 3 h, compared to group 1, who had a median increase of 4.3 mmhg (p = .04). a lower initial fluid resuscitation rate was associated with a later vasopressor use after septic shock onset (p < .001). a higher initial fluid resuscitation rate was associated with a higher mean fluid balance at 3 h (p < .001), but not with the mean fluid balance for the rest of the micu stay (p = .1). the volume of infused fluid from t 3 to the micu discharge was significantly higher in group 4 compared to groups 1 (168 vs. 107 ml/kg, p < .001) and 2 (168 vs. 124 ml/kg, p < .001). relative to group 4, fewer patients in group 1 required mechanical ventilation (or = 1.91; 95% ci = 1.34, 2.73; p = .001), and for the ones who needed mechanical ventilation, the duration was shorter (mean = 1.88; 95% ci = 0.40, 3.36 days; p = .01). group 1 also had a more significant decline in sofa score . .002 † table 2 ). the proportions of alive discharges from icu and hospital (p < .001 for both) significantly differed among the groups. similarly, micu (p < .001) and hospital durations (p < .001) were different. compared to group 4, group 1 had a shorter micu (2.9 vs.4.9 days; p < .001) and hospital (10.1 vs. 17.7 days; p < .001) stay. the 28-day mortality was also significantly different among the groups (p < .001). compared to group 4, group 1 had lower 28day mortality (16.0% vs.34.0%; p < .001) ( table 2 ). using 0.25 ml/kg/min as threshold for intravascular fluid replacement rate, patients with a higher fluid rate (≥ 0.25 ml/kg/min) were more likely to survive at 28 days (hr = 0.71; 95% ci 0.60-0.85; p < .001) compared to ones with a lower fluid rate (< 0.25 ml/kg/min) (fig. 3b) . table 3 and fig. 4 show associations between fluid resuscitation rate and vis at various time points. fluid rate of < 0.17 ml/kg/min and increased weight were associated with lower vis scores at all time points. increased length of icu stay, apache iii, and sofa scores were associated with increased vis scores. in this retrospective analysis of micu patients with septic shock who received fluid resuscitation, we demonstrated that a fluid resuscitation rate > 0.25 ml/kg/min was associated with a shorter time to shock reversal and lower 28day mortality. based on our observations, the optimal fluid rate was 0.25-0.5 ml/kg/min (equivalent to 30 ml/kg fluid administration within 2 h). faster initial fluid resuscitation, in our study, was also associated with lower 28day mortality. this finding is consistent with a recent prospective observational cohort study, which found that sepsis patients who received initial fluid resuscitation in > 2 h after diagnosis had increased mortality rates [27] . vincent also suggested administration of 30 ml/kg of fluid over 3 h to be too slow for appropriate fluid resuscitation [28] . the goal of initial fluid resuscitation in septic shock is to restore intravascular volume, cardiac output, and oxygen delivery [29] . to restore intravascular volume, the rate of initial fluid infusion should be faster than the speed of fluid loss via leaky vascular endothelium. a faster initial fluid resuscitation rate could also decrease the early inflammation [30] and blood viscosity [31] to improve the microcirculation and tissue perfusion [4] . a higher fluid rate is also associated with a more significant increase in map and a greater reduction in lactate, a marker for tissue perfusion [32] . this finding is consistent with previous reports that showed improved microcirculation in sepsis following [33] . the improvement both in macrocirculation and microcirculation can lead to improved outcomes including less time to shock reversal, need and duration of mechanical ventilation, sofa score, hospital, micu stay, and 28-day mortality rates. on the other hand, very fast fluid replacement may increase glycocalyx shedding and exacerbate vascular dysfunction. the endothelial glycocalyx layer is damaged during sepsis, which negatively impacts its barrier function [34] [35] [36] . receiving 40-60 ml/kg iv fluid boluses in 1 h (up to 0.67-1 ml/kg/min) [11] among critically ill children led to a cardiovascular collapse in a large trial [19] . bryne and colleagues found a rapid increase in vasopressor requirement and a significant increase in glycocalyx layer damage after initial fluid resuscitation in an ovine model of endotoxemia following fluid infusion rate of 0.67 ml/kg/min [37] . in our study, while we noted rapid fluid replacement is associated with improved outcomes of septic shock, we were not able to assess the impact of very high fluid rates (> 0.67 ml/kg/min). we also identified an association between a lower initial fluid resuscitation rate and a lower vis at various time points in the first 24 h of septic shock onset. this result was most likely due to later initiation of vasopressors and the impact of higher baseline weight in calculating vis [38] [39] [40] . a higher vis at 48 h after cardiovascular surgery was found to be associated with a longer icu length of stay and longer ventilator days in pediatric sepsis patients [41] . in our study, group 4 with a lower fluid resuscitation rate and a lower vis in the first 24 h had worse clinical outcomes. this discrepancy could be due to not assessing vis beyond 24 h. also, the relationship between vis and patient outcomes has not been validated in sepsis. in our study, a faster initial fluid resuscitation rate was associated with a larger positive fluid balance in the first 3 h of resuscitation, but the differences in fluid balance among the groups were not significant at micu discharge. treating patients with septic shock inevitably would result in initial positive fluid balance, which in the early phases of fluid resuscitation increases cardiac output in most patients [42] . in a study by lee et al., septic shock patients who received a larger volume of fluid in the first 3 h were more likely to survive [43] . the differences in positive fluid balance among the groups resolved beyond the first 3 h because group 1 received fewer fluids after the initial resuscitation phase. patients who receive less fluid in the first 6 h have significantly higher fluid balance in the next 7 to 72 h, inhospital, and 28-day mortality [44] . shen and colleagues also showed a positive fluid balance during the second, but not the first 24 h of septic shock was associated with increased mortality in sepsis [45] . positive fluid balance during the initial resuscitation phase is associated with the improved outcome as long as the fluid balance is carefully monitored after the resuscitation targets are met. our study has several limitations. due to its retrospective design, we are not able to imply any causal relationship [46] . hence, prospective studies are required to verify our results. we included patients whose first recorded map of < 65 mmhg happened in micu and had no record of vasopressor utilization prior to micu admission. despite this, we still could not completely eliminate the effect of potential fluid administration prior to the micu admission. there is growing knowledge indicating that fluid resuscitation should be guided by fluid responsiveness [47] . meanwhile, as one of the limitations of our study, we were not able to acquire fluid responsiveness data. as ssc guidelines indicate the use of 30 ml/kg to septic shock patients, we believe our results are still within recommended guidelines even though it is not based on fluid responsiveness assessment. in our institution, the administration of the second or third bolus of 30 ml/kg of fluids is only guided by the fluid responsiveness assessment. lastly, the study period spanned 12 years, and changes in the clinical practice could have led to bias in our results. in septic shock patients, the minimum fluid resuscitation rate of 0.25-0.50 ml/kg/min (i.e., completion of the initial 30 ml/kg iv fluid resuscitation within the first 2 h) is associated with a shorter time to shock reversal and improved patient clinical outcomes. our findings would serve as hypothesis-generating information in order to design and conduct prospective trials for validation. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-2819-5. benchmarking the incidence and mortality of severe sepsis in the united states the third international consensus definitions for sepsis and septic shock (sepsis-3) circulatory shock fluid therapy in septic shock early goaldirected resuscitation of patients with septic shock: current evidence and future directions the surviving sepsis campaign bundle: 2018 update management of sepsis: early resuscitation surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study surviving sepsis campaign: international guidelines for management of sepsis and septic shock fluid resuscitation in severe sepsis mortality after fluid bolus in african children with severe infection effect of an early resuscitation 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sepsis campaign: research priorities for sepsis and septic shock a critique of fluid bolus resuscitation in severe sepsis evaluation and predictors of fluid resuscitation in patients with severe sepsis and septic shock vasoactive-inotropic score as a predictor of morbidity and mortality in adults after cardiac surgery with cardiopulmonary bypass informatics infrastructure for syndrome surveillance, decision support, reporting, and modeling of critical illness predictors, prevalence, and outcomes of early crystalloid responsiveness among initially hypotensive patients with sepsis and septic shock fluid management in the critically ill sepsis resuscitation: fluid choice and dose iso-osmolar prehydration shifts the cytokine response towards a more antiinflammatory balance in human endotoxemia perioperative fluid management and clinical outcomes in adults the role of lactate clearance in the resuscitation bundle effects of fluids on microvascular perfusion in patients with severe sepsis role of the glycocalyx in fluid management: small things matter variation and clinical value of endothelial glycocalyx in the patients with septic shock. zhonghua wei zhong bing ji jiu yi xue ultrastructural alteration of pulmonary capillary endothelial glycocalyx during endotoxemia unintended consequences: fluid resuscitation worsens shock in an ovine model of endotoxemia vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass evaluation of the preoperative vasoactive-inotropic score as a predictor of postoperative outcomes in patients undergoing heart transplantation vasoactive-inotropic score is associated with outcome after infant cardiac surgery: an analysis from the pediatric cardiac critical care consortium and virtual picu system registries validation of the vasoactive-inotropic score in pediatric sepsis principles of fluid management and stewardship in septic shock: it is time to consider the four d's and the four phases of fluid therapy increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: a retrospective cohort study early goal-directed therapy collaborative g. early goaldirected therapy in the treatment of severe sepsis and septic shock time-related association between fluid balance and mortality in sepsis patients: interaction between fluid balance and haemodynamics intelligently learning from data fluid responsiveness and the six guiding principles of fluid resuscitation publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions bh, zp, and kk designed this study and protocol development. mp and ep were responsible for the data collection. rf and bh were responsible for data analysis. bh and jc conducted the manuscript writing. kk, rf, yd, and zp critically revised the manuscript. bh, jc, kk, and zp provided final approval for this version to be published. all authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. the authors read and approved the final manuscript. mayo clinic rochester ccrs (critical care imp research subcommittee) small grant for statistical support. the data used for this research are available from the corresponding author on reasonable request and subject to institutional review board guidelines. this study was reviewed and approved by the institutional review board (#18-008349) at mayo clinic, rochester. the authors declare that they have no competing interests. key: cord-029516-tj93wo1s authors: chelly, jonathan; mazerand, sandie; jochmans, sebastien; weyer, claire-marie; pourcine, franck; ellrodt, olivier; thieulot-rolin, nathalie; serbource-goguel, jean; sy, oumar; vong, ly van phach; monchi, mehran title: automated vs. conventional ventilation in the icu: a randomized controlled crossover trial comparing blood oxygen saturation during daily nursing procedures (i-nursing) date: 2020-07-22 journal: crit care doi: 10.1186/s13054-020-03155-3 sha: doc_id: 29516 cord_uid: tj93wo1s background: hypoxia is common during daily nursing procedures (dnps) routinely performed on mechanically ventilated patients. the impact of automated ventilation on the incidence and severity of blood oxygen desaturation during dnps remains unknown. methods: a prospective randomized controlled crossover trial was carried out in a french intensive care unit to compare blood oxygen pulse saturation (spo(2)) during dnps performed on patients mechanically ventilated in automated and conventional ventilation modes (av and cv, respectively). all patients with fio(2) ≤ 60% and without prone positioning or neuromuscular blocking agents were included. patients underwent two dnps on the same day using av (intellivent-asv®) and cv (volume control, biphasic positive airway pressure, or pressure support ventilation) in a randomized order. the primary outcome was the percentage of time spent with spo(2) in the acceptable range of 90–95% during the dnp. results: of the 265 included patients, 93% had been admitted for a medical pathology, the majority for acute respiratory failure (52%). there was no difference between the two periods in terms of dnp duration, sedation requirements, or ventilation parameters, but patients had more spontaneous breaths and lower peak airway pressures during the av period (p < 0.001). the percentage of time spent with spo(2) in the acceptable range during dnps was longer in the av period than in the cv period (48 ± 37 vs. 43 ± 37, percentage of dnp period; p = 0.03). after adjustment, av was associated with a higher number of dnps carried out with spo(2) in the acceptable range (odds ratio, 1.82; 95% ci, 1.28 to 2.6; p = 0.001) and a lower incidence of blood oxygen desaturation ≤ 85% (adjusted odds ratio, 0.50; 95% ci, 0.30 to 0.85; p = 0.01). conclusion: av appears to reduce the incidence and severity of blood oxygen desaturation during daily nursing procedures (dnps) in comparison to cv. trial registration: this study was registered in clinical-trial.gov (nct03176329) in june 2017. graphical abstract: [image: see text] daily nursing procedures (dnps) are routinely performed several times per day in the intensive care unit (icu) and are crucial for patients' hygiene and rehabilitation, and to prevent/treat complications due to immobilization [1] [2] [3] [4] . however, these dnps induce physiological changes with potential adverse effects, especially in patients undergoing mechanical ventilation (mv) [5] [6] [7] [8] [9] . respiratory events, in particular oxygen desaturation, are often observed during dnps but are not well documented [10] . although the potential adverse effects may be serious (e.g., severe hypoxemia and cardiac arrest), these events are often downplayed, considered as a normal part of dnps, or ignored in interventional studies regarding mv in icu patients [10] . as suggested by previous works, protocols should be developed to prevent such respiratory events [11, 12] . intellivent-asv® (hamilton medical, bonaduz, switzerland) is an automated ventilation mode (av) that automatically adjusts ventilation and oxygenation settings to keep end-tidal co 2 (petco 2 ) and spo 2 in target ranges set by the clinician [13] . briefly, minute volume is adjusted according to petco 2 information or respiratory rate in passive or spontaneously breathing patients respectively and fio2 and peep are adjusted according to blood oxygen pulse saturation (spo 2 ) information. the safety, feasibility, and efficacy of this mode have been demonstrated with promising results that show a reduction in both the number of manual interventions needed and the incidence of blood oxygen desaturation for various patient conditions, including acute respiratory failure, post-cardiac surgery, and weaning from mv [13] [14] [15] [16] [17] [18] [19] [20] . to our knowledge, however, no study has assessed the impact of av on the incidence of respiratory events during dnps. the aim of our study was to compare the incidence and severity of blood oxygen desaturation during dnps performed on patients ventilated in av and in conventional ventilation mode (cv). this single-center randomized controlled crossover study was conducted from september 2016 to march 2018 in a 22-bed, mixed icu of a french tertiary center. all patients of both sexes mechanically ventilated for at least 48 h with a fraction of inspired oxygen (fio 2 ) ≤ 60% were included. exclusion criteria were prone positioning, use of neuromuscular blocking agents, age < 18 years old, pregnant women, patients with a contraindication to av (delirium, broncho-pleural fistula, respiratory drive disorder such as cheyne-stokes breathing), and patients with a low-quality measurement for spo 2 . the study was initiated and supported by the groupe hospitalier sud ile de france (melun, france). the study protocol was approved on the 13th of september 2016 by the ethical committee (comité de protection des personnes ile de france vi) and registered in clinicaltrials.gov (nct03176329). patients or their next-of-kin gave their informed consent before randomization. all included patients were ventilated using a hami lton-s1 ventilator (hamilton medical, bonaduz, switzerland) and spo 2 was monitored using a dedicated sensor (masimo set®, masimo corporation, irvine, usa) connected to the patient's monitor (beneview t8®, mindray, shenzhen, china). after randomization, each patient underwent two dnps on the same day, with 6 h between the two. one was performed in cv and the other in av in a randomized order defined at inclusion. dnps were performed by two nurses and included a bundle of care covering patient hygiene (bathing, change of bed linen), mobilization (repositioning), ventilatorassociated pneumonia prevention (oral hygiene care, subglottic secretion drainage, adjustment of endotracheal tube cuff pressure), and pressure ulcer prevention and treatment (massage of back and pressure points). all the patient's monitoring and ventilation parameters, including heart rate, mean arterial pressure, spo 2 , fio 2 , expiratory tidal volume, total and spontaneous respiratory rate, positive end-expiratory pressure (peep), and inspiratory and mean airway pressure, were automatically recorded every minute during the dnp using evolucare intensive 6.4® (evolucare technologies, villers-bretonneux, france). arterial blood gas samples were performed 5 min before each dnp to determine the pao 2 /fio 2 ratio. all events that occurred during the dnps, such as blood oxygen desaturation, change of ventilation mode, accidental disconnection of the ventilator, the need for manual ventilation, activation of an oxygen bypass, or endotracheal suctioning, were also reported by the nurse in charge. at least 30 min before each of the two dnps, the attending physician set the mv mode according to the randomized order. for the cv period, the mode and ventilator settings were selected by the attending physician according to patient's pathologies and conditions: either volume control (vc), biphasic positive airway pressure (bipap), or pressure-support ventilation (psv). in vc mode, the tidal volume (v t ) was set below 7 ml/ kg predicted body weight (pbw) for acute respiratory distress syndrome, below 9 ml/kg pbw for subjects with normal lungs, and below 11 ml/kg pbw for subjects with chronic obstructive pulmonary disease. in bipap and psv, inspiratory pressure and pressure support were set according to the same v t limits as in vc. plateau pressure was limited to 30 cmh 2 o, while positive endexpiratory pressure (peep) and fio 2 were set to maintain spo 2 before the dnps at between 94 and 98% [21, 22] . during the dnps, nurses were responsible for maintaining spo 2 within an acceptable range of 90-95% by adjusting the fio 2 setting. the basic principles of inte llivent-asv® are detailed as previously described [13] in the online supplemental content 1. before the dnp in av, automated fio 2 and peep controllers were set by the attending physician with a lower limit for spo 2 at 90% and a peep limited to 5-15 cmh 2 o. the high limit for airway pressure was set at a maximum of 30 cmh 2 o. for both dnps, alarm limits were set by the clinicians. in the case of major blood oxygen desaturation (spo 2 ≤ 85% according to guidelines [22] ), the nurse in charge was required to apply a specific protocol (see online supplemental content 2) and a physician was always present in the icu in case a problem persisted. sedation infusion, inspiratory trigger, pressure rise, expiratory trigger, and ventilator circuit were the same in both periods. the primary outcome was the time spent with spo 2 values of 90-95% (considered to be the acceptable spo 2 range during the dnp). secondary outcomes were as follows: incidence of spo 2 in the acceptable range during the dnp; mean, minimum, and maximum spo 2 during the dnp (spo 2 mean , spo 2 min , and spo 2 max , respectively); incidence and time spent with spo 2 lower than 90%; incidence and time spent with spo 2 lower than 85%; and time spent with fio 2 at 100%. the safety outcome parameters were the occurrence of major adverse events (accidental endotracheal tube removal, bradycardia lower than 40 bpm, or cardiac arrest) during the dnp. two interim analyses for primary and safety outcome parameters were planned after 90 and 180 patients were enrolled. based on previous studies on dnps [9, 10] and retrospective data collected in our institution, we estimated that patients spent 40% of the dnp duration with spo 2 between 90 and 95%. we calculated a sample size of 267 patients by group to detect a 15% increase in the primary outcome for dnps performed in av as compared to cv (2-sided α = 0.05; power 80%). continuous variables are expressed by mean ± standard deviation and nominal variables as n (%). continuous variables were compared using the non-parametric wilcoxon test and nominal variables were compared using fisher's exact test. after a univariate analysis to assess all risk factors for primary and secondary outcomes, a multivariate analysis was performed including all univariate factors with p < 0.15. differences were considered significant where p < 0.05. all calculations were performed using spss statistics v20® (ibm, new york, usa). there were no safety issues that required premature interruption. among the 465 patients assessed for eligibility, 185 were excluded, leaving 280 for inclusion ( fig. 1) . fifteen patients in both periods were subsequently excluded from the analysis due to recording failure, resulting in 265 patients with one dnp in each period for the final analysis. baseline characteristics of the overall cohort are detailed in table 1 . patients were primarily admitted for a medical pathology (92%) and half were intubated for acute respiratory failure (52%). the mean time of mv before inclusion and the total mv duration were 4 ± 4 and 11 ± 8 days, respectively. of the 265 patients, 201 (76%) were successfully weaned from mv and 74 (28%) died before icu discharge. the interval between both dnps was 406 ± 118 min. before the dnp, spo 2 was significantly lower in av than in cv (95 ± 3% vs. 96 ± 3%, respectively; p < 0.001), whereas pao 2 /fio 2 and spo 2 /fio 2 were similar (p = 0.10 and 0.49, respectively). dnp duration varied from 2 to 55 min in the overall cohort. as detailed in table 2 , dnp duration and patient sedation levels were similar during both periods, as were hemodynamic parameters, tidal volume, total breathing rate, and peep level. during the cv period, bipap mode was largely used (87%) and patients had a significantly lower spontaneous breathing rate than during the av period (14 ± 11 vs. 22 ± 12 breath/min, respectively; p < 0.001). patients had a lower peak airway pressure (25 ± 7 vs. 27 ± 6 cmh 2 o; p < 0.001) and mean airway pressure (14 ± 4 vs. 15 ± 4 cmh2o; p < 0.001) during the av period than during the cv period. data for the primary and secondary endpoints are provided in table 3 . patients spent significantly more time in the acceptable spo 2 range during the av period (48 ± 37 vs. 43 ± 37% of dnp period; p = 0.03). in 160 patients (60%), spo 2 was in the acceptable range during the av period as compared to 123 patients (46%) during the cv period (p = 0.001). after adjustment for confounding factors, av was associated with a greater number of dnps performed with spo 2 in the acceptable range (odds ratio [or], 1.82; 95% confidence interval [ci], 1.28 to 2.6; p = 0.001; see online supplemental content 3). in the overall cohort, blood oxygen desaturation to levels < 90% and ≤ 85% occurred in 161 (30%) and 80 (15%) patients, respectively. incidences of blood oxygen desaturation to lower than 90% were less frequent during the av period than during the cv period (69 [26%] vs. 92 [35%], episodes > 1 min; p = 0.03) and were also shorter (5 ± 12 vs. 6 ± 11, % of dnp period; p = 0.02). incidences of major blood oxygen desaturation (≤ 85%) were less frequent during the av period than during the cv period (30 [11%] vs. 50 [19%] , episodes > 1 min; p = 0.02) and were also shorter (2 ± 6 vs 3 ± 8, percentage of dnp period; p = 0.03). after adjustment for confounding factors, av was associated with a lower incidence of blood oxygen desaturation ≤ 85% during dnps (or, 0.50; 95% ci, 0.30 to 0.85; p = 0.01; see online supplemental content 4). as shown in fig. 2 , more patients had spo 2min in the optimal range during the av period (p = 0.02), while more patients had the spo 2min ≤ 85% during the cv period (p = 0.002). there was no difference between the two periods for the other secondary endpoints (table 3) . nurse/physician/ventilator interventions, safety, and major adverse events all the unplanned interventions performed by a nurse or physician during dnps are detailed in the online this is the first study to test the ability of av to reduce the occurrence of oxygen desaturation during dnps routinely performed in icu patients undergoing mv. in this randomized crossover trial, the use of av (in this case intellivent®-asv®) was superior to cv with respect to maintaining spo2 within an acceptable range and reducing the incidence and severity of oxygen desaturation. although icu nurses and physicians frequently observe blood oxygen desaturation relating to dnps in their daily practice, these respiratory events remain poorly documented. in a cohort of 53 icu patients (including 45% under mv), de jong et al. observed blood oxygen desaturation ≤ 90% and ventilatory distress (severe patient-ventilator asynchrony, nonstop coughing, impossible ventilation, and/or tachypnea) in 10 and 13%, respectively, of the 184 dnps performed [9] . in a prospective study on 16 icu patients undergoing mv, 668 nursing procedures were observed and blood oxygen desaturation ≤ 90% was the most frequent adverse event described, representing 29% of the overall major physiological changes reported by the authors [10] . for our overall cohort, we reported blood oxygen desaturation < 90 and ≤ 85% during dnps in 30 and 15%, respectively. various physiological changes may be implicated by the occurrence of blood oxygen desaturation during dnps. patient mobilization is one of the most important, and in particular lateralization, which can induce a decrease in lung compliance, alveolar derecruitment, mobilization of respiratory-tract secretions, airway irritations and coughing, ventilator-patient asynchrony [10, [23] [24] [25] [26] , and an increase in oxygen consumption [5, 6] . all those physiological events could be induced by mobilization itself and/or the stress response associated with pain [10, [27] [28] [29] . the impact on patient outcomes of dnps and their related adverse events remains unclear. previous studies have suggested that early mobilization of the patient would be associated with a greater chance of achieving rehabilitation objectives in the icu setting [1] [2] [3] [4] . de jong et al. observed an incidence of cardiac arrest in 1% of the dnps performed, while we did not report any incidence of cardiac arrest or death related to dnps in our overall cohort. our study suggests av may have a protective effect when compared to cv in terms of spo 2 values and the incidence and severity of blood oxygen desaturation during dnps. a prospective randomized controlled study of 60 post-cardiac surgery patients showed that in comparison to cv, intellivent-asv® significantly reduces mv duration before inclusion-days 4 ± 4 (4-5) chest radiograph opacities-quadrants 2 ± 1 (1-2) categorical variables are expressed as n (%) and continuous variables as mean ± standard deviation (95% confidence interval) copd chronic obstructive pulmonary disease, saps-2 simplified acute physiological score 2, sofa sepsis-related organ failure assessment, icu intensive care unit, mv mechanical ventilation the percentage of time, as well as the total duration and number of episodes per patient of ventilation parameters (including tidal volume, etco 2 , plateau pressure, and spo 2 ) being within a "not acceptable" zone [14] . during the weaning period in 16 icu patients, intellivent-asv® improved the pao 2 /fio 2 ratio compared to psv [15] . in accordance with our results, another randomized trial including 80 icu patients showed that intelli-vent-asv® was superior to pressure assist-control and psv for maintaining spo 2 in an optimal range defined by the authors as between 92 and 96% [18] . the positive results of av on the incidence of blood oxygen desaturation may be explained by many factors: intellivent-asv® continuously and quickly adapts oxygenation, increasing peep and fio 2 when spo 2 decreases, but also by automatically decreasing peep and fio 2 when spo 2 is supranormal. in contrast, nurses and physicians are not able to adjust fio 2 every time while they are providing care, especially during mobilization of a patient. as suggested by our results, the need for endotracheal suctioning during dnps seems less frequent in av, which could be interpreted as the cause or the consequence of a lower incidence of blood oxygen desaturation. several factors may limit the interpretation of our data. first, this was a single-center study in a single-blinded design, carried out in an icu staffed by nurses and physicians considered as advanced users of av. however, previous studies have consistently reported on the efficacy and safety advantages of using av over cv [13] [14] [15] [16] [17] [18] [19] [20] . second, patients in unstable respiratory conditions, such as high fio2 > 60% with or without the use of neuromuscular blocking agents and/or with prone positioning, were excluded from the study. in our icu, as is general practice in many icus, dnps in patients with unstable respiratory conditions are delayed until the patient's condition peep-cmh 2 o † 9 ± 3 (9-10) 9 ± 3 (9-10) 0.07 categorical variables are expressed as n (%) and continuous variables as mean ± standard deviation (95% confidence interval) pbw predicted body weight, rr respiratory rate, petco 2 end-tidal co 2 partial pressure, peep positive end-expiratory pressure *measured the minute before starting the dnp **measured 5 min before starting the dnp ***defined as no spontaneous breathing detected by the ventilator † mean of the overall parameters monitored every minute during the dnp improves or performed with fio 2 set at 100% by default. third, we should have systematically assessed and prevented pain related to patient's care. indeed, the incidence of respiratory events decrease significantly with the application of an analgesic protocol before and during dnp, as previously described by de jong et al. future studies on dnp should take pain prevention and treatment into account [9] . moreover, we cannot draw any conclusions with respect to a protective or harmful effect of av in terms of ventilator-induced lung injury (vili) during dnps. tidal volumes were higher than the initial setting for both periods, probably due to an increase in the patient's ventilatory drive during mobilization (induced by stress, pain, etc.). however, inspiratory pressure was lower and spontaneous breathing was higher during dnps in av. future studies are needed to assess mechanical power and the risk of vili during dnps [30] . fourth, we may have underestimated the incidence of short oxygen desaturation (< 1 min) because we have not performed a breath by breath monitoring. fifth, the accuracy of spo 2 measurements remains controversial, particularly in icu patients with acute organ failure, as previously observed [31] . however, blood gas samples are not easy to perform during dnp and spo 2 represents the only parameters to assess oxygenation at bedside during this procedure. finally, although we found a significant difference in the primary outcome in favor of av during dnps, the clinical impact remains unknown. further studies are warranted to confirm our results and to assess the real impact on patient outcomes and management. categorical variables are expressed as n (%) and continuous variables as mean ± standard deviation (95% confidence interval) dnp daily nursing procedure, spo 2 blood oxygen pulse saturation, fio 2 fraction of inspired oxygen, spo 2 mean mean spo 2 during dnp, spo 2 min minimal spo 2 recorded during dnp, spo 2 max maximal spo 2 recorded during dnp *spo 2 acceptable range was ≥ 90 and ≤ 95% **for more than 1 min fig. 2 comparison between conventional and automated ventilation in terms of minimal, mean, and maximal blood oxygen saturation (spo 2 ) during daily nursing procedures (*p < 0.05) creating the animated intensive care unit strategies for post icu rehabilitation body positioning of intensive care patients: clinical practice versus standards a prospective 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effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-icu randomized clinical trial british thoracic society guideline for oxygen use in adults in healthcare and emergency settings positional hypoxemia during artificial ventilation lateral positioning of ventilated intensive care patients: a study of oxygenation, respiratory mechanics, hemodynamics, and adverse events effects of patients positioning on respiratory mechanics in mechanically ventilated icu patients the effect of patient positioning on dynamic lung compliance prevention of endotracheal suctioning-induced alveolar derecruitment in acute lung injury a meta-analysis of the effects of various interventions in preventing endotracheal suction-induced hypoxemia changes in lung volume with three systems of endotracheal suctioning with and without pre-oxygenation in patients with mild-to-moderate lung failure ventilator-related causes of lung injury: the mechanical power comparative evaluation of accuracy of pulse oximeters and factors affecting their performance in a tertiary intensive care unit publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are indebted to caroline huber-brown for editorial assistance. all authors have contributed to the final version of the manuscript as follows: jc and sj contributed to the study concept and design; jc, sm, sj, cw, fp, oe, nt, js, os, and lv contributed to patient's inclusion; jc and sm contributed to data collection; jc and sj contributed to data analysis; and jc, sj, and mm drafted and revised the manuscript. the authors read and approved the final manuscript. the study was integrally supported by the groupe hospitalier sud ile de france (melun, france). av used during dnps routinely performed on icu patients undergoing mv appears to be superior to cv in maintaining spo 2 within an acceptable range and reducing the incidence and severity of desaturation, with more spontaneous breathing and lower peak and mean airway pressure. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03155-3.additional file 1: online supplemental content 1. basic principles of intellivent-asv®. supplemental content 2. protocol for nurses in case of major blood oxygen desaturation (spo 2 ≤ 85%) during the daily nursing procedure (dnp). supplemental content 3. multivariate logistic regression test for spo 2 in the acceptable range (between 90% and 95%) during the daily nursing procedure (dnp). supplemental content 4. multivariate logistic regression test of risk factors for occurrence of at least one major oxygen desaturation (spo 2 ≤ 85%) during the daily nursing procedure (dnp). supplemental content 5. nurse/physician interventions during the daily nursing procedure (dnp) according to ventilation mode (cv conventional ventilation; av automated ventilation). the dataset used and/or analyzed during the current study are available from the corresponding author on reasonable request. the study protocol was approved on the 13th of september 2016 by the ethical committee (comité de protection des personnes ile de france vi; id number 2016-a00569-42) and registered in clinical-trial.gov (nct03176329). patient or their next-of-kin gave their informed consent before randomization. competing interests jc and sj received fees from hamilton medical for lecturing. the remaining authors declare that they have no competing interests.received: 21 february 2020 accepted: 5 july 2020 key: cord-004268-raayrjmd authors: flattres, aurelien; aarab, yassir; nougaret, stephanie; garnier, fanny; larcher, romaric; amalric, mathieu; klouche, kada; etienne, pascal; subra, gilles; jaber, samir; molinari, nicolas; matecki, stefan; jung, boris title: real-time shear wave ultrasound elastography: a new tool for the evaluation of diaphragm and limb muscle stiffness in critically ill patients date: 2020-02-03 journal: crit care doi: 10.1186/s13054-020-2745-6 sha: doc_id: 4268 cord_uid: raayrjmd background: muscle weakness following critical illness is the consequence of loss of muscle mass and alteration of muscle quality. it is associated with long-term disability. ultrasonography is a reliable tool to quantify muscle mass, but studies that evaluate muscle quality at the critically ill bedside are lacking. shear wave ultrasound elastography (swe) provides spatial representation of soft tissue stiffness and measures of muscle quality. the reliability and reproducibility of swe in critically ill patients has never been evaluated. methods: two operators tested in healthy controls and in critically ill patients the intraand inter-operator reliability of the swe using transversal and longitudinal views of the diaphragm and limb muscles. reliability was calculated using the intra-class correlation coefficient and a bootstrap sampling method assessed their consistency. results: we collected 560 images. longitudinal views of the diaphragm (icc 0.83 [0.50–0.94]), the biceps brachii (icc 0.88 [0.67–0.96]) and the rectus femoris (icc 0.76 [0.34–0.91]) were the most reliable views in a training set of healthy controls. intra-class correlation coefficient for inter-operator reproducibility and intra-operator reliability was above 0.9 for all muscles in a validation set of healthy controls. in critically ill patients, inter-operator reproducibility and intra-operator 1 and 2 reliability iccs were respectively 0.92 [0.71–0.98], 0.93 [0.82–0.98] and 0.92 [0.81–0.98] for the diaphragm; 0.96 [0.86–0.99], 0.98 [0.94–0.99] and 0.99 [0.96–1] for the biceps brachii and 0.91 [0.51–0.98], 0.97 [0.93–0.99] and 0.99 [0.97–1] for the rectus femoris. the probability to reach intra-class correlation coefficient greater than 0.8 in a 10,000 bootstrap sampling for inter-operator reproducibility was respectively 81%, 84% and 78% for the diaphragm, the biceps brachii and the rectus femoris respectively. conclusions: swe is a reliable technique to evaluate limb muscles and the diaphragm in both healthy controls and in critically ill patients. trial registration: the study was registered (clinicaltrial nct03550222). survivors of critical illness have severe long-term functional disability [1] . following the intensive care unit (icu) stay, the quality of life and return to pre-icu admission daily activities are impaired [1] [2] [3] . both diaphragm and limb muscles are affected [1, [4] [5] [6] [7] . limb muscle weakness is one of the greatest issues linked with disability and poor outcomes in survivors [1, [8] [9] [10] [11] . diaphragm weakness has also been associated with poor outcome such as dependency on mechanical ventilation, prolonged icu length of stay and mortality [4, [12] [13] [14] . muscle weakness is related to muscle mass but beyond mass, loss of muscle function and muscle quality without atrophy has been observed in the elderly and in chronic hemodialysis patient populations, [15, 16] a condition labeled as dynapenia. at the icu bedside, ultrasonography (us) is an inexpensive, user-friendly, nonvolitional and non-invasive tool widely used by intensivists. us has been suggested to be a reliable tool to approximate muscle mass by measuring the cross-sectional area and muscle thickness [7, 17] and to also approximate muscle quality by grey-scale analysis of the muscle echogenicity [18, 19] . however, subcutaneous tissue and muscle edema and inflammation, frequently observed in the critically ill, can make the grey-scale analysis difficult to interpret. moreover, diaphragm contractions during spontaneous breathing and passive stretch during mechanical ventilation may also make ultrasonography more difficult to perform in the critically ill patients than in healthy controls able to block their breathing cycle. shear wave ultrasound elastography (swe) is a method of us imaging based on the detection of shear wave propagation through the tissue. by using inversion algorithms, this method maps the waves into elastograms and determines stiffness of the tissue by measuring the shear modulus value [20] . swe has been established as an excellent diagnostic method for liver fibrosis, breast cancer and thyroid cancer [21] . in skeletal muscles, it provides a spatial representation and quantifiable measurement of the mechanical properties and an approximate of the muscle fibrosis and the activity of the disease in chronic myopathy [22] as well as a surrogate of diaphragm force production in healthy volunteers during isovolumetric inspiratory efforts [23] . although swe muscle analysis may provide new data about muscle quality during critical illness, it has never been evaluated in the very specific critically ill population which is exposed to severe structural muscular alterations. we therefore designed the present study with the aim of determining the reliability and reproducibility of swe measurements for limb muscles and the diaphragm in both healthy subjects and in critically ill patients. we conducted the ultramuscle prospective observational study at a medical icu of the university hospital of montpellier, france. institutional ethical approval was obtained (2017-cler-mtp-09-16), and the study was registered (clinicaltrial nct03550222). because the ultramuscle study was part of an image databank storage, consent was waived according to french law. we followed the strobe guidelines for observational studies [24] . we enrolled 31 adult healthy subjects and 12 consecutive adult critically ill patients. inclusion criteria for the critically ill patients were at least one organ failure (organ failure being defined by a sepsis-related organ failure assessment (sofa) score [25] equal or greater than 3 for the organ considered) and an expected length of icu stay of at least 3 days. non-inclusion criteria were pregnancy, a history of neuromuscular disease (myasthenia gravis, chronic myopathy or neuropathy), spinal cord injury, recent intracranial disease, transfer from another icu, age below 18 and refusal to participate in the trial. we first enrolled 16 healthy subjects as a training set to assess inter-operator reproducibility for each view and to determine the best view (longitudinal vs transversal) for the biceps, the rectus femoris and the diaphragm. we then enrolled an additional validation set of 15 healthy subjects to assess both inter-and intra-operator reliability for each muscle. then we enrolled 12 consecutive critically ill patients during the last 2 weeks of november 2017, to assess both the inter-and intraoperator reliability for each muscle using the best views determined in healthy controls. shear wave elastography imaging procedure general procedure an aixplorer ultrasonic scanner (supersonic imagine, aix-en-provence, france) was used with a 4-15 mhz linear transducer (sl15-4; supersonic imagine) in swe mode with musculoskeletal pre-set. all biceps, rectus femoris and diaphragm images were performed by two operators: an expert with 4 years of experience in the field of skeletal muscle ultrasound in the icu and a novice who was not familiar with muscular ultrasound. both were trained by the supersonic imagine engineer before enrolling the first participant. all acquired images and data were stored and analysed secondarily as recommended by nijholt et al. using osirix dicom viewer software (pixmeo, geneva, switzerland) [26] . healthy controls and patients were assessed in supine position, with their knees in passive extension and neutral rotation, and their arms by their sides and with forearms supinated and elbows at 30°of flexion. conscious subjects were instructed to remain relaxed, to breathe as quietly as possible throughout the procedure, and to maintain an apnea at functional residual capacity for swe acquisition. for mechanically ventilated patients, an end-expiratory pause was applied during swe acquisition and the absence of diaphragm contraction was assessed using ventilator curves and ultrasound realtime images. the absence of movements and limb muscle contraction was also clinically carefully checked in the critically ill patients. we collected all measurements in triplicate, from the three muscles on the right side and at a resting position: diaphragm, biceps brachii and the rectus femoris. to enable repeat ultrasound assessments at the same location, a mark was drawn on the subject's arm, leg and chest during the first measurement procedure, and was used by the two operators for all measurements. during image acquisition, transducers were placed with minimal compression on top of a generous amount of coupling gel to avoid distortion of the underlying tissue [27] . for all muscles, we collected both a transversal view that refers to the transducer being positioned perpendicular to the fibers and a longitudinal view that refers to the transducer being positioned parallel to the fibers. for the diaphragm views, the transducer was placed at the zone of apposition at the 8th-10th intercostal space between the right anterior and midaxillary lines to better identify the three-layered structure. all diaphragm views were acquired at the end of expiration when the muscle is the thinnest. all peripheral muscle images were acquired after 5 s of motionlessness assessed clinically. for the biceps brachii views, the transducer was placed perpendicular to the long axis of the arm on its anterior surface, over the mid-distance of the long head of the biceps brachii. for the rectus femoris images, the transducer was placed perpendicular to the long axis of the thigh on its anterior surface, at three fifths of the distance from the anterior superior iliac spine to the superior patellar border. in biomechanics, stiffness is defined by the proportional relationship between the stress (the external force or compression) and strain (deformation) applied to it. transmission of a longitudinal pulse leads to tissue displacement, which is detected by pulse echo ultrasound and allow the measurement of the shear wave velocity [v in m s −1 ]. the shear wave velocity v is proportional to the shear modulus (μ expressed in kpa) using the formula: μ = ρ.v 2 (where ρ is the tissue density, equals to 1000 kg m 3 in the human body). hard tissues have a higher μ and v than soft ones. we performed the measurements at the middle portion of each muscle belly avoiding tendons, aponeurosis and fascial tissues to avoid measurement biases. when activating the swe mode, a color-coded box representing the region of interest was super-imposed on the image (fig. 2) . swe images were continuously acquired at a sampling rate of 2 hz during apnea at the end of expiration for healthy subjects, or during an end-expiratory pause for mechanically ventilated patients. an elastography real-time 3-s cine loop was stored. we then offline manually drew the widest region of interest possible (labeled as a "q-box trace") in a homogenous frozen image to average the shear modulus measurement into the drawn q-box and to carefully exclude the surroundings tissue from the measurement. descriptive statistics are reported as numbers (%), mean ± standard deviation (sd) or median (and interquartile [25-75%] ). kolmogorov-smirnov test was used to test normality. differences in mean shear modulus (kpa) were compared using student's t test, mann-whitney test or wilcoxon matched pairs signed rank test, as appropriate. between-operator reproducibility and within-operator reliability were calculated using an analysis of variance intra-class correlation coefficient (icc). an icc is measured on a scale of 0 to 1; 1 represents perfect reliability with no measurement error, whereas 0 indicates no association. measurement reliability was classified as follows: 0-0.49 "poor agreement", 0.50-0.74 "moderate agreement", 0.75-0.89 "good agreement", 0.90-1 "excellent agreement". the best icc measured in the training set in the healthy controls was used to perform the measurements in both the validation set in the healthy controls and in the critically ill patients. to look for a minimum icc value of 0.8 with an 80% power and the significance level set at p < 0.05, we calculated that 56 pairs of measures would be necessary for each muscle. because this is the first study performed in the critically ill by intensivists and taking into the risk of uninterpretable images, we chose to increase this number by 25% (70 measures). the 31 healthy controls cohort was split into a training and a validation set (84-86 measures) and we enrolled 12 consecutive critically ill patients (68-72 measures). finally, we used a bootstrap sampling method to assess the consistency of our findings. statistical analysis was conducted using graphpad, prism (graphpad software, la jolla, ca, usa) and r software version 3.5.1 (https:// www.r-project.org/). we collected 560 us examinations in healthy controls and in critically ill patients. clinical characteristics are reported in table 1 . in the training set obtained from 16 healthy controls, we compared 192 swe measurements collected from transversal and longitudinal images in the diaphragm, the biceps brachii and the rectus femoris by the two operators. figure 2 is an illustration of the images obtained for the three evaluated muscles. the training set allowed us to determine that the best interoperator reliability was obtained with the longitudinal views for the diaphragm and the biceps brachii. no significant difference in inter-operator reliability was observed between the transversal and the longitudinal views for the rectus femoris (table 2) . figures 1 and 2 show how the images were obtained for the three evaluated muscles. in the validation set obtained from 15 healthy controls, 158 swe measurements were analysed. inter-operator and intra-operator reliability, measured on triplicates for each muscle were excellent, the median icc being above 0.90 for each muscle for both the novice (intra-operator 2) and expert (intra-operator 1) operator (table 3) . bland and altman analysis confirmed the excellent inter and intra-operator reliability of the measurements (fig. 3) . we then enrolled 12 critically ill patients (table 1 ) and analysed 210 images. global shear modulus in kpa was 13.7 (± 4.4), 17.8 (± 9.4) and 16.6 (± 9.6) for diaphragm, biceps brachii and rectus femoris respectively. no significant differences were found between the novice and expert operators as shown in the bland-altman graphs (fig. 4) . the average inter-operator reproducibility was excellent for the three muscles with iccs being above 0.90. the intra-operator reliability of the swe measurements was also excellent, icc being above 0.9 ( table 4 ). the inter-operator reliability of the swe measures was assessed using bootstrap resampling with replacement (10,000 samples) to the measures performed on the 12 critically ill patients. the probability to reach good to excellent iccs between operators (above 0.8) for diaphragm, biceps brachii and rectus femoris in a 10,000 bootstrap sample was 81%, 84% and 78% respectively. this study shows that intra-and inter-operator reliability of shear modulus evaluation, a parameter of muscle quality in limb muscles and the diaphragm in both healthy controls and in critically ill patients, is excellent. us evaluation of critically ill patients at the bedside has been largely adopted by intensivists because it is easily available, non-expensive and non-invasive and it can be used as a monitoring tool during the icu stay. therefore, besides its large indications in cardiovascular or respiratory management, it has also often been described to evaluate limb muscle and diaphragm mass in weak patients during the icu stay [7, [28] [29] [30] [31] [32] . very few us studies have however focused on parameters that reflect muscle quality. in a landmark study, puthucheary et al. critically ill patients that changes in vastus intermedius but not rectus femoris echogenicity over time were correlated with physical function tests collected at icu awakening and at icu discharge [28] . beyond quantitative analysis of the muscle mass, non-invasive tools are urgently needed to provide measurable parameters of limb and respiratory muscle quality. real-time nonvolitional tools, available at the bedside such as swe, would provide targets for clinical trials aiming at improving quality of life and autonomy in survivors of critical illness [33] . because different pathologic and healthy tissues reveal a similar echogenicity pattern and similar grey-scale but different shear modulus values, sonoelastographic techniques such as swe measurement might be a promising tool to evaluate and to monitor muscle quality and in vivo contractile property changes over time [27, 34] . for instance, high shear modulus is associated with muscle stiffness in cerebral palsy or in late duchenne's myopathy [35] , while low shear modulus is associated with atrophy in a gne chronic myopathy [22] . moreover, shear modulus but not echogenicity is associated with muscle fibrosis. no study has ever been performed to evaluate shear modulus measurement feasibility and reliability in the critically ill population at high risk of muscle edema. we report herein that shear modulus measurement was reliable and easy to learn for both expert and novice non-radiologist operators working with critically ill patients. few others have assessed inter-operator and intra-operator reliability in measuring muscle shear modulus and have reported similar results. tas et al. reported in 12 healthy subjects an excellent intra-operator reliability and inter-operator reproducibility for rectus femoris (icc above 0.9) [36] . dorado-cortez et al. reported better reliability and reproducibility for shear wave velocity measured in longitudinal plane than transverse plane in healthy lower limb muscles [37] . du et al. found a good agreement for shear modulus reproducibility in patients with parkinson's disease, and a significant difference in biceps brachii stiffness between healthy controls (24 ± 5 kpa), mildly symptomatic patients (48 ± 24 kpa) and remarkably symptomatic patients (60 ± 21 kpa) [38] . to assess the muscle globally and to avoid intramuscular heterogenous measurements, we chose to use the largest square possible as the region of interest. in the present study, we explored both the limb muscles and the diaphragm, the main inspiratory muscle. nowadays, since specific phrenic nerve stimulation tools to explore critical illness-associated diaphragm weakness are not routinely available at the bedside [4, 12] (and diaphragmatic biopsies are very difficult to obtain in humans [5, 39, 40] ), non-invasive tools to explore the diaphragm using us is more and more popular. us may help by approximating diaphragm mass by measuring fig. 3 bland-altman plot of the difference of shear modulus between operators in healthy subjects thickness as well as approximating diaphragm contractile activity by measuring the excursion and the thickening fraction [41] . a pioneer study by goligher has reported that during critical illness and mechanical ventilation, the diaphragm thickness may decrease (supposedly because of atrophy), but may not change during the stay or may increase (supposedly because of myotrauma) [30, 42] . since diaphragmatic shear modulus has been associated with diaphragmatic function in spontaneously breathing volunteers [43] , shear modulus analysis of the diaphragm in the critically ill may pave the way towards a non-invasive better understanding of diaphragm quality changes during critical illness. our study presents limits that should be discussed. first, we did not perform muscle biopsies to correlate shear modulus to pathology. however, most of the studies that have evaluated swe in muscles did not show pathology data either [27, 34] . second, precautions must be taken into consideration when shear modulus is measured. position of the patient, muscle contraction and pressure applied to the muscle by the probe do indeed influence the shear modulus value [27, 34, 44] . we therefore took extreme precautions to limit any measurement bias and used an excessive amount of gel, did not apply any pressure to the muscle during the evaluation and used triplicates to calculate the mean shear modulus. we also paid extra attention to measure the shear modulus in muscles with no contractions and at the end of the expiration for the diaphragm. in the healthy controls, we report a diaphragm shear modulus above the range observed by bachasson et al. [23] . two main differences should be noted between the two studies. we performed the measurements in the supine position rather than the semi-recumbent position which may have impaired the diaphragm to completely relax at the end of the expiration. we designed the present study as a real-life bedside study and did not use a pneumotachograph or a transdiaphragmatic pressure monitoring. therefore, even after taking extra precautions to measure the shear modulus at the end of expiration with no diaphragm contraction, it is possible that some of the measurements were performed above the functional residual capacity. however, because both intra-operator reliability and inter-operator reproducibility icc were very high, our results suggest that shear wave elastography is a feasible technique to describe diaphragm ultrastructure. diaphragm biopsies using critically ill animal models may help assessing the accuracy of the shear wave elastography technique in phenotyping diaphragm weakness. to limit the influence of muscle anisotropy on the measured value, we chose to use a large square as the region of interest to measure the signal. third, we used shear modulus measurement rather than shear wave velocity. all commercially available us elastography systems are based on the prerequisite assumption that the material is elastic, incompressible, homogenous and isotropic, with a density which equals 1 g/cm 3 . the muscle tissue is however anisotropic and shear modulus should therefore be used as a variation during the course of the disease. our study shows for the first time that a non-volitional, non-invasive ultrasonographic evaluation of muscle abbreviations: icc intra-class coefficient correlation, kpa kilopascals, sd standard deviation. icc are presented with 95% confidence interval stiffness and contractile properties using shear modulus measurement is reliable in the critically ill population for both the limb muscles and the diaphragm. swe is an us tool that should be investigated in a larger population of critically ill patients to assess whether it might serve as a tool to identify different patient's phenotypes of muscle weakness. abbreviations icc: intra-class correlation coefficient; icu: intensive care unit; sd: standard deviation; sofa: sepsis-related organ failure assessment; swe: shear wave ultrasound elastography; us: ultrasonography; μ: shear modulus the recover program: disability risk groups and 1-year outcome after 7 or more days of mechanical ventilation long-term cognitive impairment and functional disability among survivors of severe sepsis predictors of return to work in survivors of critical illness diaphragmatic dysfunction in patients with icu-acquired weakness and its impact on extubation failure rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation acute skeletal muscle wasting in critical illness functional disability 5 years after acute respiratory distress syndrome acute outcomes and 1-year mortality of intensive care unitacquired weakness. a cohort study and propensity-matched analysis early mobilization and recovery in mechanically ventilated patients in the icu: a bi-national, multi-centre, prospective cohort study respective contribution of intensive care unit-acquired limb muscle and severe diaphragm weakness on weaning outcome and mortality: a post hoc analysis of two cohorts diaphragm dysfunction on admission to the intensive care unit. prevalence, risk factors, and prognostic impact-a prospective study diaphragm weakness in mechanically ventilated critically ill patients diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications mechanisms of chronic muscle wasting and dysfunction after an intensive care unit stay. a pilot study physical inactivity and protein energy wasting play independent roles in muscle weakness in maintenance haemodialysis patients quantitative neuromuscular ultrasound in intensive care unit-acquired weakness: a systematic review muscle ultrasound from diagnostic tool to outcome measure--quantification is the challenge reliability of a novel ultrasound system for gray-scale analysis of muscle supersonic shear imaging: a new technique for soft tissue elasticity mapping efsumb guidelines and recommendations on the clinical use of ultrasound elastography. part 2: clinical applications skeletal muscle in healthy subjects versus those with gne-related myopathy: evaluation with shearwave us--a pilot study diaphragm shear modulus reflects transdiaphragmatic pressure during isovolumetric inspiratory efforts and ventilation against inspiratory loading the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine the reliability and validity of ultrasound to quantify muscles in older adults: a systematic review shear-wave elastography: basic physics and musculoskeletal applications ultrasonography in the intensive care setting can be used to detect changes in the quality and quantity of muscle and is related to muscle strength and function muscle mass, strength and functional outcomes in critically ill patients after cardiothoracic surgery: does neuromuscular electrical stimulation help? the catastim 2 randomized controlled trial evolution of diaphragm thickness during mechanical ventilation. impact of inspiratory effort mechanical ventilation and diaphragmatic atrophy in critically ill patients: an ultrasound study the course of diaphragm atrophy in ventilated patients assessed with ultrasound: a longitudinal cohort study skeletal muscle ultrasound in critical care: a tool in need of translation shear wave sonoelastography of skeletal muscle: basic principles, biomechanical concepts, clinical applications, and future perspectives noninvasive assessment of muscle stiffness in patients with duchenne muscular dystrophy shear wave elastography is a reliable and repeatable method for measuring the elastic modulus of the rectus femoris muscle and patellar tendon: shear wave elastography of the rectus femoris muscle and patellar tendon ultrasound shear wave velocity in skeletal muscle: a reproducibility study ultrasound shear wave elastography in assessment of muscle stiffness in patients with parkinson's disease: a primary observation rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans diaphragm muscle fiber weakness and ubiquitinproteasome activation in critically ill patients critical illness-associated diaphragm weakness diaphragmatic myotrauma: a mediator of prolonged ventilation and poor patient outcomes in acute respiratory failure diaphragmatic shear modulus at various submaximal inspiratory mouth pressure levels the effect of unit, depth, and probe load on the reliability of muscle shear wave elastography: variables affecting reliability of swe publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank claudine gniadek, rn, and the members of the medical and nursing team for their participation in the present study. we also thank julie carr, md, for her advices writing the manuscript. authors' contributions af and ya performed all the measurements, analysed the results and participated to the manuscript editing, sn contributes to the result analysis and to the manuscript editing, fg, rl and ma contributed to the study design and patient enrolments, kk contributed to the study design and to the manuscript editing, pe and gs reviewed some of the measurements and participated to the result analysis, sj contributed to the study's design, result analysis and manuscript editing, nm performed the statistical analysis, sm reviewed some of the measurements and participated to the result analysis, bj designed the study, participated to the manuscript editing and approved its final version. all authors read and approved the final manuscript. this study has received funding by departmental resources, the medical school of the montpellier university (yassir aarab, young researcher grant) and the regenhab fhu (aurelien flattres, phd grant). the authors of this manuscript consent to share the collected data to others. data are provided to qualified investigators free of charge. required documents to request data include a summary of the research plan, request form and irb review. datasets will be shared after careful examination by the study board of investigators. data will be available 12 months after the main publication and indefinitely.ethics approval and consent to participate institutional ethical approval was obtained (2017-cler-mtp-09-16), and the study was registered (clinicaltrial nct03550222). because the ultramuscle study was part of an image databank storage, consent was waived according to french law. not applicable. the ultrasound equipment aixplorer was made available for the study by supersonic imagine s.a. (aix-en-provence, france). the supersonic company did not have any access to the study's design, the results and the manuscript editing. the authors declare that they have no competing interests. key: cord-048199-5yhe786e authors: alvarez, gonzalo; hébert, paul c; szick, sharyn title: debate: transfusing to normal haemoglobin levels will not improve outcome date: 2001-03-08 journal: crit care doi: 10.1186/cc987 sha: doc_id: 48199 cord_uid: 5yhe786e recent evidence suggests that critically ill patients are able to tolerate lower levels of haemoglobin than was previously believed. it is our goal to show that transfusing to a level of 100 g/l does not improve mortality and other clinically important outcomes in a critical care setting. although many questions remain, many laboratory and clinical studies, including a recent randomized controlled trial (rct), have established that transfusing to normal haemoglobin concentrations does not improve organ failure and mortality in the critically ill patient. in addition, a restrictive transfusion strategy will reduce exposure to allogeneic transfusions, result in more efficient use of red blood cells (rbcs), save blood overall, and decrease health care costs. anaemia is a common condition in critically ill patients, and rbc transfusions are often used in the treatment and management of this patient population. in fact, one study [1] reported that 25% of all critically ill patients received rbc transfusions. many laboratory studies [2] [3] [4] [5] [6] [7] [8] have examined the physiological responses (ie compensatory mechanisms) of the body to anaemia, which include the following [9] : increased cardiac output, decreased blood viscosity, capillary changes, increased oxygen extraction, and other tissue adaptations to meet oxygen requirements. although critically ill patients are affected by a number of factors that predispose them to the adverse consequences of anaemia, persistence of this condition is of particular concern because it may cause the compensatory mechanisms in these patients to become impaired, risking oxygen deprivation in vital organs [9] . however, critically ill patients may also be at increased risk from the adverse effects of rbc transfusions, such as pulmonary oedema from volume overload, immune suppression resulting in increased risk of infection, and microcirculatory injury from poorly deformable rbcs. it is the aim of the present commentary to justify the statement 'transfusing to normal haemoglobin concentration will not improve outcome.' if we define normal haemoglobin as being greater than 115 g/l for women and greater than 125 g/l for men, then there is no evidence in the literature to justify maintaining such high concentrations by the use of rbc transfusions in any anaemic patient. there may, however, be some debate about adopting a transfusion threshold of 100 g/l, which is well below 'normal'. transfusion threshold would, obviously, reduce the number of allogeneic rbcs transfused. it is our goal to impress upon the reader that transfusing to a level equal to or greater than 100 g/l does not improve mortality and other clinically important outcomes in a critical care setting. we first explore the reasons why a reduction in the total number of allogeneic blood transfusions would be beneficial. second, we examine the current evidence for using a lower transfusion strategy, specifically that employed in the transfusion requirements in critical care (tricc) trial. rbc transfusions have inherent risks that may be categorized as follows [11] [12] [13] [14] [15] : transfusion-transmitted infections; immune-related reactions (acute or delayed haemolytic reactions, febrile, allergic, anaphylactic reactions and graft-versus-host disease); and nonimmunerelated reactions (fluid overload, hypothermia, electrolyte toxicity and iron overload). major improvements in donor screening procedures and laboratory testing have dramatically improved the safety of the blood supply [16] . currently, the risk of transmitting an infectious agent through blood transfusion ranges from 1:100,000 for hepatitis b virus to 1:1,000,000 for hiv (canadian blood services, personal communication, 2000). the most important threats to the blood supply remain new and unknown pathogens. more recently, concern has focused on the potential transmission of prions through rbcs. also, infectious agents with long latency periods pose particular risks to young individuals who require rbcs, such as multiple trauma victims. the risk : benefit ratio for a 24-year-old trauma victim with a 50-year life expectancy differs markedly from that for a person aged 80 years who is undergoing coronary artery bypass surgery. in summary, because there is a risk of transmitting diseases through the blood supply, we should always strive to use rbcs according to the best available evidence in order to ensure that we do more good than harm to our patients. it is a long-standing observation [17] [18] [19] [20] [21] that blood transfusions are associated with immune suppression. this clinical phenomenon was first observed in renal transplant patients who had received blood transfusions while on dialysis before the transplant [22] , and has been observed repeatedly in transplant centres around the world [23, 24] . recently, opelz et al [25] reported a multicentre clinical trial in which all renal allograft recipients received modern immunosuppressive regimens. those patients who were allocated to receive three allogeneic rbc units before renal transplant had a 1-year graft survival rate of 90%, as compared with 82% for patients who were not transfused (p = 0.02). these data suggest that there are long-term immunosuppressive effects following transfusion of nonleukocyte-reduced allogeneic rbcs. a large number of studies [26] [27] [28] [29] [30] [31] [32] [33] [34] have also suggested that allogeneic transfusions accelerate cancer growth, perhaps due to altered immune surveillance. these altered immune responses after allogeneic rbc transfusions may also predispose critically ill transfusion recipients to nosocomial infections [35] [36] [37] [38] [39] [40] and increased rates of multiplesystem organ failure [41] , which may ultimately result in higher mortality rates. however, most studies that examined the association between cancer recurrence and postoperative infection after transfusion [42, 43] only provided weak causal inferences because of poor study design and the lack of independence between allogeneic rbc transfusions and the potential complication. a recent meta-analysis [44] combined the results from seven rcts, and was unable to detect clinically important decreases in mortality and postoperative infections. we added the results of a new rct by van de watering et al [45] to the above meta-analysis. the relative risk for allcause mortality was 1.05 (95% confidence interval 0.88-1.25), and was 1.10 (95% confidence interval 0.85-1.43) for postoperative infections. however, this meta-analysis excluded two positive rcts [40, 46] because of the significant statistical heterogeneity introduced by these two studies. if all available rcts are combined, ignoring heterogeneity, then the relative risk difference for postoperative infections across all studies is 1.60 (95% confidence interval 1.00-2.56; p = 0.05). thus, the available evidence suggests that universal prestorage leukoreduction could have clinical effects that range from none to decreasing rates of infection by as much as 50% in high-risk patients. in summary, despite convincing laboratory evidence and some supportive clinical studies, the clinical significance of the immunosuppressive effects of allogeneic rbc transfusions have not been clearly established [47] . more importantly, the impact of a leukoreduction programme has not been studied in a large population of patients who are expected to have significant exposure to allogeneic rbcs. the majority of complications from allogeneic rbc transfusion, however, are no more frequent in the intensive care setting than in other patient populations, with the possible exception of pulmonary oedema, hypothermia and electrolyte disturbance. hypothermia and electrolyte disturbances occur most frequently with massive transfusions. in critically ill patients, the optimal effective circulatory volume may be difficult to determine, and as a consequence pulmonary oedema may be a much more frequent complication of rbc transfusion than in other patient populations. this may explain the significantly higher rate of pulmonary oedema in patients transfused using a threshold of 100 g/l (5.3% in the restrictive transfusion group versus 10.7% in the liberal transfusion group; p < 0.01), as reported in the tricc trial [10] . as an alternative explanation, the more frequent use of rbcs might have resulted in more frequent episodes of transfusion-related acute lung injury in the liberal strategy group (7.7% in the restrictive strategy versus 11.4% in the liberal strategy; p = 0.06), as reported in the tricc trial. clinical evidence is also insufficient to definitively establish a correlation between the age of rbcs being transfused and patient mortality; however, laboratory evidence has shown many storage-related changes that may result in impairment of blood flow and oxygen delivery at the microcirculatory level. marik et al [48] demonstrated an association between a fall in gastric intramucosal ph and transfusion of rbcs stored for longer than 15 days. in addition, there is ample laboratory evidence that prolonged rbc storage adversely affects rbcs, potentially results in the generation of cytokines, and alters host immune function. in another study, fitzgerald et al [49] , using an animal model of transfusion, consistently observed a lack of efficacy of transfused, stored rat blood to improve tissue oxygen consumption as compared with fresh cells or other blood substitutes. three retrospective clinical studies tested the association between the age of transfused blood and duration of stay in the intensive care unit (icu) [50] and mortality [51, 52] . martin et al [50] observed a statistically significant association between the transfusion of aged blood (>14 days old) and increased duration of icu stay (p = 0.003) in 698 critically ill patients. in patients who received a transfusion, aged rbcs was the only predictor of duration of stay (p < 0.0001). in survivors, only median age of blood was predictive of duration of stay (p < 0.0001). purdy et al [51] demonstrated a negative correlation (r = -0.73) between the proportion of rbc units of a given age transfused to survivors and increasing age of rbcs in patients admitted to the icu with a diagnosis of severe sepsis (n = 31). those investigators also noted that these latter units were more likely to be older. a recently reported study by vamvakas and carven [52] evaluated the effect of duration of rbc storage on postoperative pneumonia in 416 consecutive patients undergoing coronary artery bypass grafting. those investigators noted an adjusted increase of 1% in the risk of postoperative pneumonia per day of average increase in the duration of rbc storage (p < 0.005) in transfused patients. each of these three studies also noted that patients who received a large number of rbc units had a higher mortality. although these risks are relatively small when viewed collectively, they become significant when one considers that 25% of all critically ill patients in canada are transfused during their icu stay [1] . until recently, physicians have depended on clinical judgement when deciding at what haemoglobin level to transfuse a critically ill patient. as a result, significant variation has been shown to exist in transfusion practice among canadian critical care physicians [53] , which is due largely to a lack of published data on the subject. an arbitrary haemoglobin level of 100 g/l has historically been used as a threshold to transfuse critically ill patients. six observational studies investigated the importance of anaemia on transfusion practices in various settings. of these, three large cohort studies, which were performed in different patient populations (intensive care [1] , coronary artery bypass surgery [54] and hip fractures [55]), reached different conclusions. rbc transfusions in particular improved outcome in critically ill patients with cardiovascular disease, but increased the risk of myocardial infarction in coronary artery bypass surgery patients. transfusion had no impact on short-term or long-term mortality in hip-fracture patients. three smaller studies [56] [57] [58] evaluated the relationship between anaemia and adverse outcomes in vascular disease patients. although increased numbers of ischaemic events were observed in anaemic patients, the validity of these studies is uncertain, given that the decision to transfuse a patient was often correlated with illness burden of the patient. it is also possible that comorbidity was not adequately adjusted for in those studies. transfusion thresholds were compared in 10 randomized clinical trials [10, [59] [60] [61] [62] [63] [64] [65] [66] [67] . although the clinical settings varied, each trial randomized patients to be transfused on the basis of a 'conservative' or a 'liberal' strategy. the definitions of conservative and liberal strategies varied, and actually overlapped between studies. of these 10 trials, only three included more than 100 patients and only one trial evaluated the impact of transfusion on symptoms. in the first trial of patients undergoing elective coronary artery bypass surgery [65] , the differences between perioperative haemoglobin levels were small, event rates were very low, and there were no differences in any outcome. in the second trial [67] , patients undergoing knee arthroplasty were randomly assigned to receive autologous blood transfusion immediately after surgery or to receive autologous blood if haemoglobin level fell below 9 g/dl [67] . again, no differences in outcome were observed. the third trial of hip fracture patients undergoing surgical repair [64] found no differences in outcomes; however, five deaths were recorded at 60 days after surgery in the symptomatic group, and two deaths occurred in the 10 g/dl group. the numbers of patients in these trials were too small to evaluate the effect of lower transfusion triggers on clinically important outcomes such as mortality, morbidity and functional status. in 1999, hebert et al [10] reported the results of the tricc trial. patients (n = 838) were randomized either to a restrictive strategy (haemoglobin concentration maintained between 70 and 90 g/l, with a trigger set at 70 g/l) or to a liberal strategy (haemoglobin concentration maintained between 100 and 120 g/l, with a trigger at 100 g/l). to date, the tricc trial is the only large study that has investigated these parameters. the groups were comparable at baseline. the average daily haemoglobin concentration ranged from 85 ± 7.2 g/l in the restrictive group to 107 ± 7.3 g/l in the liberal group (p < 0.01). the average number of transfusions was reduced by 52% in the restrictive group (2.6 ± 4.1 versus 5.6 ± 5.3 rbcs/patient; p < 0.01). cardiac events, primarily pulmonary oedema and myocardial infarction, were more frequent in the liberal strategy (p < 0.01; table 1 ). on examination of composite outcomes, the number of patients with multiorgan failure was found to be substantially increased in both groups, with the results being marginally better in the restrictive strategy group (20.6% versus 26.0%; p = 0.07; table 2 ). overall, the restrictive transfusion group showed a lower 30-day mortality (18.7% versus 23.3%; p = 0.11; fig. 1 ). kaplan-meier survival curves, however, were significantly different in the subgroup of patients with an acute physiology and chronic health evaluation ii score of 20 or less (p = 0.02; fig. 2 ). in addition, although 60-day mortality (22.8% versus 26.5%; p = 0.23) and icu mortality (13.9% versus 16.2%; p = 0.29) were not statistically significant, they did show a consistent trend in terms of absolute values that favoured the restrictive strategy. the key observation from the tricc trial is not that the restrictive strategy is better, but rather that it is at worst equivalent to the liberal strategy and at best superior to the liberal strategy. at this juncture, preclinical and clinical evidence support the adoption of a more restrictive transfusion strategy in most critically ill patients. however, there remain divergent views regarding the risks and benefits of treating anaemia in patients with cardiovascular disease. laboratory-based studies [68, 69] suggest that patients with cardiovascular disease may require higher haemoglobin concentrations to maintain oxygen delivery in partially occluded or diseased coronary arteries. studies to demonstrate how anaemia affects contractile function of the left ventricle have rarely shown important effects above haemoglobin concentrations of 70 g/l. indeed, it is more important to address the underlying pathophysiological causes of the acute coronary syndrome with proven therapy such as aspirin and β-blockers, rather than treating mild-to-moderate anaemia as an initial step. if the effects of rbc transfusion were either limited or increased then there would be no debate; however, the use of allogeneic rbcs has been shown to be associated with immunomodulation [12, 47] and/or alteration in the delivery of oxygen in the microcirculation [70, 71] , resulting in increased rates of infections and organ failure. few clinical studies have attempted to elucidate the risk : benefit ratio of anaemia and transfusion in cardiac patients. two small rcts [62, 72] examined transfusion practice in patients undergoing coronary artery bypass grafting, and concluded that a conservative approach to the administration of rbcs may be safe. however, two recent cohort studies suggested that anaemia may increase the risk of mortality in critical illness [73] and following surgery in patients with cardiovascular disease [74] . there were 418 and 420 patients in the restrictive and liberal transfusion groups, respectively. *difference calculated by subtracting mean values of restrictive group from those of liberal group. † three patients were lost to 60-day mortality rate; therefore n = 835. ‡ nonsurvivors are considered to have all organs failing on date of death. § changes in mod score from baseline, while also incorporating adjustment for death. data from hébert et al [10] . in a study of jehovah's witnesses (a group that refuses rbc transfusion on religious grounds) undergoing surgical procedures [74] , it was noted that mortality was significantly increased in patients with cardiac disease after a decrease in haemoglobin levels from 100-110 g/l to 60-69 g/l. in that study, patients with no cardiac disease and similar changes in haemoglobin levels showed no increase in mortality, which is in accordance with the results of the tricc trial [10] . in the study by hébert et al. [73] of 4470 critically ill patients, a correlation between critical care vol 5 no 2 alvarez et al [10] . kaplan-meier estimates of survival in the 30 days after admission to the icu in the restrictive and liberal transfusion strategy groups (all patients). data from hébert et al [10] . kaplan-meier estimates of survival in the 30 days after admission to the icu in the restrictive and liberal transfusion strategy groups (patients with apache ii score ≤20). data from hébert et al [10] . anaemia and mortality rates was observed. those investigators also found that the risk of anaemia appeared to decrease with rbc transfusion in patients with cardiac disease. in patients with cardiac disease, mortality increased when haemoglobin concentrations were below 95 g/l, as compared with anaemic patients with other diagnoses (55% versus 42%; p = 0.09). in the subgroup of patients with cardiac disease, increasing haemoglobin values in anaemic patients was associated with improved survival (odds ratio 0.80 for each 10 g/l increase; p = 0.012). one possible explanation for the discrepancy between the tricc trial and this observational study may be that the attending physicians who recruited patients into the study did not enter those patients who were considered to have severe cardiac disease. hébert et al. [73] sought to examine further whether a restrictive transfusion strategy was at least as effective as a liberal strategy in critically ill patients with cardiac disease. in the subgroup of patients with cardiovascular disease from the tricc trial, those investigators suggested that most haemodynamically stable critically ill patients with cardiovascular disease may be transfused when haemoglobin concentrations fall below 70 g/l, and that the hemoglobin concentration should be maintained between 70 and 90 g/l. average daily haemoglobin concentrations were 85 ± 6.2 g/l in the restrictive transfusion group and 103 ± 6.7 g/l in the liberal transfusion group (p < 0.01). in the 357 patients with cardiovascular disease, the 30-day mortality rate was 23% in the restrictive transfusion group versus 23% in the liberal group (95% confidence interval of the difference -8.4% to 9.1%; p = 1.00). other mortality rates, including 60-day (26% versus 27%; p = 0.90), icu (19% versus 16%; p = 0.49) and hospital mortality (27% versus 28%; p = 0.81), were not significantly different between groups. kaplan-meier survival curves comparing time to death demonstrated similar trends in the two groups ( fig. 3 ; p = 0.98). the multiple organ dysfunction (mod) scores, during the entire study period, were also not significantly different between groups (8.6 ± 4.9 versus 9.0 ± 4.4; p = 0.40), but the change in mod score from baseline values was significantly lower in the restrictive group than in the liberal group (0.2 ± 4.2 versus 1.3 ± 4.4; p = 0.02). combined measures of morbidity and mortality, or composite outcomes, were also examined. when all patients who died were given a score of 24, the total mod score between groups was not different (p = 0.39), or were the changes in mod scores significantly different from baseline (2.7 ± 6.9 versus 4.0 ± 7.3; p = 0.08). among the specific subset of cardiac patients with ischaemic heart disease (n = 257), there were no discernible differences in 30-day and 60-day as well as icu mortality rates. however, a nonsignificant (p = 0.3) decrease in overall survival rate in the restrictive group was noted in those patients with confirmed ischaemic heart disease, severe peripheral vascular disease or severe comorbid cardiac disease (fig. 4) . in conclusion, a restrictive rbc transfusion strategy generally appears to be safe in most critically ill patients with cardiovascular disease, with the possible exception of patients experiencing acute myocardial infarction or unstable angina. survival over 30 days in patients with ischemic heart disease in the restrictive and liberal allogeneic rbc transfusion strategy groups. this graph illustrates kaplan-meier survival curves for all patients with ischemic heart disease in both study groups. there is no difference in mortality in patients in the restrictive group (dashed line) as compared to the liberal group (solid line) (p = 0.30). the need to reduce the amount of allogeneic blood transfusions in order to reduce the associated risks has been firmly established. rbcs are associated with clinically important immune suppression, and stored rbcs have been shown to cause adverse microcirculatory effects that result in increased organ failure. the question for some time has been whether critically ill patients are able to tolerate lower levels of haemoglobin without deleterious effects, thus reducing the amount of exposure to allogeneic transfusions. in the only large rct, hébert et al [10] established that there was no difference in mortality rates between restrictive and liberal transfusion strategies in noncardiac, critically ill patients. although those investigators were able to show convincing trends that the liberal strategy may in fact be deleterious in terms of absolute values, statistical significance was not achieved. however, the fact that no difference between the two strategies was achieved is of great importance, because this means that the total number of transfusions can be reduced by approximately half without any impact on mortality. in addition, these findings are easily put into clinical practice. although many questions remain, the tricc trial and many laboratory and clinical studies have established that transfusing to normal haemoglobin concentrations does not improve organ failure and mortality in the critically ill patient. as such, a restrictive transfusion strategy will reduce exposure to allogeneic transfusions, result in more efficient use of rbcs, save blood overall, and decrease health care costs. a canadian survey of transfusion practices in critically ill patients acute normovolemic anemia: effect on the adequacy and distribution of coronary blood flow blood viscosity and cardiac output in acute experimental anemia ventricular performance in acute normovolemic anemia and effects of beta blockade some circulatory effects of experimental hypovolemic anemia the adequacy of subendocardial oxygen delivery. the interaction of determinants of flow, arterial oxygen content and myocardial oxygen need physiologic effects of acute anemia: implications for a reduced transfusion trigger effects of polycythemia and anemia on cardiac output and other circulatory factors transfusion triggers and occam's rusty razor the transfusion requirements in critical care investigators: a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care the risks of blood transfusion: the relative influence of acquired immunodeficiency syndrome and non-a, non-b hepatitis current issues in transfusion therapy. 1. risks of infection perioperative haemotherapy: ii. risks and complications of blood transfusion transfusion risks risks of transfusion on behalf of the current tti study: prospective investigation of transfusion transmitted infection in recipients of over 20000 units of blood transfusion-associated immunomodulation and universal white cell reduction: are we putting the cart before the horse? transfusion mechanisms of transfusioninduced immunosuppression immunomodulatory aspects of transfusions. a once and future risk? immunosuppressive effects of blood transfusion in anaesthesia and surgery transfusion-induced immunosuppression effect of blood transfusions on subsequent kidney transplants annotation. blood transfusion and renal transplantation immunological effects of blood transfusion prospective evaluation of pretransplant blood transfusions in cadaver kidney recipients perioperative transfusions associated with colorectal cancer surgery: clinical judgement versus the hematocrit red for danger: blood transfusion and colorectal cancer blood transfusion and tumor growth: studies in animal models the relationship of blood transfusion, tumor staging, and cancer recurrence association between transfusion of whole blood and recurrence of cancer transfusion and host defenses against cancer recurrence and infection relation between cancer of the colon and blood transfusion relationship between blood transfusion and tumour behaviour perioperative blood transfusion and outcome after resection for colorectal carcinoma risk of infection after penetrating abdominal trauma beneficial effects of autologous blood transfusion on infectious complications after colorectal cancer surgery postoperative infections following autologous and homologous blood transfusions infection or suspected infection after hip replacement surgery with autologous or homologous blood transfusions homologous blood transfusion as a risk factor for postoperative infection after coronary artery bypass graft operations postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery the multiple organ dysfunction (mod) score: a reliable descriptor of a complex clinical outcome perioperative haemotherapy: i. indications for blood component transfusion perioperative blood transfusion and colorectal cancer recurrence: a qualitative statistical overview and meta-analysis perioperative allogeneic blood transfusion does not cause adverse sequelae in patients with cancer: a meta-analysis of unconfounded studies beneficial effects of leukocyte depletion of transfused blood on postoperative complications in patients undergoing cardiac surgery. a randomized clinical trial randomised comparison of leucocyte-depleted versus buffy-coat-poor blood transfusion and complications after colorectal surgery biologic effects of leukocytes present in transfused cellular blood products effect of stored-blood transfusion on oxygen delivery in patients with sepsis transfusing red blood cells stored in citrate phosphate dextrose adenine-1 for 28 days fails to improve tissue oxygenation in rats age of transfused red blood cells is associated with icu length of stay association of mortality with age of blood transfused in septic icu patients transfusion and postoperative pneumonia in coronary artery bypass graft surgery: effect of the length of storage of transfused red cells variation in red cell transfusion practice in the intensive care unit: a multicentre cohort study risk of bacterial infection associated with allogeneic blood transfusion among patients undergoing hip fracture repair blood conservation in coronary artery surgery relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit the effect of hemodilution on regional myocardial function in the presence of coronary stenosis effect of early blood transfusion on gastrointestinal haemorrhage influence of hematocrit on cardiopulmonary function after acute hemorrhage the illness of trauma comparison of two transfusion strategies after elective operations for myocardial revascularization transfusion requirements in critical care. a pilot study a pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions following hip fracture lowering the hemoglobin threshold for transfusion in coronary artery bypass procedures: effect on patient outcome a prospective, randomized trial limiting perioperative red blood cell transfusions in vascular patients predonated autologous blood transfusions after total knee arthroplasty coronary and cardiovascular dynamics and oxygen availability during acute normovolemic anemia graded coronary stenosis and coronary flow during acute normovolemic anemia acceptable hematocrit levels in surgical patients quantitative evidence of microcirculatory compromise in skeletal muscle of normotensive hyperdynamic septic sheep limitations of blood conservation does transfusion practice affect mortality in critically ill patients? effect of anaemia and cardiovascular disease on surgical mortality and morbidity dr hébert is a career scientist of the ontario ministry of health. key: cord-004427-dy9v9asg authors: bissell, brittany d.; laine, melanie e.; thompson bastin, melissa l.; flannery, alexander h.; kelly, andrew; riser, jeremy; neyra, javier a.; potter, jordan; morris, peter e. title: impact of protocolized diuresis for de-resuscitation in the intensive care unit date: 2020-02-28 journal: crit care doi: 10.1186/s13054-020-2795-9 sha: doc_id: 4427 cord_uid: dy9v9asg objective: administration of diuretics has been shown to assist fluid management and improve clinical outcomes in the critically ill post-shock resolution. current guidelines have not yet included standardization or guidance for diuretic-based de-resuscitation in critically ill patients. this study aimed to evaluate the impact of a multi-disciplinary protocol for diuresis-guided de-resuscitation in the critically ill. methods: this was a pre-post single-center pilot study within the medical intensive care unit (icu) of a large academic medical center. adult patients admitted to the medical icu receiving mechanical ventilation with either (1) clinical signs of volume overload via chest radiography or physical exam or (2) any cumulative fluid balance ≥ 0 ml since hospital admission were eligible for inclusion. patients received diuresis per clinician discretion for a 2-year period (historical control) followed by a diuresis protocol for 1 year (intervention). patients within the intervention group were matched in a 1:3 ratio with those from the historical cohort who met the study inclusion and exclusion criteria. results: a total of 364 patients were included, 91 in the protocol group and 273 receiving standard care. protocolized diuresis was associated with a significant decrease in 72-h post-shock cumulative fluid balance [median, iqr − 2257 (− 5676–920) ml vs 265 (− 2283–3025) ml; p < 0.0001]. in-hospital mortality in the intervention group was lower compared to the historical group (5.5% vs 16.1%; p = 0.008) and higher icu-free days (p = 0.03). however, no statistically significant difference was found in ventilator-free days, and increased rates of hypernatremia and hypokalemia were demonstrated. conclusions: this study showed that a protocol for diuresis for de-resuscitation can significantly improve 72-h post-shock fluid balance with potential benefit on clinical outcomes. early intravenous (iv) fluid resuscitation is a necessary tool to improve hemodynamic stability and organ perfusion and possibly decrease mortality in critically ill patients admitted to the intensive care unit (icu) [1, 2] . however, the benefit of continued fluid administration after the first 24-48 h is unclear. paradoxically, a positive fluid balance secondary to excess fluid accumulation has been associated with diverse and persistent detriment on a multitude of organ systems [3] . perpetuating clinical harm has been demonstrated on pulmonary and renal function, as well as important clinical outcomes such as mortality and length of stay [1] . despite the growing body of evidence supporting the adverse aspects of positive fluid balance, fluid overload remains common in icu patients [4] . one approach to correcting fluid balance is shifting focus onto the post-or de-resuscitation period with appropriate diuresis, or renal replacement therapy (rrt) in those non-responsive to diuresis, once hemodynamic stability is achieved [5] . effective diuresis may be challenged by many hindrances. an overall lack of standardization exists in identification of fluid-overloaded patients as optimal transition times between fluid resuscitation and fluid removal are not clear, and clinical signs of fluid overload are delayed relative to onset of organ damage [5] [6] [7] . standard of care diuretic treatment regimens may be inadequate via sustained delays in initiation from shock resolution or inadequate dosing and follow-up. additionally, apprehension for side effects can be seen, including serum creatinine rises and new onset acute kidney injury (aki). however, the preponderance of adverse event data surrounding these medications is found in non-critical care populations, frequently non-translatable to patients in the icu [8] . previous protocols guiding volume removal in the critically ill can be found in specific populations including acute decompensated heart failure, aki, or rrt weaning, with protocolized approaches often improving clinical outcomes versus standard of care [9] [10] [11] . further, while limited evidence is available steering diuretic deresuscitation in the broad icu population, protocols have relied upon dated monitoring parameters, including central venous or pulmonary artery occlusion pressures [12] [13] [14] . in this study, we aimed to evaluate the impact of a novel diuresis protocol utilizing common bedside monitoring parameters and simplified loop diuretic dosing on cumulative fluid balance over the first 72 h following hemodynamic stability, as compared to standard of care. this was a pilot study to evaluate a service line level change in diuresis practice. patients requiring mechanical ventilation with a net-positive or -even cumulative fluid or clinical signs of fluid overload determined via chest x-ray or physical exam between april 1, 2018, and april 1, 2019, received the diuresis protocol (see additional file 1). inclusion and exclusion criteria are summarized in additional file 1. patients were assessed for inclusion and exclusion daily while in the icu. in order to approximate an experimental design using observational electronic health record (ehr) data, each patient visit within the intervention group was matched to three patient visits meeting the above inclusion and exclusion criteria from the historical time period of all medical icu admits between january 2016 and december 2017 who received furosemide. diuresis practices in the historical group were non-protocolized and left to physician discretion. patients who met the inclusion criteria from the historical cohort who were not matched with a patient from the intervention group were excluded from the analysis to prevent significant heterogeneity between groups. patient identification occurred by the clinical pharmacist 7 days per week in collaboration with the medical team. after identification of appropriate patients for inclusion a net 24 h fluid balance (ranging from − 1000 ml to − 3000 ml) was established during interdisciplinary rounds which was divided into three shift goal fluid balance targets to assess at 8-h intervals. upon establishment of goal, diuretic orders were entered, with dose selection based on previous diuretic exposure and baseline renal function. orders included conditional diuretic orders if shift fluid balance targets were not met, basic metabolic panels, goal parameters, and hold parameters for adverse events (see additional file 1). combination diuresis was permitted once the maximum dose of furosemide was reached (200 mg iv) or potential hypernatremia. available options included metolazone 10 mg oral or chlorothiazide 500 mg iv in instances when no enteral access was available. indications for continuous infusion diuresis included a lack of response to 200 mg or failure of sustained diuretic response resulting in failure to achieve goal fluid balance. in order to ensure appropriate compliance during overnight hours with decreased staffing ratios, an order set was created requiring nursing evaluation of urine output at the designated intervals. conditional medication orders could be activated by the bedside nurse based on individual patient response and pharmacistdriven goal parameters. diuresis hold parameters were established to minimize adverse events. the overall management of patients outside of diuresis protocol was left to physician discretion. given the paucity of evidence surrounding diuresis in this population, investigators involved in this study performed an interim analysis to promote a quality improvement corollary to the protocol. a data monitoring committee (dmc) was formed for data analysis after 50% of chronologic study completion. the dmc consisted of the division chief, independent statistical committee (isc), and non-committee physicians, pharmacists, and nursing. approximately 6 months from protocol initiation, the isc performed data extraction which was brought forward to the dmc, without statistical analysis. a protocol modification occurred per the request of the dmc (see additional file 1). this study protocol and modification were approved by the institutional review board. as this project was considered a quality improvement initiative, a waiver of informed consent was granted. the primary outcome of this study was the net cumulative fluid balance 72 h following shock resolution. secondary outcomes included icu mortality, icu length of stay, hospital length of stay, ventilator-free days, incidence of aki (defined by kdigo criteria), and the incidence of a severe metabolic disturbance including hypokalemia, hypernatremia, or de novo metabolic alkalosis, defined as a potassium < 3 mmol/l, sodium > 150 mmol/l, or bicarbonate > 40 mmol/l with a ph of > 7.50, respectively. ventilator-free days were defined as the number of days from day 1 to day 28 in which a patient was able to breathe without assistance with death as a competing risk with an assignment of zero free days. for time-dependent interventions, medication administration record medication scans were utilized for medication-related times, respiratory therapy documentation was utilized for ventilator therapy, while admission, transfer, and discharge orders were collected for durations of stay. from our previous study of diluent change in the medical icu, the average fluid balance in our patients at 72 h was positive 2.4 ± 5.1 l [15] . based on these data, we calculated a sample size of 104 patients in each group to achieve a ≥ 2-l decrease in fluid balance at 72 h postshock, maintaining an 80% power and an alpha of 0.05. continuous data were assessed for distribution and evaluated via t test or mann-whitney u, as appropriate. chi-square or fisher's exact were utilized for categorical data. data for analysis was pulled by a data analyst and validated with prospectively collected data, with discrepancies resolved by the analyst. the same inclusion and exclusion criteria used to enroll patients in the protocol were applied to selection of the control patients in the pre-protocol group. mahalanobis distance matching was used to measure similarities of each patient in the control and protocol group. age, gender, insurance type, home county classification, admission source, diagnosisrelated group (drg) weight, sequential organ failure assessment (sofa) score at time of diuresis initiation, baseline serum creatinine prior to first dose of furosemide, pre-diuretic fluid balance, time from ventilator to first diuretic administration, pre-diuretic vasopressor administration, chronic obstructive pulmonary disease (copd) diagnosis, and acute respiratory distress syndrome (ards) diagnosis were used as matching variables in the distance calculation. nearest neighbor matching was then used to select the three control visits "closest" to each protocol visit, based on the distance calculation. the utilization of drg was chosen by data analysis experts to bolster the validity of the severity of illness scores between groups. further, a test of interaction was performed for patient enrollment pre-and post-protocol modification regarding the magnitude of difference on 72 h fluid balance. a logistic regression model was defined a priori to be built for all-cause mortality. forward selection was utilized with variables included in the model if p < 0.05 in the univariate analysis or if deemed biologically plausible and clinically relevant. these initial variables incorporated into the model included sofa score, drg weight, age, intervention versus standard therapy assignment, mechanical ventilation time to initiation of first dose of furosemide, net cumulative fluid balance prior to furosemide, and vasoactive therapy. if the intervention group was not to be identified as a significant covariate, it was predetermined that such would be manually entered into the final model to ascertain the point estimate. collinearity was assessed with the use of variance inflation factors while goodness of fit was assessed with the hosmer-lemeshow test. given the potential for pertinent changes in clinical practice that are unrelated to the protocol, an interrupted time series was performed. further, given the subjective nature of the inclusion criterion clinical signs of fluid overload determined via chest x-ray or physical exam, a subgroup analysis was performed including only those included based on objective volume status (net positive cumulative fluid balance at furosemide start). a subgroup was also collected for pre-and post-protocol amendments to assure no significant impact on clinical outcome. over the study period, 832 patients met criteria for inclusion upon screening, of which, 741 were excluded based on pre-defined exclusion criteria (fig. 1) . a total of 273 standard therapy patients who met study criteria were matched 3:1 to patients in the intervention group (n = 91), for a total of 364 study patients. the matching procedures resulted in balanced groups, based on the pre-defined variables used in the matching algorithm (table 1 ). further, no major difference in other baseline clinical criteria was found with the exception of a higher arterial ph in the intervention group, as well as a higher incidence of rhabdomyolysis on admission (see additional file 1). no difference was demonstrated in the utilization of concomitant medications, other than a higher incidence of use of intravenous anti-viral medications in the protocol group (table 2) . regarding diuretic exposure, the diuresis protocol group received a higher dose of furosemide upon initiation, day 1-3, and cumulatively; however, diuretic dosing and patient response was variable (fig. 2 ). more patients in the protocol group received concomitant metolazone or acetazolamide therapy, while the standard therapy group had more adjunctive albumin use. the median (iqr) fluid balance within this study at 72-h post-shock resolution was 265 ml (− 2283-3025) vs − 2257 ml (− 5676-920) in the historical and interventional cohorts, respectively (p < 0.0001) ( table 3) . there was also a significant difference in 24-and 48-h fluid balance in the intervention group when compared to the historical cohort. the test of interaction demonstrated no statistical significance regarding those enrolled in the protocol before or after modification (see additional file 1), and the subgroup analysis excluding those patients based on subjective clinical criteria (physical exam findings, concern for pulmonary edema) showed similar findings (see additional file 1). in the interrupted time series accounting for potential practice variation over time, no significance was demonstrated relative to time before or after intervention (see additional file 1). however, a significant difference was demonstrated in 72-h post-shock fluid balance with protocol use (see additional file 1). for the secondary outcomes, while patients had an additional ventilator-free day in the intervention group, this difference was not statistically significant. within the intervention cohort, there was a statistically significant increase in the rate of electrolyte disturbances, primarily driven by an increase in hypernatremia and hypokalemia, despite higher total potassium replacement in the intervention group. in-hospital mortality in the intervention group was lower compared to the historical group (5.5% vs 16.1%; p = 0.008). there was also a higher rate of icu-free days, with these patients having 2 more days free of icu care (p = 0.03). in multivariable analysis, protocolized therapy was associated with a 75% (32-91%) decreased odds of hospital mortality after adjustment for sofa, fluid balance upon furosemide initiation, time on mechanical ventilation prior to furosemide therapy, and age (see additional file 1). given known limitations of serum creatinine as a marker of kidney function during acute illness, a post hoc analysis was performed of rrt dependence at discharge. rrt dependence at discharge was found to be significantly higher in the standard therapy cohort compared to the protocol group. regarding protocol compliance, a total of 204 patient days on protocol were available for evaluation. the most common indication for a furosemide hold was due to protocol discontinuation (see additional file 1). a total of 27 deviations occurred within the 204 patient days, 8 for a decrease in dosing frequency prior to protocol modification, 2 for doses administered despite hold criteria, 2 missed nursing activations of conditional orders, and 12 inappropriate holds, 7 of which for unknown reasons, 1 for nursing concern regarding furosemide interval, and 4 for urine output. eighteen patient days required a dose adjustment per protocol, 11 of which were driven by conditional orders. this study was the first to evaluate a volume deresuscitation protocol utilizing pharmacologic diuresis in the medical intensive care unit. this study has several strengths, including the protocol with easily obtainable bedside monitoring parameters within the ehr, the multi-disciplinary approach to protocol development, fig. 1 selection of patients for study population utilization, and modification, frequency of monitoring, and selection of matching parameters. several potential confounders on 72-h fluid balance were matched between groups, systematically decreasing between-group difference. further, results of the interrupted time series showed no significant difference in slopes of fluid balance over time, while the association between improved 72-h post-shock fluid balance and intervention group remained significant (fig. 3) . we demonstrated a significant decrease in 72 h cumulative fluid volume with the addition of a diuresis protocol in the critically ill. this correlates with previous protocols within acute respiratory distress syndrome and heart failure which demonstrated improved volume status with strategized diuresis without an increase in kidney failure [11, 14] . unlike studies within the heart failure population, our protocol prioritized intermittent dosing to decrease intravenous access concerns and protocolized electrolyte and safety monitoring [14] . with such, a significant increase in the rate of hypernatremia and hypokalemia was seen within the intervention group. no statistically significant difference in duration of mechanical ventilation wean was found. this does not correlate with previous evidence within the critically ill population, demonstrating increased ventilator-free days with conservative volume management [14] . comparatively, while our study utilized more specific titration strategies and common bedside monitoring parameters, this was a single-center, nonrandomized study and likely underpowered to detect a difference in ventilator duration. key considerations to this study include a decrease in mortality and increased icu-free days in the intervention group. known correlates of mortality within the sepsis population, including baseline weight and admission source, were included as parameters within the regression model [16] [17] [18] . the variables previously correlated with mortality were accounted for in the matching criteria of this cohort. studies demonstrate that almost ubiquitous organ dysfunction has been associated with positive volume status in the icu. it is possible that the implication of volume de-resuscitation seen in the current study could be casually linked with mortality, in line with a vast number of previous studies demonstrating the impact of fluid status on survival rates aside of its effect on ventilator days; however, this study can only show correlation given the nature of its design. particularly, patients in the intervention group also had a decrease in rrt dependence at discharge. rrt receipt prior to hospital discharge has been associated with progression to end stage renal disease, cardiovascular disease, and increased mortality [19, 20] . regarding ventilator days, ventilation wean procedures are not standardized at this institution. daily spontaneous breathing trials are performed in all patients who meet criteria; however, extubation orders are left to provider discretion. this lack of ventilator wean protocolization may have affected ventilator-free days between groups. however, reintubation rates were in alignment with previous studies with ranges 13.8-22.6% and were not significantly different between groups which supports relative uniformity on wean strategies [21] . further of note, changes to the institutional nursingdriven electrolyte replacement protocol occurred midimplementation (see additional file 1). the protocol modification sought more aggressive potassium replacement; however, nursing adherence was not evaluated. as follow-up potassium evaluations were mandated with protocol implementation, it is possible that incidences of hypokalemia were increased secondary to more frequent monitoring relative to the historical cohort; however, frequency of serum potassium collections were not recorded. in regard to rates of hypernatremia, providers were permitted to request continuation of furosemide despite elevated sodium levels, likely resulting in the subsequent increased rate of metolazone use in the intervention group. there was a significant difference in cumulative fluid balance that was likely due to higher furosemide exposure in the intervention group, as demonstrated in previous protocols of furosemide in acute kidney injury [10] . the significant increase in episodes of hypernatremia and hypokalemia are predictable and reversible within this strategy. if replicated in future randomized trials, improvements in icu length of stay and mortality may take precedence over concern for electrolyte abnormalities. future protocol designs should account for these episodes of hypernatremia and hypokalemia with creation of more explicit electrolyte replacement rules. further, electrolyte derangements may be of greater consideration in an alternative icu population, including cardiothoracic/cardiology critical care. patient-specific factors should be taken into consideration with implementation of this protocol. a key limitation to this study is the lack of randomization and blinding. given the nature of the protocol, blinding to the medical staff was not possible. a pre-and post-intervention study was chosen given the lack of blinding. it was anticipated that an overall change in practice may occur over the study timeframe given increased awareness of the detrimental effects of fluid overload and approach to diuretic dosing in critically ill patients, a phenomenon recently found in management of septic shock [22, 23] . however, given the limited time lapse between the historical group and protocol implementation and lack of emergence of guidelines regarding volume de-resuscitation, changes in overall approaches to care based on external factors were unlikely. to limit potential bias further, patients were matched on a large number of relevant variables and objective outcome measures were utilized, with the exception of the drg weight. however, the authors opted for inclusion of this variable versus international classification of disease coding given its consideration for up to eight diagnoses, including the primary diagnosis, and up to six procedures performed during the stay, likely increasing its objectiveness versus retrospective chart review. regardless, it is still possible for potential residual confounders on illness severity to have been missed. given that volume overload and positive fluid balance may be markers of severity of illness rather than a parameter for early diuresis intervention, the differences in mortality and length of stay must be replicated in a larger, randomized controlled trial for confirmation. worth nothing, true blinding in a randomized controlled trial would likely be unfeasible by nature of the protocol design and a parallel design could subject the trial to potential for a significant hawthorne effect. protocol modifications in the study may also be seen as a potential limiting factor. however, in the subgroup analysis performed, protocol inclusion did not appear to significantly impact the primary result. additionally, the inclusion rate appeared relatively low at 11%. recent studies have demonstrated small recruitment rates within the critically ill [24, 25] . a significant portion of our patients were excluded for active vasoactive therapy or aki. clinical inertia is a consideration, particularly given this protocol's pilot nature. further, consideration must be made for a lag in adaptation, particularly in times of low staffing. lastly, the selection of outcome parameters is worth mentioning. we evaluated 72-h net cumulative fluid balance in accordance with previous literature; however, evidence suggests that fluid balance documentation is not always accurate. the utilization of ehr flowsheets decreases potential for error in icu documentation. the frequency in documentation required via the protocol aligns with standard of care within the icu. recent studies have challenged the validity of net cumulative fluid balance in the icu and its relationship to body weight or clinical signs of fluid overload [26, 27] . because this practice is not tightly protocolized, we did not utilize body weight as a monitoring parameter. however, it is possible that this study demonstrated that a pharmacist-driven diuresis protocol of volume de-resuscitation was significantly associated with a lower cumulative fluid balance at 72 h post-shock. the addition of the diuresis protocol was likely effective for a multitude of reasons, including the overall increased awareness of avoidance of volume overload and tailored diuresis utilization, the standardization of doses and follow-up monitoring, as well as an increase in furosemide dosing as demonstrated in this study. however, with increased dosing of furosemide, increased rates of adverse events were found, namely hypernatremia and hypokalemia. risk versus benefit of active volume de-resuscitation and electrolyte fluctuations must be considered. the increased mortality and decreased number of icu-free days in the standard therapy group are hypothesis-generating, particularly given the lack of difference between-groups in ventilator-free days. using a diuresis protocol for volume de-resuscitation, we demonstrated a significant decrease in net cumulative fluid balance at 72 h following shock resolution, with potential benefit on clinical outcomes including renal recovery, mortality, and icu length of stay. although this study supports the implementation of a diuresis protocol in the icu, larger randomized controlled trials are needed to confirm or refute the potential benefits of de-resuscitation, through protocol-driven diuresis, on important patient centered outcomes, such as icu length of stay, ventilator-free days, and in-hospital mortality, as suggested by observed associations in the present study. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-2795-9. additional file 1. supplementary digital content this file includes relevant study protocols, definitions, as well as subgroup analyses and additional informational tables beyond manuscript content. higher fluid balance increases the risk of death from sepsis: results from a large international audit fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: a systematic review fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluidrelated medical interventions and hospital death pharmacological management of fluid overload fluid overload fades away! time for fluid stewardship fluid-management strategies in acute lung injury--liberal, conservative, or both? relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: insights from the dose trial successful weaning from continuous renal replacement therapy. associated risk factors the effect of low-dose furosemide in critically ill patients with early acute kidney injury: a pilot randomized blinded controlled trial (the spark study) a diuretic protocol increases volume removal and reduces readmissions among hospitalized patients with acute decompensated heart failure protocol-guided diuretic management: comparison of furosemide by continuous infusion and intermittent bolus frusemide administration in critically ill patients by continuous compared to bolus therapy comparison of two fluidmanagement strategies in acute lung injury insidious harm of medication diluents as a contributor to cumulative volume and hyperchloremia: a prospective, open-label, sequential period pilot study icu admission source as a predictor of mortality for patients with sepsis does obesity protect against death in sepsis? a retrospective cohort study of 55,038 adult patients unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates high incidence of transition to esrd in patients discharged with dialysis dependent aki: the cleveland clinic experience. presented in poster format at kidney week predictors of long-term prognosis in acute kidney injury survivors who require continuous renal replacement therapy after cardiovascular surgery a comparison of four methods of weaning patients from mechanical ventilation. spanish lung failure collaborative group early goal-directed therapy in the treatment of severe sepsis and septic shock goal-directed therapy for septic shock -a patient-level meta-analysis recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the united kingdom health technology assessment programme effect of hydrocortisone on development of shock among patients with severe sepsis: the hypress randomized clinical trial fluid balance in critically ill patients. should we really rely on it? estimation of fluid status changes in critically ill patients: fluid balance chart or electronic bed weight? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank the physician and nursing staff and leadership who played an integral part in the implementation and improvement of the project.authors' contributions bb and ml designed the protocol. af, bb, ml, and mt assisted in the patient enrollment and data collection. af, bb, ml, mt, and jp collected the data. ak and jr assisted in the statistical analysis and retrospective data collection. jn and pm assisted with the protocol implementation and paper design. all authors read and approved the final manuscript. financial support for this study was provided by the american society of health-systems pharmacists foundation new investigator grant. the datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request. ethics approval and consent to participate this work was performed at the university of kentucky healthcare. institutional review board approval was received (medxp protocol 42820). not applicable. the authors declare that they have no competing interests.author details 1 key: cord-028337-md9om47x authors: ketcham, scott w.; sedhai, yub raj; miller, h. catherine; bolig, thomas c.; ludwig, amy; co, ivan; claar, dru; mcsparron, jakob i.; prescott, hallie c.; sjoding, michael w. title: causes and characteristics of death in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: a retrospective cohort study date: 2020-07-03 journal: crit care doi: 10.1186/s13054-020-03108-w sha: doc_id: 28337 cord_uid: md9om47x background: acute hypoxemic respiratory failure (ahrf) and acute respiratory distress syndrome (ards) are associated with high in-hospital mortality. however, in cohorts of ards patients from the 1990s, patients more commonly died from sepsis or multi-organ failure rather than refractory hypoxemia. given increased attention to lung-protective ventilation and sepsis treatment in the past 25 years, we hypothesized that causes of death may be different among contemporary cohorts. these differences may provide clinicians with insight into targets for future therapeutic interventions. methods: we identified adult patients hospitalized at a single tertiary care center (2016–2017) with ahrf, defined as pao(2)/fio(2) ≤ 300 while receiving invasive mechanical ventilation for > 12 h, who died during hospitalization. ards was adjudicated by multiple physicians using the berlin definition. separate abstractors blinded to ards status collected data on organ dysfunction and withdrawal of life support using a standardized tool. the primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. results: we identified 385 decedents with ahrf, of whom 127 (33%) had ards. the most common primary causes of death were sepsis (26%), pulmonary dysfunction (22%), and neurologic dysfunction (19%). multi-organ failure was present in 70% at time of death, most commonly due to sepsis (50% of all patients), and 70% were on significant respiratory support at the time of death. only 2% of patients had insupportable oxygenation or ventilation. eighty-five percent died following withdrawal of life support. patients with ards more often had pulmonary dysfunction as the primary cause of death (28% vs 19%; p = 0.04) and were also more likely to die while requiring significant respiratory support (82% vs 64%; p < 0.01). conclusions: in this contemporary cohort of patients with ahrf, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. the vast majority of deaths occurred after withdrawal of life support. ards patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ards. conclusions: in this contemporary cohort of patients with ahrf, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. the vast majority of deaths occurred after withdrawal of life support. ards patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ards. keywords: acute respiratory distress syndrome, acute hypoxemic respiratory failure, mortality, cause of death background acute hypoxemic respiratory failure (ahrf) is among the most common causes of critical illness, with a hospital mortality of approximately 30% [1] . in patients meeting the definition of acute respiratory distress syndrome (ards), mortality is approximately 40% [2] . however, while ahrf and ards are each defined by severe hypoxemia and associated with high mortality, death due to refractory hypoxemia is reportedly rare. in cohorts of ards patients treated in the 1990s, only 13-19% of deaths were due to refractory hypoxemia, while deaths due to multi-organ failure from sepsis were the cause of up to 50% of deaths [3] . these findings suggested that therapies focused on reducing the complications of sepsis would have a greater impact at improving ards survival than therapies for severe hypoxia. since the 1990s, however, cause of death specifically related to organ system dysfunction has not been described despite substantial evolution in critical care practices. ventilator management now focuses on minimizing ventilatorinduced lung injury, as opposed to normalizing oxygenation and ventilation [4] , which may have led to further reduction in death due to refractory hypoxemia. in addition, there has been growing attention to minimization of sedation, early mobilization, and sepsis recognition and treatment, the latter of which may mitigate mortality due to sepsis [5] [6] [7] [8] . finally, there has been an increased focus on palliative care in the intensive care unit (icu), which may lead to earlier treatment limitations [9] [10] [11] . because of these changes in practice and how they may affect causes of death in the icu, we hypothesized that causes of death among ahrf and ards patients may be different from historical cohorts. an updated understanding of the causes of death in these populations would help identify the most important targets for new therapies and help direct future investigation to improve survival. we sought to determine the causes and circumstances of death in a contemporary cohort of ahrf patients, and assess whether causes of death differed among patients with and without ards. we performed a retrospective cohort study of adult patients (aged ≥ 18 years) hospitalized at michigan medicine (january 1, 2016, to december 30, 2017) with ahrf who experienced in-hospital death. patients were identified via an electronic query tool of the electronic health record. as in prior studies [12, 13] , patients were defined as having ahrf when the following criteria were met: (1) receipt of invasive mechanical ventilation for at least 12 h (to exclude routine post-operative ventilation) in the medical, surgical, cardiac, trauma, or neurologic icu, and (2) a pao 2 /fio 2 ratio ≤ 300. lowtidal volume ventilation and protocols for daily awakening and spontaneous breathing trials for mechanically ventilated patients were employed [14] . demographics, comorbidities, highest sequential organ failure assessment (sofa) score within the first 24 h of ahrf onset, the lowest glasgow coma scale during the 72 h prior to death, and icu setting were also collected from the electronic health record through use of the electronic query tool. patients were classified as having ards by multiple physician adjudication as part of a prior study [12] . specifically, two critical-care trained physicians reviewed each ahrf hospitalization to determine whether patients met berlin criteria [15, 16] for ards: (1) new or worsening respiratory symptoms began within 1 week of a known clinical insult, (2) pao 2 /fio 2 ≤ 300 while receiving a positive end-expiratory pressure ≥ 5 cm h 2 o, (3) bilateral opacities on chest x-ray, (4) unlikely to be cardiogenic pulmonary edema, and (5) no other explanation for these findings. disagreement between physicians was resolved by a third physician in 21% of patients [12] . in addition to ards status, specific ahrf or ards risk factors were collected as part of the prior study (pneumonia, aspiration, non-pulmonary sepsis, non-cardiogenic shock, major trauma, major surgery, transfusion, pancreatitis, major burn, inhalation injury, vasculitis, pulmonary contusion, drowning, or none) [12] . patients transferred from another hospital were excluded as we were unable to reliably determine ards status, ahrf risk factors, or illness severity on presentation. patient data were reviewed by one of 5 internal medicine-trained physicians who did not participate in the adjudication of ards and were blinded to adjudicated ards status. data regarding causes and circumstances of death were collected using a structured abstraction form (appendix 1, online supplement). specifically, we abstracted presence and severity of sepsis, presence and severity of organ system dysfunction, withdrawal of life-sustaining treatments, and cause of death, as described further below. all data required for abstractions were available in the electronic medical record. to ensure consistency across reviewers, excellent inter-rater reliability was demonstrated on an initial test set of 10 charts (appendix 2, online supplement). for each patient, we assessed for sepsis and dysfunction of 8 organ systems during the 72 h prior to death. we classified sepsis and each organ dysfunction as severe or irreversible using definitions from a prior study by stapleton et al. [3] , with the following changes (table 1) . we changed the sepsis definition to align with sepsis-3 (appendix 3, online supplement). in addition, we changed the definition of severe pulmonary dysfunction from specific diagnoses (ards, bilobar pneumonia, bronchopleural fistula, or pulmonary embolism) to receipt of significant respiratory support (high-flow oxygen, invasive mechanical ventilation, or non-invasive positive-pressure ventilation) to better capture patients with severe pulmonary dysfunction. if a patient underwent withdrawal of life support before meeting any of the objective organ dysfunction criteria outlined in table 1 , abstractors were instructed to assign irreversible dysfunction to the organ system primarily responsible for the decision to withdraw life support in order to accurately capture cause of death (appendix 4, online supplement). finally, as in stapleton et al., we defined multi-organ failure as organ dysfunction in at least two organ systems [3] . for each patient, we assessed (1) the primary organ system responsible for death, (2) whether death was related to progression of an initial ahrf risk factor or a complication after ahrf, and (3) whether withdrawal of life support occurred prior to death. the primary organ system responsible for death was defined as the organ dysfunction ( table 1 ) that most directly resulted in the patient's death or the decision to withdraw life support (appendix 5, online supplement). for patients with a primary cause of death other than pulmonary dysfunction, cause of death was further classified as being due to progression of an ahrf risk factor (e.g., sepsis, aspiration) or a complication that arose after ahrf onset (appendix 4, online supplement). withdrawal of life support was determined from clinical documentation of intent to withdraw life support and/or not escalate life support in the event of clinical decompensation and subsequent removal or nonescalation of life-sustaining interventions. we present data as numbers (proportions) or medians (inter-quartile range). we compared characteristics of ards vs non-ards patients using chi-square and kruskal-wallis tests and considered p < 0.05 to be significant. data analysis was completed in r. the study was deemed exempt by the institutional review board since all patients were deceased. we identified 385 adult patients with ahrf who died during a hospitalization in 2016-2017, of whom 127 (33%) had ards. the cohort was a median age of 63 years (55-73), 43% female, 82% white, and had a median sofa score of 12 (10) (11) (12) (13) (14) at ahrf onset. most patients were admitted to a medical icu (59%). patients had a median of 2 (1-3) risk factors for ahrf, most commonly non-cardiogenic shock (59% of patients), transfusion (41%), sepsis (39%), and pneumonia (37%, table 2 ). patients with ards had a higher median sofa score within the first 24 h of ahrf onset (14 vs 12; p = 0.002) and had higher prevalence of pneumonia (52% vs 30%; p < 0.001), aspiration (22% vs 12%; p = 0.01), and noncardiogenic shock (78% vs 50%; p < 0.001) compared to patients who did not meet the berlin definition of ards (table 2) . among the 385 patients, there were 1154 occurrences of organ system dysfunction in the 72 h prior to death (etable 1, online supplement). there were 101 (26.2%) patients that had multiple organ systems with irreversible dysfunction. the most common organ system dysfunctions were pulmonary (70%), neurologic (39%), and cardiac (29%). sepsis was present in 273 (71%) patients and 214 patients (56%) had multi-organ failure prior to death. however, irreversible pulmonary dysfunction was only present in 19 (5%) patients (table 3 )-7 (2% of all patients) with insupportable oxygenation or ventilation, and 12 patients with withdrawal of life support because of a poor pulmonary prognosis. patients with ards higher rates of sepsis (84% vs 64%; p < 0.001), pulmonary dysfunction (82% vs 64%; p < 0.001), irreversible pulmonary dysfunction (9% vs 3%; p = 0.004), and hematologic dysfunction (41% vs 26%; p = 0.003) compared to patients without ards. overall, the most common primary causes of death were sepsis (26%), pulmonary dysfunction (22%), and neurologic dysfunction (19%, fig. 1 ). among the 302 patients whose primary cause of death was not pulmonary dysfunction, 212 (55% of all patients) died primarily due to progression of an ahrf risk factor and 90 (23%) died primarily due to complications that arose after the onset of ahrf (table 4 ). cause of death by icu setting can be found in etable 2 in the supplementary appendix, with some variation in causes of death noted. ards patients were more likely to have a primary cause of death due to pulmonary dysfunction (28% vs 19%; p = 0.04) compared to patients without ards and less likely to have a primary cause of death from cardiac dysfunction (10% vs 19%; p = 0.03, table 4 ). in addition, ards patients were also more likely to die while receiving substantial respiratory support (82% vs 64%; p < 0.001). the majority of patients (85%) died after withdrawal of life support. the proportion of deaths that occurred after withdrawal of life support did not differ between patients with and without ards (87% vs 84%; p = 0.58, table 4 ). in this contemporary cohort of 385 adult patients with ahrf, the most common primary causes of death were sepsis, pulmonary dysfunction, and neurologic dysfunction. the majority of patients had multi-organ failure prior to death, most commonly due to sepsis. more than half of patients were receiving substantial respiratory support at the time of death and the vast majority of patients died after withdrawal of life support. sepsis and pulmonary dysfunction were the top two primary causes of death among both patients with and without ards. our study is consistent with prior reports indicating that sepsis is the leading cause of death among patients with respiratory failure. stapleton et al. found that sepsis was the most common cause of death in ards patients pulmonary°inability to liberate from mechanical ventilation, non-invasive ventilation, or heated high flow nasal cannula due to inadequate oxygenation or ventilation without aforementioned support insupportable oxygenation or ventilation defined as pao 2 < 40 mmhg on fio 2 -1.0 for > 2 h or respiratory acidosis with ph < 7.1 on maximum ventilator settings ∞ . option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to pulmonary organ system dysfunction. either cardiac output < 2.0 l/min/m 2 or documented cardiogenic shock or reversible ventricular fibrillation or asystole cardiogenic shock or arrhythmia not responsive to treatment. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to cardiac organ system dysfunction. glasgow coma scale < 8 for ≥ 3 days meets brain death criteria. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to neurologic organ system dysfunction. microvascular bleeding with either fibrinogen < 100 mg/dl, prothrombin time and partial thromboplastin time > 1.5 times control, or platelets < 60, 000/μl ongoing microvascular bleeding not surgically correctable with map < 65 mmhg not reversible with blood products. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to hematologic organ system dysfunction. hemorrhage map < 65 mmhg for > 2 h (or requiring vasopressors) necessitating blood transfusions and excluding other causes of hypotension uncontrollable "surgical" bleeding from a non-microvascular source. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to hemorrhage. hepatic bilirubin > 5.0 mg/dl and albumin < 2.0 g/dl and prothrombin time or partial thromboplastin time > 1.5 times control severe criteria plus hepatic encephalopathy and/or hepatorenal syndrome not responsive to treatment. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to hepatic organ system dysfunction. gastrointestinal resectable ruptured or necrotic bowel, or pancreatitis causing shock (map < 65 mmhg for > 2 h or requiring vasopressors) inoperable ruptured or necrotic bowel or pancreatitis causing irreversible shock. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to gastrointestinal organ system dysfunction. either creatinine > 5.0 mg/dl or requiring hemodialysis renal failure with acidosis, hyperkalemia, and/or hypercalcemia causing irreversible cardiac arrest. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to renal organ system dysfunction. *definition of sepsis changed to reflect current practices. please see appendix 3, online supplement for previous definition of severe and irreversible sepsis syndrome°d efinition of severe pulmonary organ system dysfunction changed to reflect current practices. previously defined by stapleton et al. as "[acute respiratory distress syndrome], bilobar pneumonia, bronchopleural fistula, or pulmonary embolism documented by high-probability ventilation/perfusion scan or pulmonary angiogram" ∞ pao 2 arterial partial pressure of oxygen, fio 2 fraction of inspired oxygen † blood pressure parameters previously described by stapleton et al. as "hypotension" for irreversible hematologic organ system dysfunction or "systolic bp < 80" for severe hemorrhagic and gi organ system dysfunction changed to "map < 65 mmhg" treated in the 1990s [3] . despite increased attention to earlier identification and treatment of sepsis in the intervening decades [17, 18] , our study found that sepsis remained the most common cause of death in ahrf patients. this is consistent with recent studies showing that sepsis is the leading contributor to death among patients hospitalized for any cause [19] . sepsis was slightly more common in patients with ards than those without ards, which may reflect the higher rates of pneumonia and sepsis as risk factors for ards. however, it may also suggest that ards patients are at a heightened risk for secondary infections compared to patients without ards. these findings suggest that therapies targeting sepsis-induced multi-organ dysfunction may have the greatest impact on survival among ahrf patients. we found only small differences in the causes and circumstances of death among ahrf patients with and without ards. patients with ards were more likely to have a pulmonary dysfunction as the primary cause of death and more likely to die while receiving substantial pulmonary support than patients without ards. this indicates that the berlin ards definition identifies a subset of patients with ahrf who are more likely to die directly from respiratory failure and would benefit from therapies to enhance resolution of respiratory failure. however, the difference in rates of pulmonary dysfunction as the primary cause of death was relatively small among patients with and without ards. our study confirms the findings in prior studies indicating that insupportable oxygenation and/or ventilation is rare among patients with respiratory failure. one of the major findings of stapleton et al.'s study was the relatively low proportion of deaths due to insupportable ahrf acute hypoxemic respiratory failure, ards acute respiratory distress syndrome *sofa sequential organ failure assessment. represents the highest sofa score within the first 24 h of ahrf onset † other risk factors for ards/ahrf, each present in < 10% of the cohort, include major trauma (9%), major surgery (7%), pulmonary contusion (3%), pancreatitis (2%), major burn (1%), inhalation injury (1%), vasculitis (< 1%), or drowning (0%) oxygenation or ventilation, occurring in only 13-19% [3] . given the increased awareness and effort to treat sepsis in the period after this original study, we hypothesized that pulmonary dysfunction may be a more common primary cause of death in a contemporary ahrf cohort. however, we found that only 22% of patients had pulmonary dysfunction as the primary cause of death, and only a handful of patients (2%) had insupportable oxygenation and/or ventilation. there are several potential explanations for these findings. first, with more consistent use of lung protective ventilation, contemporary ahrf patients may be less likely to develop ventilator induced lung injury and progressive respiratory failure [20] . second, patients with severe ards may be more likely to be initiated on extra-corporeal membrane oxygen therapy prior to developing refractory pulmonary dysfunction [21] . finally, other strategies such as prone positioning may prevent refractory hypoxemia [22] . however, these hypotheses do not explain why a similar proportion of patients still ultimately die from respiratory failure despite not developing insupportable oxygenation and/or ventilation. while some patients may be supported through the initial phase of their respiratory failure, eventually life support is withdrawn when providers are unable to completely reverse their need for significant respiratory support. our study also highlights the increasing proportion of deaths that occur after a decision to withdraw or not escalate life support. stapleton et al. showed that from 1981 to 1998, the proportion of ards deaths that occurred after withdrawal of life support rose from 40 to 67% [3] . similar trends have been reported for all-cause critically ill patients during this time period [9] . our study suggests that this trend has continued, as we report that 85% of all deaths among ahrf are now occurring after a decision to withdraw or not escalate life support. our finding is also consistent with a recent study showing that 90% of deaths among critically ill patients treated in europe from 2015 to 2016 occurred in the setting of treatment limitations [23] . there are likely several explanations for why a growing proportion of deaths occur after withdraw of life support. stapleton et al. hypothesized that icu clinicians have earlier and more frequent goals-of-care discussions [3] , as is recommended in various clinical practice guidelines [17] . indeed, early multidisciplinary meetings with patients and families may lead to an earlier transition to palliative care among patients likely to die [24, 25] . more recently, there has been increased emphasis on family involvement in icu decision-making and treatment planning, for example, as recommended in the abcdef treatment bundle [26] . overall, the greater emphasis on family involvement in early shared decision making may contribute to earlier transitions to palliation among patients who ultimately die in the icu [27] . our study has several limitations. first, as a singlecenter study, it is possible that it may be lacking generalizability. however, we examined all deaths among patients with ahrf over a 2-year period who were treated in 5 distinct icus with different practice patterns. as such, we believe these findings are more broadly applicable. second, while we tried to harmonize our study definitions to those of stapleton et al. to facilitate cross-study comparisons, some changes had to be made to account for interval changes in definitions (e.g., sepsis) and treatments (e.g., high-flow oxygen). we limited deviations in study definitions to those deemed absolutely necessary to reflect the current state of icu practice. third, patients were classified as having undergone withdrawal of life support regardless of the time lag between withdrawal and death. for patients in whom only minutes elapsed between withdrawal of support and death, death may be more accurately representative of the cessation of medical interventions due to futility. however, our approach for determining rates of withdrawal and the rates of withdrawal we observed are consistent with prior reports [9] . fourth, given a high rate of withdrawal of life support, the most proximate cause of death is cessation of support. however, our methodology identifies which organ dysfunction or syndrome most directly led to that decision, thereby reflecting the primary pathophysiologic cause of death. fifth, there may be some subjectivity to assigning cause of death. however, we developed a standardized approach to assess causes of death based on the presence of irreversible and severe organ dysfunctions and confirmed excellent interrater reliability in identifying the primary cause of death among reviewers, which serves to strengthen the validity of our methodology. furthermore, chart review was performed by physicians only, as medical training may limit the subjectivity in identifying cause of death. in this contemporary cohort study of 385 patients who died after ahrf, the most common primary causes of death were sepsis and pulmonary dysfunction. few patients had insupportable oxygenation or ventilation, but most received substantial respiratory support in the 72 h prior to death. the vast majority of deaths occurred after a decision to withdraw or not escalate life support. patients with ards were more likely to have a primary cause of death of pulmonary dysfunction and to receive substantial respiratory support during the 72 h prior to death. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03108-w. additional file 1: appendix 1. redcap abstraction tool. appendix 2. inter-rater reliability. appendix 3. previous definition of severe and irreversible sepsis syndrome. appendix 4. examples. appendix 5. determining cause of death by organ system. etable 1. total organ system dysfunction. etable 2. cause of death by icu setting. abbreviations ahrf: acute hypoxemic respiratory failure; ards: acute respiratory distress syndrome; icu: intensive care unit; sofa: sequential organ failure assessment the epidemiology of acute respiratory failure in critically iii patients epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries causes and timing of death in patients with ards an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial a binational multicenter pilot feasibility randomized controlled trial of early goal-directed mobilization in the icu early intensive care unit mobility therapy in the treatment of acute respiratory failure increasing incidence of withholding and withdrawal of life support from the critically ill palliative care in intensive care units: why, where, what, who, when, how the changing role of palliative care in the icu interobserver reliability of the berlin ards definition and strategies to improve the reliability of ards diagnosis differences between patients in whom physicians agree and disagree about the diagnosis of acute respiratory distress syndrome evaluating delivery of low tidal volume ventilation in six icus using electronic health record data acute respiratory distress syndrome: the berlin definition the berlin definition of ards: an expanded rationale, justification, and supplementary material surviving sepsis campaign: international guidelines for management of sepsis and septic shock the third international consensus definitions for sepsis and septic shock (sepsis-3) hospital deaths in patients with sepsis from 2 independent cohorts comparison of the berlin definition for acute respiratory distress syndrome with autopsy extracorporeal life support organization registry report 2012 prone positioning in severe acute respiratory distress syndrome changes in end-of-life practices in european intensive care units from 1999 to an intensive communication intervention for the critically ill impact of a proactive approach to improve end-of-life care in a medical icu the abcdef bundle in critical care limitation of life-sustaining care in the critically ill: a systematic review of the literature publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank daniel molling, ms, of va ccmr, for his careful data analysis. authors' contributions sk made substantial contributions to the conception and design of the work, acquisition, analysis, and interpretation of the data, and drafted and substantively revised the work. ys, hm, tb, aw, ic, dc, and jm made substantial contributions to the acquisition of data. hp made substantial contributions to the conception and design of the work, analysis, and interpretation of the data and drafted and substantively revised the work. ms made substantial contributions to the conception and design of the work, acquisition, analysis, and interpretation of the data and drafted and substantively revised the work. all authors have approved the submitted version and have agreed both to be personally accountable for the authors' own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. dr. prescott was supported in part by k08 gm115859 from the nih/nigms. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. this study was approved by the university of michigan institutional review board. this study does not involve living individuals and therefore consent was waived. competing interests this material is the result of work supported with resources and use of facilities at the ann arbor va medical center. this manuscript does not represent the views of the department of veterans affairs or the us government. the authors declare that they have no competing interests. key: cord-000086-bnkbwh3w authors: kneyber, martin cj; van heerde, marc; twisk, jos wr; plötz, frans b; markhors, dick g title: heliox reduces respiratory system resistance in respiratory syncytial virus induced respiratory failure date: 2009-05-15 journal: crit care doi: 10.1186/cc7880 sha: doc_id: 86 cord_uid: bnkbwh3w introduction: respiratory syncytial virus (rsv) lower respiratory tract disease is characterised by narrowing of the airways resulting in increased airway resistance, air-trapping and respiratory acidosis. these problems might be overcome using helium-oxygen gas mixture. however, the effect of mechanical ventilation with heliox in these patients is unclear. the objective of this prospective cross-over study was to determine the effects of mechanical ventilation with heliox 60/40 versus conventional gas on respiratory system resistance, air-trapping and co2 removal. methods: mechanically ventilated, sedated and paralyzed infants with proven rsv were enrolled within 24 hours after paediatric intensive care unit (picu)admission. at t = 0, respiratory system mechanics including respiratory system compliance and resistance, and peak expiratory flow rate were measured with the avea ventilator. the measurements were repeated at each interval (after 30 minutes of ventilation with heliox, after 30 minutes of ventilation with nitrox and again after 30 minutes of ventilation with heliox). indices of gas exchange (ventilation and oxygenation index) were calculated at each interval. air-trapping (defined by relative change in end-expiratory lung volume) was determined by electrical impedance tomography (eit) at each interval. results: thirteen infants were enrolled. in nine, eit measurements were performed. mechanical ventilation with heliox significantly decreased respiratory system resistance. this was not accompanied by an improved co2 elimination, decreased peak expiratory flow rate or decreased end-expiratory lung volume. importantly, oxygenation remained unaltered throughout the experimental protocol. conclusions: respiratory system resistance is significantly decreased by mechanical ventilation with heliox (iscrtn98152468). respiratory syncytial virus (rsv) is the most important causative agent of lower respiratory tract disease (lrtd) in infancy [1] . approximately 100,000 infants are annually admitted with rsv-induced bronchiolitis in the usa, and the number of hospitalizations is increasing [2] . because of this, rsv-associated disease imposes a major burden on health care resources [3] . there is no effective therapy against rsv available, prevention can only be achieved through passive immunisation using monoclonal antibodies [4] . rsv lrtd is pathophysiologically characterized by sloughed necrotic epithelium, excessive mucus secretion, bronchial mucosal oedema and peribronchial inflammation that contributes to airway obstruction resulting in increased airway resistance with subsequent air-anova: analysis of variance; ards: acute respiratory distress syndrome; co 2 : carbon dioxide; cstat: static compliance; eelv: end-expiratory lung volume; eit: electrical impedance tomography; elisa: enzyme-linked immunosorbent assay; et-co 2 : end-tidal carbon dioxide; fio 2 : fraction of inspired oxygen; lrtd: lower respiratory tract disease; map: mean airway pressure; mv: mechanical ventilation; oi: oxygenation index; paco 2 : partial pressure of arterial carbon dioxide; pao 2 : partial pressure of arterial oxygen; peep: positive end-expiratory pressure; pefr: peak expiratory flow rate; picu: paediatric intensive care unit; pip: positive inspiratory pressure; ptrach: intratracheal pressure; relative δ eelv : relative change in end-expiratory lung volume; rlung: lung resistance; rrs: respiratory system resistance; rsv: respiratory syncytial virus; spo 2 : oxygen saturation; v d : dead space; vi: ventilation index; vte: expiratory tidal volume. trapping and respiratory acidosis [5, 6] . although the majority of infections run a mild disease course, mechanical ventilation (mv) for up to 10 days is necessitated in approximately 2% to 16% of previously healthy hospitalised infants due to severe lower respiratory tract infection including bronchiolitis or pneumonia [1, 7, 8] . helium is an inert gas with a density that is one-seventh that of air. in addition, carbon dioxide (co 2 ) diffuses more easily through helium than through air [9] . with helium, a more laminar flow is preserved in narrowed airways, resulting in lower resistance to gas flow allowing for increased bulk flow [10] . based on these properties, mv with heliox could be considered in mechanically ventilated infants with rsv lrtd. its use in these patients has been studied once but with inconclusive results [11] . we hypothesized that the use of heliox in mechanically ventilated infants with rsv lrtd would result in decreased respiratory system resistance (r rs ). in addition, mv with heliox would result in less air-trapping defined by the relative change in end-expiratory lung volume (eelv), and improved co 2 clearance. the objective of our study was to test this hypothesis in a prospective, double cross-over intervention trial comparing heliox 60/40 with conventional gas (nitrox) using lung function testing and electrical impedance tomography (eit) measurements. the study protocol (iscrtn98152468) was approved by the hospital's institutional review board and written informed consent was obtained from patients before enrollment. eligible for inclusion were infants younger than 12 months of age with a virologically confirmed clinical diagnosis of rsv lrtd (either a positive direct immunofluorescent assay or elisa) who were admitted to the nine-bed paediatric intensive care unit (picu) facility of the vu university medical center for mv during the rsv seasons (autumn and winter) between 2005 and 2007. infants were excluded if no informed consent was obtained, fraction of inspired oxygen (fio 2 ) was more than 0.4, corticosteroids were used prior to admission, they were on high-frequency oscillatory ventilation or a haemodynamically significant congenital heart defect (i.e. significant left-to-right shunting with or without pulmonary hypertension) was present. patients were in supine position, intubated with an uncuffed endotracheal tube size 3.5 or 4.0 mm, and put on a timecycled, pressure-limited ventilation mode (pressure control, avea ventilator, cardinal health, yorba linda, ca, usa). aims of ventilation were transcutaneously measured oxygen saturation (spo 2 ) 88 to 92%, and partial pressure of arterial carbon dioxide (paco 2 ) 45 to 65 mmhg (if ph >7.25). inspir-atory times were fixed at 0.5 seconds, positive end-expiratory pressure (peep) was set 1 to 2 cmh 2 o below total peep (i.e. extrinsic peep + intrinsic peep). the flow-time curve was observed thoroughly throughout the study period in each patient to examine if expiration was complete in order to prevent dynamic hyperinflation. patients were sedated with midazolam and morphine, paralysis was achieved using intravenous rocuronium. endotracheal suctioning was performed 30 minutes prior to the start of, but not during, the experimental protocol. bronchodilators (either nebulized or intravenous) or ketamine were not used before or during the study period. arterial blood samples were drawn from an arterial line to determine paco 2 and partial pressure of arterial oxygen (pao 2 ). end-tidal carbon dioxide (et-co 2 ) concentration, and expiratory tidal volume (v te ) were measured at the airway opening. et-co 2 was measured using a side-stream microstream (philips medical systems, best, the netherlands) and v te was measured with a proximal flow sensor connected to the avea ventilator (cardinal health, yorba linda, ca, usa). the ventilator is designed to detect which gas is used and adjusts its pneumotachograph automatically in order to measure the correct v te . a chest radiograph was obtained and evaluated by one pediatric radiologist in each patient prior to the start of the experimental protocol to evaluate the presence of hyperinflation (defined by a depression of the diaphragm below the sixth anterior rib) or an infiltrate (described as opacities with irregular markings without loss of volume) [12] . the experimental protocol started within 24 hours of picu admission and lasted for 90 minutes. at four intervals (t = 0 (baseline), t = 30, t = 60, and t = 90 minutes) data were collected and respiratory variables measured. at t = 0 and t = 60, patients were ventilated with nitrox. at t = 30 and t = 90, patients were ventilated with heliox (helium 60%, oxygen 40%). ventilator settings were kept constant throughout the experimental protocol. positive inspiratory pressure (pip), intratracheal pressure (ptrach), mean airway pressure (map), peep, spo 2 , et-co 2 , respiratory rate and v te were measured. ptrach was measured with a pressure transducer placed at the distal end of the endotracheal tube. blood samples were drawn for the determination of the pao 2 , paco 2 and ph. static compliance (c stat ), r rs and peak expiratory flow rate (pefr) were measured using the avea ventilator (cardinal health, yorba linda, ca, usa) according to the manufacturer's manual. in summary, r rs was defined by the ratio of the airway pressure differential to the inspiratory flow 12 ms prior to the end of inspiration. lung resistance (r lung ) was defined by the ratio of the tracheal pressure differential to the inspiratory flow 12 ms prior to the end of inspiration. at each interval, eit measurements were made using the göttingen goe-mf ii eit system (cardinal health, yorba linda, ca, usa). sixteen electrodes (blue sensor br-50-k, ambu, denmark) were applied circumferentially around the infant's chest at the mammary line. a 30 second reference measurement at 13 hz scan rate was recorded. all further measurements were referenced to this measurement. all other measurements were made at a scan rate of 44 hz for 180 seconds. a 5 ma peak-to-peak, 50 khz electrical current was injected at each adjacent electrode pair, and the resultant potential differences were measured at the remaining adjacent electrode pairs. subsequently, all adjacent electrode pairs were used for current injection, thus completing one data cycle. the impedance map was built using the back-projection image reconstruction algorithm [13] . it calculates the relative impedance δz, defined by (z inst -z ref )/z ref (where z inst is the instantaneous local impedance and z ref the reference impedance, determined from each cycle of current injections and voltage measurements in each pixel). both the respiratory and cardiac components of the eit signal were identified in the frequency spectra generated from all eit measurements (fourier transformation). the eit data was lowpass filtered with a cut-off frequency of 2 hz to eliminate small impedance changes synchronous with the heart beat [14] . the calculations performed on the sums of values from all pixels of the 32 × 32 pixel matrix eit image were described as 'global'. in addition, sums of values from the left and right lung regions were described separately, and the entire eit image was divided into 64 regions-of-interest (32 left and 32 right lung) from anterior to posterior as previously described by frerichs and colleagues [15] . ventilation-induced tidal volume (δz vt ) was quantified by measuring the relative δz from the highest point at end inspiration to the lowest point at end expiration, and an average δz was calculated from multiple breaths. changes in δz vt were calibrated to volume using the known v t . the relative change in end-expiratory lung volume (relative δz eelv ) was determined by measuring the median impedance from the lowest point at expiration during the sampling time (z eelv ) [16] . the relative δz eelv was normalized to volume (relative δ eelv in ml) by multiplying the median impedance with the ratio v t /δz vt . the oxygenation index (oi) was calculated as follows: (fio 2 × 100 × map in cmh 2 o)/pao 2 in mmhg. the ventilation index (vi) was calculated as follows: (paco 2 in mmhg × respiratory rate × (pip -peep in cmh 2 o))/1000. vi is used as determinant for co 2 elimination because the respiratory rate, pip, and peep were kept constant throughout the study period [17] . dead space (v d ) was calculated according to the bohr-enghoff equation: v d = v te × (1 -(p et-co2 /paco 2 )) [18] . as no data on relative δ eelv in mechanically ventilated infants with rsv lrtd were available, we performed a power analysis after inclusion of all patients using the paired t-test. the data were analyzed with one-way repeated measures analysis-of-variance (anova) with tukey post-hoc testing between t = 0 versus t = 30, t = 30 versus t = 60, and t = 60 versus t = 90. p < 0.05 was accepted as being statistically significant. data are expressed as mean ± standard deviation unless stated otherwise. statistical analysis was performed using spss version 15.0 (chicago, il, usa). thirteen patients were included in 11 eit studies; good-quality eit signals were obtained from nine patients. descriptive data, ventilator settings and baseline data of respiratory system mechanics and gas exchange are summarized in table 1 . although three patients were born prematurely (one at 32 weeks and two at 36 weeks' gestation), none of the patients had chronic lung disease. hyperinflation was present in 10 patients, four of these patients also had infiltrates. ten patients had hypercapnia (paco 2 >45 mmhg) and seven infants had pao 2 /fio 2 less than 200 at baseline (t = 0). tidal volume remained constant throughout the experiment (figure 1 ). leakage around the uncuffed endotracheal tube was less than 5% in all patients. mechanical ventilation with heliox had an overall significant effect on r rs (p < 0.001; figure 2 ). r rs decreased from 69.1 ± 6.9 cmh 2 o/l/sec at t = 0 to 50.2 ± 6.0 cmh 2 o/l/sec (p = 0.020) after 30 minutes of ventilation with heliox. after reintroduction of nitrox, r rs increased significantly to 70.7 ± 7.2 cmh 2 o/l/sec (p = 0.016) but decreased again to 42.9 ± 3.3 cmh 2 o/l/sec (p = 0.001) when heliox was reintroduced. course of tidal volume course of tidal volume. (page number not for citation purposes) r lung was not significantly influenced by mv with heliox ( figure 3 ). pefr was not significantly improved by mv with heliox compared with nitrox (p = 0.520; figure 4 ). c stat was 1.9 ± 0.4 l/ cmh 2 o at t = 0 and not significantly different throughout the study (p = 0.214; figure 5 ). the mean relative δ eelv ± standard deviation at t = 0 was 76.6 ± 15.1 ml. with an estimated reduction of 25% with heliox, nine patients were needed to recruit in order to detect a statistically significant difference with α 0.05 and β 0.90. the degree of airtrapping as defined by the relative δ eelv in ml was overall not significantly reduced by heliox (p = 0.493; figure 6 ). this was due to differences in response to mv with heliox. five patients showed a reduction in relative δ eelv when heliox was introduced, and when conventional gas was reintroduced relative δ eelv increased in only three patients (table 2 ). there were also patients who had an increase of relative δ eelv with heliox that was either reversed or increased when conventional gas was reintroduced. to investigate if a time-dependent effect of heliox could be found, the change in relative δ eelv was correlated with the change in r rs for t = 30 to t = 0 (r 2 0.068, p = ns), t = 60 to t = 30 (r 2 0.110, p = ns) and t = 90 to t = 60 (r 2 0.498, p = 0.01). fractional ventilation (i.e. the distribution between left and right lung), as well as the center of ventilation of the left and right lung, also remained constant throughout the study period (table 3) . table 4 summarizes the effect of mechanical ventilation with heliox on indices of gas exchange and v d /v t . elimination of co 2 defined by the vi (p = 0.661), as well as a reduction in v d /v t (p = 0.929) was not positively influenced by mv with heliox. importantly, oxygenation as defined by the oi (p = c stat = static compliance; eit = electrical impedance tomography; n/a = not available; paco 2 = partial pressure of arterial carbon dioxide; pao 2 = partial pressure of arterial oxygen; peep = positive end-expiratory pressure; pefr = peak expiratory flow rate; pip = positive inspiratory pressure; pt = patient; r rs = respiratory system resistance. 0.477) and alveolo-arterial oxygen gradient (aa-do 2 ) remained unaltered throughout the study period. the major finding of our study is that mv of infants with rsv lrtd with heliox 60/40 resulted in a significant reduction of the respiratory system resistance. increased r rs resulting from airway narrowing due to sludging, excessive mucus secretion, edema, and possible bronchoconstriction has been described in mechanically ventilated infants with rsv lrtd [19] [20] [21] [22] [23] . measures to alleviate increased r rs such as nebulisation of bronchodilators or nitric oxide have yielded inconclusive results [20, 22, 24, 25] . however, these studies are methodologically different compared with ours. for instance, we excluded patients with chronic lung disease or congenital heart disease. the decrease in r rs led not to an improved co 2 clearance as defined by the vi or a reduction in pefr. some explanations for this may be proposed. first, it is uncertain how much of the observed reduction in r rs could be partitioned to the ventilator circuit or the endotracheal tube because no endotracheal suctioning was performed during the study. increased mucus production during rsv lrtd is common, and may further obstruct the airways [26] . as the avea ventilator is able to calculate the r lung , we also studied if mv with heliox resulted in a reduction in r lung , but were unable to demonstrate this. this could mean that mv with heliox does not affect the resistance of the small airways of the infants; it cannot be ruled out, howeffect of mechanical ventilation with heliox on respiratory system resist-ance effect of mechanical ventilation with heliox on respiratory system resistance. data are expressed as mean ± standard deviation. * p < 0.05 t = 30 vs t = 0; ** p < 0.05 t = 60 vs t = 30; *** p < 0.05 t = 90 vs t = 60. effect of mechanical ventilation with heliox on lung resistance effect of mechanical ventilation with heliox on lung resistance. data are expressed as mean ± standard deviation. effect of mechanical ventilation with heliox on peak expiratory flow rate effect of mechanical ventilation with heliox on peak expiratory flow rate. data are expressed as mean ± standard deviation. effect of mechanical ventilation with heliox on static compliance effect of mechanical ventilation with heliox on static compliance. data are expressed as mean ± standard deviation. ever, that the resolution of the avea's signal of r lung (1 decimal) might not be sufficient enough to detect true differences in r lung in small children with little tidal volume. second, the measured r rs in our patients is lower than previously reported in mechanically ventilated infants with rsv lrtd designated to have an obstructive disease phenotype [20, 22, 27] . this could indicate that our patients had mild-to-moderate airway obstruction, although hyperinflation suggesting airway obstruction on chest radiograph was present in all but one patient. unfortunately, there is no gold standard for the radiological definition of hyperinflation especially in mechanically ventilated infants. furthermore, the degree of air-trapping might vary between patients, indicating that severe rsv lrtd necessitating mv is a heterogeneous disease in which patients express to a varying degree both restrictive and obstructive disease characteristics explaining why some patients had a pao 2 /fio 2 ratio of less than 200 or a c stat less than 0.3 ml/cmh 2 o/kg in our study. this assumption opposes the previously proposed dichotomization of rsv lrtd by hammer and colleagues, who have observed that mechanically ventilated infants with rsv lrtd showed either a disease pattern compatible with acute respiratory distress syndrome (ards) or a disease pattern characterized by increased airway resistance [27] . although our study was not designed to investigate differences in clinical phenotype, we would dare to challenge this dichotomy in clinical phenotype for several reasons. hammer and colleagues included prematurely born infants with chronic lung disease and infants with congenital heart disease [27] . c rs is significantly lower in these patients compared with healthy infants [28] [29] [30] . in addition, the term 'bronchiolitis' to describe rsv lrtd is strictly speaking a histopathologic diagnosis and hampered by universal differences in its clinical interpretation [31] . controversy exists about whether differences in parameters for gas exchange correlate with clinical phenotype [32, 33] . the lack of improved co 2 clearance in our study is compatible with the observations by gross and colleagues [11] . they were unable to demonstrate a beneficial effect on paco 2 of various heliox mixtures (ranging from 50%/50% to 70%/30%) compared with t = 0 (paco 2 45 ± 10 mmhg) in 10 mechanically ventilated infants with moderate severe rsv lrtd. it should be mentioned, however, that our study population was probably more ill than theirs based on a higher t = 0 paco 2 and lower pao 2 /fio 2 ratio. previously, we did observe a beneficial effect of heliox in a small infant with obstructive airway effect of mechanical ventilation with heliox on relative change in end-expiratory lung volume effect of mechanical ventilation with heliox on relative change in endexpiratory lung volume. data are expressed as mean ± standard deviation. negative values indicate a decrease in relative change in end-expiratory lung volume (relative δ eelv ). eit = electrical impedance tomography. disease [34] . this disparity in results cannot easily be explained except for the fact that this particular patient had severe respiratory acidosis. eit is a non-invasive bedside technique to assess global and regional lung volumes that has primarily been used in acute lung injury or ards [35] . hinz and colleagues have shown that compared with the validated nitrogen-washout method it is an appropriate tool to study eelv in critically ill patients [16] . to our knowledge, the use of eit in the determination of the dynamic process of air-trapping in patients with small airway disease has not been used before, although its use in this disease condition can be rationalised. in our study, mv with heliox did not result in a universal reduction of air-trapping as defined by the relative δ eelv . however, there were some patients who seemed to benefit from mv with heliox as they did show a reduction in relative δ eelv that was reversed by mv with conventional gas. several explanations for the non-universal reduction in relative δ eelv may be proposed. first, not all alveoli have the same degree of hyperinflation due to the difference in time constants throughout the lung, indicating that hyperinflation is a regional phenomenon rather than a global problem [36] . this would implicate that the technique of eit may be insufficient to detect regional differences in viralinduced small airway disease due to heterogeneity of the disease, a problem that can be overcome by increasing the reso-lution of the eit signal. in favor of eit, however, is the study by adler and colleagues showing that with eit dynamic hyperinflation could be adequately monitored [37] . second, during the study no endotracheal suctioning was performed. increased mucus production could obstruct the airways, resulting in the collapse of alveoli that is reflected by a decrease in eelv. as tidal volume remained constant throughout the experiment, we think that not performing endotracheal suctioning did not influence our results ( figure 5 ). third, if there is a difference in expression of clinical phenotype of rsv lrtd a universal response in relative δ eelv would not be expected. some patients responded with a decrease in relative δ eelv whereas others did not in our study. also, redistribution of ventilation within each lung or between the left and right lung was not significantly influenced by mv with heliox. this is in line with a heterogeneous clinical phenotype of rsv lrtd. there are some limitations to our study that should be mentioned. first, the small sample size of our study. this sample size does not allow discrimination between responders and non-responders nor a categorization of clinical phenotype based on chest radiographs, but this should be the subject of further research. second, patients were paralyzed throughout the study, thus prohibiting spontaneous breathing and mucus clearance by the patient itself. we choose to do so to eliminate any confounding effect of spontaneous breathing on the data are expressed as mean ± standard deviations. aa-do2 = alveolo-arterial oxygen gradient; oi = oxygenation index; vi = ventilation index; v d /v t = dead-space/tidal volume ratio. (page number not for citation purposes) degree of dynamic hyperinflation in order to truly assess the effect of mv with heliox. however, our findings require re-evaluation in spontaneously breathing mechanically ventilated infants. supportive therapy maintaining spontaneous breathing could very well be a key element while awaiting therapeutic modalities for mechanically ventilated infants with rsv lrtd [38] . third, the measurements of our study were not blinded because connection of the heliox and the measurements were conducted by one investigator (mk). however, this might have introduced measurement bias. fourth, ventilation with heliox may have influenced the tidal volume measurements of the avea ventilator. the avea is equipped with the bicore cp100™ pulmonary mechanics monitor that has been validated previously [36, 39] . finally, the avea performs in a similar way with respect to tidal volume measurement when heliox is used [40, 41] . mv with heliox significantly reduced r rs in mechanically ventilated infants with rsv lrtd with a heterogenous effect on the degree of hyperinflation and co 2 elimination. these findings warrant further study in order to identify a subgroup of mechanically ventilated infants with rsv lrtd who might benefit from mv with heliox. • mv with heliox decreases respiratory system resistance in rsv lrtd. • mv with heliox does not reduce air-trapping in rsv lrtd. • mv with heliox does not improve gas exchange in rsv lrtd. • rsv lrtd may actually be a heterogeneous disease. respiratory syncytial virus and parainfluenza virus bronchiolitis-associated hospitalizations among us children recent trends in severe respiratory syncytial virus (rsv) among us infants advances in respiratory syncytial virus vaccine development the pathogenesis of respiratory syncytial virus disease in childhood pathological changes in virus infections of the lower respiratory tract in children mechanical ventilatory support in infants with respiratory syncytial virus infection ribavirin in ventilated respiratory syncytial virus bronchiolitis. a randomized, placebo-controlled trial heliox administration in the pediatric intensive care unit: an evidence based review theoretical validation of the respiratory benefits of helium-oxygen mixtures helium-oxygen mixture does not improve gas exchange in mechanically ventilated children with bronchiolitis the radiological findings in respiratory syncytial virus infection in children. part i. definitions and interobserver variation in the assessment of abnormalities on the chest x-ray electrical impedance tomography (eit): a review regional lung volume changes in children with acute respiratory distress syndrome during a derecruitment maneuver lung volume recruitment after surfactant administration modifies spatial distribution of ventilation end-expiratory lung impedance change enables bedside monitoring of end-expiratory lung volume change ventilation index and outcome in children with acute respiratory distress syndrome volumen inefficax, bemerkungen zur frage des schadlichen raumes respiratory oscillation mechanics in infants with broncholitis during mechanical ventilation albuterol responsiveness in infants with respiratory failure caused by respiratory syncytial virus infection respiratory system mechanics in patients receiving aerosolized ribavirin during mechanical ventilation for suspected respiratory syncytial viral infection effect of inhaled nitric oxide on respiratory mechanics in ventilated infants with rsv bronchiolitis peep does not improve pulmonary mechanics in infants with bronchiolitis aerosolized albuterol improves airway reactivity in infants with acute respiratory failure from respiratory syncytial virus bronchial reactivity in infants with acute respiratory failure with viral bronchiolitis hop wcj, de hoog m, merkus pjfm: recombinant human deoxyribonuclease in infants with respiratory syncytial virus bronchiolitis acute respiratory distress syndrome caused by respiratory syncytial virus lung function tests in neonates and infants with chronic lung disease: lung and chest-wall mechanics lung mechanics in normal infants and infants with congenital heart disease lung mechanics in infants with left-toright shunt congenital heart disease is bronchiolitis an obsolete term? time course of severe respiratory syncytial infection in mechanically ventilated infants respiratory indices do not characterize clinical phenotype of respiratory syncytial virus lower respiratory tract disease mechanical ventilation with heliox decreases respiratory system resistance and facilitates co2 removal in obstructive airway disease noninvasive assessment of lung volume: respiratory inductance plethysmography and electrical impedance tomography measurement of air trapping, intrinsic positive end-expiratory pressure, and dynamic hyperinflation in mechanically ventilated patients electrical impedance tomography can monitor dynamic hyperinflation in dogs cpap and hfov: different guises of the same underlying intensive care strategy for supporting rsv bronchiolitis the bicore pulmonary monitor. a device to assess the work of breathing while weaning from mechanical ventilation accuracy of volumes deliverd and monitored by the viasys avea ventilator during heliox administration resp care heliox delivery using the avea ventilator resp care the authors declare that they have no competing interests. mk designed and performed the study, performed the statistical analysis and wrote the manuscript. mvh assisted in performing the study. jt assisted in the statistical analysis and contributed to the writing of the manuscript. dm analyzed the eit data and contributed to the writing of the manuscript. key: cord-002240-38aabxh1 authors: prina, elena; ceccato, adrian; torres, antoni title: new aspects in the management of pneumonia date: 2016-10-01 journal: crit care doi: 10.1186/s13054-016-1442-y sha: doc_id: 2240 cord_uid: 38aabxh1 despite improvements in the management of community-acquired pneumonia (cap), morbidity and mortality are still high, especially in patients with more severe disease. early and appropriate antibiotics remain the cornerstone in the treatment of cap. however, two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. adjuvant treatments, such as corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects. the use of corticosteroids in patients with severe cap and a strong inflammatory reaction can reduce the time to clinical stability, the risk of treatment failure, and the risk of progression to acute respiratory distress syndrome. the administration of intravenous immunoglobulins seems to reinforce the immune response to the infection in particular in patients with inadequate levels of antibodies and when an enriched igm preparation has been used; however, more studies are needed to determinate their impact on outcome and to define the population that will receive more benefit. despite the use of early and appropriate antibiotic treatment, mortality related to community-acquired pneumonia (cap) is still high [1] , especially in patients with severe disease. previous studies have shown that approximately 18 % of patients hospitalized for cap matched the criteria for severe cap. these patients more frequently present with septic shock and need for * correspondence: atorres@clinic.ub.es 1 servei de pneumologia, institut del torax, hospital clinic, idibaps, universitat de barcelona, barcelona, spain 2 centro de investigación biomedica en red-enfermedades respiratorias (ciberes, cb06/06/0028), barcelona, spain full list of author information is available at the end of the article mechanical ventilation, with a mortality of approximately 29 % [2] . in addition to the infection, septic shock is generally thought to be caused by an excessive or uncontrolled pro-inflammatory response [3] . pneumonia is a complex disease caused by the action of pathogens and the local and systemic inflammatory responses of the patient. a stronger inflammatory response has been shown to be associated with treatment failure and mortality [4] . in particular, high levels of interleukin (il)-6, il-8, and il-10 have been detected in patients with severe pneumonia and excess il-6 and il-10 was associated with increased mortality (from 4.8 to 11.4 %) [5, 6] . moreover, in some patients with cap, excessive levels of cytokines can be released (called the jarisch-herxheimerlike reaction) after the initiation of antibiotics, causing damage similar to other infections characterized by high bacterial load (e.g., meningococcal meningitis) [7, 8] . another aspect regarding the immune response to the infection is that low levels of immunoglobulins are found, particularly in patients with recurrent episodes of pneumonia, and may be responsible for the predisposition to recurrent infections and worse outcome [9] . considering that pathogens resistant to the empiric antibiotic treatment are not a common cause of cap, two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. adjuvant treatments, such as corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects. glucocorticosteroid drugs reproduce effects similar to endogenous cortisol: they have anti-inflammatory activity by switching genes on and off, resulting in a reduction of inflammatory cytokines and chemokines. corticosteroids have an effect on structural cells of the respiratory tract: they act on epithelial cells by inhibiting transcription factors such as nf-kb, on mucous glands by decreasing mucus secretion, and on smooth muscle cells by increasing β2 receptors [11] . another aspect that may contribute to the beneficial effect of corticosteroid treatment is related to the presence of adrenal insufficiency or inadequate adrenal function in some cases of severe cap [12] . in an animal model of mechanically ventilated piglets with pneumonia due to pseudomonas aeruginosa, we demonstrated the presence of lower bacterial burden in the lungs and less severe histological pneumonia in the group treated with antibiotics plus corticosteroids in comparison with the group treated with antibiotics plus placebo, suggesting a potential beneficial effect of corticosteroids on bacterial burden and lung tissue severity, in addition to the systemic inflammatory response [13] . in acute respiratory distress syndrome (ards), the presence of high levels of cytokines is associated with a higher risk of nosocomial infection because the inflammatory biomarkers appear to favor bacterial growth. meduri et al. [14] , in an in vitro study, showed that the addition of methylprednisone to monocytes stimulated by lipopolysaccharide can increase the ability to suppress bacterial replication. the main studies on corticosteroids in pneumonia are summarized in table 1 [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] . several studies have evaluated the effects of corticosteroids in cap. the first studies and meta-analyses included a heterogeneous population evaluating different outcomes, resulting in controversial data. a cochrane meta-analysis [19] selected six randomized controlled trails (rcts) of corticosteroids in pneumonia including a total of 437 participants. the use of corticosteroids accelerated the resolution of symptoms and time to clinical stability (defined as improvement in chest x-ray and normalization of temperature, respiratory rate, and inflammatory markers). corticosteroids provided no benefit in terms of mortality and the authors concluded that it was not possible to make any definitive recommendations because the studies analyzed in the meta-analysis did not provide strong evidence. another meta-analysis [20] including nine rcts with a total of 1001 patients showed that the use of corticosteroids was not associated with significantly lower mortality considering all the patients (odds ratio (or) 0.62, 95 % confidence interval (ci) 0.37-1.04; p = 0.07). however, a survival benefit was detected in the subgroup of patients with severe cap (or 0.26, 95 % ci 0.11-0.64; p = 0.003) and among patients receiving more prolonged corticosteroid treatment (or 0.51, 95 % ci 0.26-0.97; p = 0.04). prolonged corticosteroid treatment was defined as more than 5 days of corticosteroid treatment and a maximum of 9 days. in terms of adverse effects, corticosteroids increased the risk of hyperglycemia (or 2.64, 95 % ci 1.68-4.15; p < 0.001) but did not increase the risk of superinfection (or 1.36, 95 % ci 0.65-2.84; p = 0.41) or gastroduodenal bleeding (or 1.67, 95 % ci 0.41-6.80; p = 0.47). in conclusion, these studies were not able to provide definitive results regarding the use of corticosteroids in cap. the main limitations regarded the inclusion of a heterogeneous population in terms of severity (from mild to severe) and level of inflammatory response (e.g., defined by the level of c-reactive protein (crp)) and the use, in some cases, of inadequate dosage of corticosteroids (low or excessively high). two recent multicenter rcts have been published regarding the use of corticosteroids in cap. in a multicenter, double-blind, randomized, placebocontrolled trial [24] , a total of 785 patients with cap were randomized to receive oral corticosteroids (50 mg of prednisone for 7 days) or placebo as adjunctive treatment. the corticosteroid group reported a shorter time to reach clinical stability in comparison with the placebo group (3 days versus 4.4 days). in the study, the time to clinical stability was defined as the days until reaching stable vital signs for 24 h or longer (including normalization of temperature, heart rate, spontaneous respiratory rate, systolic blood pressure, mental status, ability for oral intake, and adequate oxygenation on room air). the complications related to pneumonia were not significantly different in the groups whereas the prednisone group more frequently presented hyperglycemia needing insulin treatment (19 versus 11 %; or 1.96; 95 % ci 1.31-2.93; p = 0.001). however, other adverse events typically associated with corticosteroid use (such as gastrointestinal bleeding, nosocomial infections) were rare and similar in both groups. the mortality rate, considered as a secondary outcome in the study, was not different in the two groups (n = 16 (4 %) in the prednisone group versus n = 13 (3 %) in the placebo group; p = 0.57). this study presented some limitations, in particular the use of a weak outcome such as clinical stability, which included some items such as temperature that could be influenced by the use of corticosteroids. moreover, the majority of patients had a mild disease presentation, thereby decreasing result validation for the most severe diseases. we recently published a multicentre rct [23] where we compared patients with severe cap and strong inflammatory response (defined by a crp >150 mg/l) treated with corticosteroids plus antibiotics versus placebo plus antibiotics. we used intravenous methylprednisolone at a dose of 0.5/mg/kg every 12 h for 5 days. we included only patients with severe cap, defined according to the modified american thoracic society criteria or by a pneumonia severity index risk class v [27] . the patients receiving corticosteroids had significantly lower treatment failure in comparison with the placebo group (13 versus 31 %, respectively; p = 0.02). this difference was due to late treatment failure (developing between 72 and 120 h after treatment initiation) and, in particular, patients in the corticosteroid group showed a more evident effect on the reduction of radiological late failure (>72 h after admission) was more common in the prednisolone group than in the placebo group (19.2 versus 6.4 %, respectively; p = 0.04). meijvis et al. 2011 [18] bicenter rct in netherlands reduction in length of stay in dexamethasone group compared with the placebo group (6.5 versus 7.5 days, respectively; p = 0.048) dexamethasone versus placebo patients with cap chen et al. 2011 [19] meta-analysis accelerated the resolution of symptoms or time to clinical stability and decreased the rate of relapse of the disease patients with pneumonia nie et al. 2012 [20] meta-analysis corticosteroids did not significantly reduce mortality in the general population ( the association between treatment failure, with radiographic progression as a criterion, and mortality has been shown by menendez et al. [5] . the protective effect of corticosteroids on radiographic progression could be interpreted as an effect preventing the development of ards or blocking the jarisch-herxheimer-like reaction [8] . no significant difference was observed in mortality between the two groups (10 % in the methylprednisolone arm versus 15 % in the placebo arm; p = 0.37); however, the study was not powered for mortality as this was not the primary outcome. importantly, we detected no significant side effects in patients receiving corticosteroids. the strength of this study is the homogeneous population with severe cap and a strong inflammatory response and the use of an outcome (treatment failure) closely associated with mortality [5] . the limitation of this study was the prolonged recruitment period. in fig. 1 we propose a flowchart for the management of patients with severe cap. a recent meta-analysis [26] including nine rcts (1667 patients) and six cohort studies (4095 patients) showed that the use of corticosteroids is not associated with a significant reduction in mortality in patients with cap (risk ratio (rr) 0.72; 95 % ci 0.43-1.21; evidence rank low) or in the subgroup of patients with severe cap (rct rr 0.72, 95 % ci 0.43-1.21, evidence rank low; cohort study rr 1.00, 95 % ci 0.86-1.17). however, corticosteroids produced a benefit in terms of reduction of ards (rr 0.21, 95 % ci 0.08-0.59), length of hospital and icu stay, duration of iv antibiotics, and time to clinical stability without a significant increase in side effects. in contrast, another meta-analysis [25] demonstrated a reduction in all causes of mortality in patients receiving corticosteroids (12 trials, 1974 in conclusion, all these studies confirm that the use of corticosteroids in cap is associated with the following benefits: reduced length of hospital stay, reduced time to clinical stability, and prevention of ards. no definitive answer is available yet regarding the effect of corticosteroids on the reduction of death and larger studies are needed to define the effect on mortality. in particular, some meta-analyses suggested that corticosteroids may decrease mortality in the subgroup of patients with severe cap; however, these data have not been confirmed in other studies. the effects of corticosteroids in some specific infections are the subject of debate. for example, a meta-analysis showed a benefit in pneumocystic jiroveci pneumonia [28] , although this result came from small rcts. in patients with cap due to viral infection, the effects of corticosteroids are still not clear. in h1n1 infection, corticosteroid use was associated with a higher incidence of pneumonia and mortality. in a chinese descriptive study of influenza a (h7n9) viral pneumonia, the subgroup of patients receiving very high doses of corticosteroids (>150 mg/d methylprednisolone or equivalent) had increased mortality but no significantly worse outcome was detected with low to moderate doses of corticosteroids (25-150 mg/d methylprednisolone or equivalent) [29] . a recent meta-analysis by cochrane [30] of corticosteroids as adjunctive treatment in influenza found insufficient evidence to determine the efficacy of corticosteroids in these patients. delaney et al. [31] recently published an observational multicenter study of patients with influenza a (h1n1pdm09)-related critical illness. the crude hospital mortality was higher in patients who received corticosteroids compared with patients without corticosteroid treatment (25.5 versus 16.4 %, p = 0.007). nevertheless, after adjusting for potential confounders, the authors did not find a significant association between corticosteroids and mortality in this population. it appears that the use of corticosteroids was associated with a higher mortality but this result has to be carefully interpreted because only observational studies of low quality were included and rtcs were not identified for the analysis. more studies are needed to clarify this point. the main side effects associated with corticosteroids, especially with prolonged use, are hyperglycemia, myopathy, weight gain, brushing, and osteopenia (fig. 2) [32] . as well as these side effects, corticosteroids have strong immunosuppressive effects, raising concerns regarding their use in acute infections, despite their potential effect in controlling excessive inflammatory response. the immunosuppressant effect of corticosteroids is related to dose and treatment duration. for example, the use of 40 mg of prednisolone per day for more than 1 week or 20 mg prednisolone or equivalent per day for a month can produce immunosuppression. in acute infection, a low dose for a short period (some days) may be useful for reducing inflammation and may not cause so much harm by producing immunosuppression. moreover, a short period of corticosteroid treatment may reduce the risk for side effects. hyperglycemia is a frequent effect associated with corticosteroid use. this occurs in about 50 % of hospitalized patients receiving high doses of corticosteroids [33] and patients with chronic obstructive pulmonary disease (copd) receiving oral corticosteroid treatment presented a more than fivefold risk of developing hyperglycemia. hyperglycemia is associated with higher mortality and, in particular, hyperglycemia secondary to corticosteroids increased the risk of death by 10 % for each 18 mg/dl increase in blood glucose after adjusting for age, sex, and diabetes mellitus [34] . detection of hyperglycemia in the first 24 h in patients with copd reactivation was associated with worse outcomes [35] . on the other hand, strict management of glucose levels decreased morbidity and mortality in critically ill patients admitted to the surgical icu [36] . for patients in the medical icu, a benefit was shown in terms of morbidity but not mortality [37] . myopathy is another side effect associated with acute and chronic corticosteroid treatment, especially in older patients, patients with cancer and respiratory muscle diseases, and physically inactive patients [38] . corticosteroids induce myopathy by decreasing protein synthesis and increasing protein breakdown. this mechanism leads to muscle atrophy with a reduction of myofibrillar protein content and cross-sectional fiber area. in critically ill patients, the development of myopathy produces peripheral muscle weakness with longer duration of [39, 40] . there is a gap in knowledge regarding whether the beneficial anti-inflammatory effect of corticosteroids may be potentiated by the administration of a macrolide, which has an immunomodulatory effect. the best antibiotic strategy for the treatment of cap is currently a subject of debate. for severe cap, international guidelines suggest the use of two antibiotics such as a βlactam plus a macrolide or a β-lactam plus respiratory quinolone (levofloxacin or moxifloxacin) [40] . however, many observational studies and a recent meta-analysis have shown that the use of a β-lactam plus a macrolide is the best choice because it is associated with a better outcome and lower mortality in patients with severe cap, especially in bacteremic pneumococcal cap. the mechanisms responsible for the favorable effects related to the use of macrolides are not clear and have been attributed in part to their immunomodulatory effect, as observed in some studies [41] . in vitro and in vivo experimental models have shown that macrolides inhibit cytokine secretion by inflammatory and structural cells of the respiratory tract [42] . in patients admitted to the ward with non-severe cap [43] , monotherapy with a β-lactam was not inferior to a βlactam plus a macrolide or fluoroquinolone in terms of 90-day mortality. in another trial, the authors found no non-inferiority of β-lactam monotherapy in comparison with a β-lactam plus a macrolide in patients with moderate-severe cap, considering as outcome the proportion of patients who did not reach clinical stability in 7 days [44] . in an experimental mouse model of mycoplasma pneumoniae respiratory infection, the use of clarithromycin and dexamethasone was more effective than clarithromycin alone in decreasing levels of cytokines and histological signs of lung inflammation [45] . another study in patients with non-responding pneumonia demonstrated a reduction in inflammatory biomarkers such as il-6 and il-8 in bronchoalveolar lavage in patients receiving treatment with corticosteroids plus a macrolide [46] . the combination of a macrolide plus a corticosteroid is currently used without scientific evaluation, although we do not know whether this combination may decrease the inflammatory response to a very low level, thereby increasing the risk of side effects. we therefore need to better investigate the effects of corticosteroids and macrolides together in order to provide data that may be used to support clinical indications for this combination in severe cap. corticosteroids have proven benefits in the treatment of acute exacerbation of copd and the presence of chronic respiratory disease is the main reason for adding corticosteroids to antimicrobial treatment in pneumonia [47] . patients with copd and cap presented a different early inflammatory pattern compared with patients with cap only. in particular, on the day of admission to hospital, the patients with copd had lower levels of tumor necrosis factor (tnf), il-1, and il-6 but no differences in levels of crp, procalcitonin, il-8, and il-10. these differences were mediated in part by corticosteroids; in fact, lower levels of tnf-α persisted after excluding patients who received inhaled and oral corticosteroids at home [48] . in contrast with this result, another study showed that copd patients with cap who had received prior treatment with inhaled corticosteroids had lower levels of tnf-α after adjusting for other confounders in comparison with the overall population [49] . in addition, another study found that on days 1 and 3, patients with cap and a history of copd had significantly higher levels of crp, procalcitonin, tnf-α, and il-6 than patients admitted with acute exacerbation of copd [50] . these results were maintained after adjusting for inhaled pharmacotherapy. in conclusion, patients with cap and a history of copd represent a specific population with a different inflammatory pattern and further studies are needed to clarify the use of corticosteroids in these patients during cap episodes, especially in those receiving inhaled corticosteroids. fluoroquinolones have also shown an immunomodulatory effect [51] . in vitro, fluoroquinolones favor the synthesis of il-2 but reduces the production of il-1 and tnf. in vivo, they affect cellular and humoral immunity by attenuating cytokine responses. in addition, certain fluoroquinolones enhance hematopoiesis by increasing concentrations of colony-stimulating factors (csfs) in the lung and in the bone marrow. csfs have a role in the response to infections. in fact, csf knockout mice developed lung infections and the administration of csf in neutropenic mice with candida reduced the risk of mortality and lung injury. more studies are needed, especially in the clinical setting, to assess the immunomodulatory effects of fluoroquinolones. although the recent rcts provide data which have increased our knowledge regarding the usefulness of corticosteroids in severe cap, more studies are needed to clarify the effect of corticosteroids on mortality. moreover, we need to clarify which corticosteroids and what doses and durations of therapy are most indicated and to define the specific populations that may benefit from this adjunctive treatment, such as severe cap with a strong inflammatory response or infections with specific pathogens. another interesting topic is the effect of combination therapy with macrolides and corticosteroids in the modulation of the immune response. we have some promising data from experimental models but more data are needed. in patients with sepsis and septic shock, low levels of immunoglobulins (igs) were detected, with a reduction in igg of between 25 and 61 % and a reduction in igm of between 19 and 33 % [52] . however, a recent metaanalysis pointed out the limitations of the studies on this topic due to the use of heterogeneous cutoffs to define normal levels of igg [53] . hypogammaglobulinemia and low levels of igg subclasses were noticed in patients with recurrent episodes of pneumonia and may be responsible for the predisposition to recurrent infections [9] . a case-control study [54] showed that patients with cap had significantly lower levels of igg (especially igg2 subclass) and iga on diagnosis in comparison with a control group of healthy patients without pneumonia. low levels of igs persisted in the convalescent phase in approximately 25 % of patients. hypogammaglobulinemia was more frequently found in patients requiring hospitalization than in outpatients and in patients with pneumonia due to a bacterium other than streptococcus pneumoniae or a virus or without pathogen isolation. another study [55] confirmed that severe viral infection due to h1n1 was associated with lower levels of the igg2 subclass. indeed, lower levels of igs appeared to be associated with more severe disease, viral infection, or bacterial infection other than streptococcus pneumoniae. the reason why patients with pneumonia and sepsis can have low levels of igs is still not clear. two different mechanisms may be involved: the infection may be responsible for hypogammaglobulinemia by consuming the igs or the presence of hypogammaglobulinemia may be the cause of the infection because it contributes to an inadequate defense response. for these reasons, in recent years, it has been suggested that the administration of intravenous igs may be an effective adjunctive treatment to modulate the immune response in these patients. some trials have evaluated the effects of exogenous igs as adjunctive treatment in patients with sepsis and, in particular, in patients with cap. however, the results of these studies are still the subject of debate [56] . a meta-analysis [57] reported a general reduction in mortality (approximately 21 %) in adult patients with sepsis and septic shock who received polyclonal igs and a more evident effect on mortality in the subgroup receiving igm-enriched immunoglobulin. a more recent meta-analysis by cochrane published in 2013 [56] showed a reduction in mortality in patients who received polyclonal intravenous igs, although this positive effect disappeared on analyzing only trials with low bias. a large retrospective study in japan [58] evaluated the effect of intravenous immunoglobulin as an adjunctive treatment in patients with septic shock due to pneumonia. a total of 8264 patients were studied, of whom 1324 were treated with intravenous igs, in comparison with 6940 patients who did not receive the igs. no benefit was found in terms of mortality in the group of patients receiving the igs. a multicentre, randomized, placebo-controlled phase ii trial [59] is ongoing with the aim of evaluating the efficacy and safety of igm-enriched immunoglobulin preparations (pentaglobin™, 12 % igm, 12 % iga, and 76 % igg) as adjunctive treatment in patients with mechanical ventilation for cap. the primary outcome is the number of ventilator-free days. the use of corticosteroids in patients with severe cap and a strong inflammatory reaction can reduce the time to clinical stability and the risk of treatment failure, especially radiological progression. the administration of intravenous immunoglobulins can reinforce the immune response to infection, particularly in patients with inadequate levels of antibodies and when an enriched igm preparation is used. however, more studies are needed to evaluate their effects in patients with cap. abbreviations ards, acute respiratory distress syndrome; cap, community acquired pneumonia; ci, confidence interval; copd, chronic obstructive pulmonary disease; crp, c-reactive protein; csf, colony-stimulating factor; icu, intensive care unit; ig, immunoglobulin; il, interleukin; or, odds ratio; rct, randomized controlled trial; rr, risk ratio; tnf, tumor necrosis factor risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study epidemiology and outcome of severe pneumococcal pneumonia admitted to intensive care unit: a multicenter study septic shock systemic cytokine levels in community-acquired pneumonia and their association with disease severity risk factors of treatment failure in community acquired pneumonia: implications for disease outcome markers of treatment failure in hospitalised community acquired pneumonia severity of meningococcal disease associated with genomic bacterial load corticosteroids for severe community-acquired pneumonia: not for everyone primary immunodeficiencies: 2009 update antiinflammatory action of glucocorticoids-new mechanisms for old drugs treatment with antiinflammatory drugs in community-acquired pneumonia adrenal insufficiency in septic shock effects of glucocorticoids in ventilated piglets with severe pneumonia effects of methylprednisolone on intracellular bacterial growth hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study effects of systemic steroids in patients with severe community-acquired pneumonia efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial corticosteroids for pneumonia corticosteroids in the treatment of communityacquired pneumonia in adults: a meta-analysis adjuvant steroid therapy in community-acquired pneumonia: a systematic review and metaanalysis corticosteroid therapy for severe community-acquired pneumonia: a meta-analysis effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial corticosteroid therapy for patients hospitalized with communityacquired pneumonia: a systematic review and meta-analysis efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis a prediction rule to identify low-risk patients with community-acquired pneumonia adjunctive corticosteroids for pneumocystis jiroveci pneumonia in patients with hiv infection: a metaanalysis of randomised controlled trials adjuvant corticosteroid treatment in adults with influenza a (h7n9) viral pneumonia corticosteroids as adjunctive therapy in the treatment of influenza the influence of corticosteroid treatment on the outcome of influenza a(h1n1pdm09)-related critical illness association between systemic corticosteroids and outcomes of intensive care unit-acquired pneumonia prevalence and predictors of corticosteroid-related hyperglycemia in hospitalized patients hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease hyperglycaemia as a predictor of outcome during non-invasive ventilation in decompensated copd intensive insulin therapy in the critically ill patients intensive insulin therapy in the medical icu glucocorticoid-induced myopathy paresis acquired in the intensive care unit: a prospective multicenter study infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults anti-inflammatory effects of macrolides-an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? immunomodulatory effects of macrolides during community-acquired pneumonia: a literature review antibiotic treatment strategies for community-acquired pneumonia in adults beta-lactam monotherapy vs beta-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial efficacy of increasing dosages of clarithromycin for treatment of experimental mycoplasma pneumoniae pneumonia lung inflammatory pattern and antibiotic treatment in pneumonia systemic corticosteroids for community-acquired pneumonia: reasons for use and lack of benefit on outcome systemic inflammatory pattern of community-acquired pneumonia (cap) patients with and without chronic obstructive pulmonary disease (copd) inhaled corticosteroids and systemic inflammatory response in community-acquired pneumonia: a prospective clinical study pneumonic and non-pneumonic exacerbations of copd: systemic inflammatory response and clinical characteristics immunomodulatory effects of quinolones assessment of plasmatic immunoglobulin g, a and m levels in septic shock patients endogenous igg hypogammaglobulinaemia in critically ill adults with sepsis: systematic review and meta-analysis serum immunoglobulins in the infected and convalescent phases in community-acquired pneumonia pooled human immunoglobulin therapy in critically ill patients with pandemic 2009 influenza a(h1n1) pneumonitis and immunoglobulin g2 subclass (igg2) deficiency intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock intravenous immunoglobulin and mortality in pneumonia patients with septic shock: an observational nationwide study concept for a study design in patients with severe community-acquired pneumonia: a randomised controlled trial with a novel igm-enriched immunoglobulin preparation-the cigma study not applicable. adrian ceccato is a recipient of an ers long term fellowship. all authors participated in the design and writing of the paper. all authors read and approved the final manuscript. key: cord-005495-0mi0n2zn authors: de laet, inneke e.; malbrain, manu l. n. g.; de waele, jan j. title: a clinician’s guide to management of intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients date: 2020-03-24 journal: crit care doi: 10.1186/s13054-020-2782-1 sha: doc_id: 5495 cord_uid: 0mi0n2zn this article is one of ten reviews selected from the annual update in intensive care and emergency medicine 2020. other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. further information about the annual update in intensive care and emergency medicine is available from http://www.springer.com/series/8901. intra-abdominal hypertension (iah) and abdominal compartment syndrome (acs) are established causes of morbidity and mortality in critically ill patients [1] . when interest in postoperative iah after major vascular, trauma, and general surgery arose in the 1980s, overt acs was the only clinical syndrome recognized and decompressive laparotomy the only definitive treatment [2] . since then, less extreme elevations in intraabdominal pressure (iap), defined as iah, have been recognized to be highly prevalent among all types of patients admitted to the intensive care unit (icu) [3] . significant advances in the understanding of the pathophysiology, diagnosis, and management of iah and acs have occurred over the last few decades. the importance of iah has been studied specifically in critically ill patients, leading to a better understanding of the mechanisms of organ dysfunction due to increased iap and earlier opportunities for therapeutic intervention. further, medical and minimally invasive techniques have been developed and reported to be potentially effective in small studies [4] . the world society for the abdominal compartment syndrome (wsacs, recently renamed as wsacs-the abdominal compartment society [5] ) was founded in 2004 to "promote research, foster education and improve the survival of patients with iah/acs." consensus papers on iap measurement and diagnosis and management of iah/acs were first published in 2006 and 2007 [1, 6] and a medical management algorithm in 2009 [7] . subsequently, in 2013, the wsacs published an updated evidence-based version of the definitions, guidelines, and medical management algorithm using grade methodology (box 1) [8] . in this last manuscript, the definitions relating to iap were updated. the current medical management algorithm for iah/ acs still has some limitations ( fig. 1) . first, there is not enough evidence to support some of the interventions described in the algorithm. second, the use of the algorithm at the bedside also requires an experienced clinician to select the treatment best suited to an individual patient as it does not provide clear, easy, patientspecific recommendations. finally, management recommendations are chiefly based on a measured iap value only, an approach likely to underestimate the importance of the dynamic evolution in the patient's situation. depending on the course of disease and concomitant organ dysfunction, some cases of acs can be managed conservatively whereas some cases of iah may require immediate aggressive treatment including fast decision to proceed to decompressive laparotomy before reaching the value of 20 mmhg of iap. this is important because use of decompressive laparotomy is associated with a number of potential complications (e.g., massive ventral hernia, enteric fistulae, and intra-abdominal sepsis), increased morbidity, and decreased quality of life, especially in younger patients [9] [10] [11] [12] . the philosophy of the wsacs guidelines has been to publish the best available evidence at the time of writing, with the hope that future research would necessitate ongoing revisions and updating of the guidelines. the aim of this chapter is to provide the reader with a conceptual framework of how to translate the principles of the formal consensus guidelines into a practical approach at the bedside to manage a specific patient with iah and acs, taking into account patient physiology, current scientific evidence, and clinical experience. it is important to understand that iah, in contrast to acs, is a continuum from (often) asymptomatic elevation of iap to an immediately life-threatening situation (fulminant acs), where dynamic evolution in both directions is possible. therefore, it is difficult to identify triggers for interventions that may lead to complications (e.g., percutaneous drainage) or have adverse effects (e.g., sedation, muscle relaxation). despite this, the optimal treatment choice for a specific patient with iah/ acs should take into account three critical elements: (1) the measured iap value (or the degree/magnitude of iap increase); (2) organ dysfunction characteristics (or the impact of increased iap); and (3) nature and course of the underlying disease (fig. 2 ). using this triangular treatment paradigm enables us to fully acknowledge the importance of the two other factors in addition to the measured iap value. although the iap value has always been considered the most important factor in managing iah/acs, it should always be viewed within its context. factors that need to be considered in an individual patient include the iap measurement strategy and the context in which iap is measured, the expected baseline value of iap, the evolution of iap over time, and the duration of time that the patient has already been exposed to iah. the reference standard for intermittent iap measurement is via the bladder with a maximal instillation volume of 25 ml of sterile saline. iap should be measured at endexpiration in the supine position after ensuring that abdominal muscle contractions are absent and with the transducer zeroed at the level where the midaxillary line crosses the iliac crest [8] . this generally means that iap measurement is most reliable in completely sedated, mechanically ventilated patients. however, many mechanically ventilated patients in the icu are at some stage of a weaning process, exhibiting spontaneous breathing movements and possible patient-ventilator asynchrony and pain or distress. similarly, critically ill patients who are not mechanically ventilated may be managed with noninvasive ventilation or exhibit respiratory failure, forced expiration, and pain or stress. all of the above processes may lead to abdominal wall muscle contraction and increased iap that may not reflect an increase in intra-abdominal volume [13, 14] . although there are no data as to whether increased iap due to abdominal muscle activity in these groups of patients has the potential to cause organ dysfunction, it has been reported that in awake, non-critically ill patients without suspicion of iah, iap can be as high as 20 mmhg without causing discernible organ dysfunction [15] . the impact of high positive end-expiratory pressure (peep; >12 cmh 2 o) on iap is considered to be mild and adds 1-2 mmhg at most [16] . as deepening of sedation or using neuromuscular blocking agents may help to decrease iap and control iah for a limited period of time, it needs to be considered that deepening of sedation may have deleterious effects on hemodynamics. switching from assisted to controlled mechanical ventilation may sometimes result in a significant increase in intrathoracic pressure even with muscle relaxation and the expected positive effect on iap will be negligible compared to its negative effects. the baseline iap may vary in individual patients. obese patients in particular have higher baseline iap values [17] , which in some cases may be higher than the threshold for iah. one review found that iap in individuals with a normal weight was around 5-6 mmhg, whereas it was much higher in obese patients with values above 12 mmhg and even above 14 mmhg in morbid obesity [16] . other conditions associated with "physiologically" increased iap include pregnancy [18] and liver cirrhosis with ascites [19] . although this chronic iap elevation may contribute to chronic forms of organ failure, including chronic kidney failure in patients with congestive heart disease and obesity [20] or pseudotumor cerebri in patients with obesity [21] , slight increases from a higher starting value may have limited implications in critically ill patients. as such, an iap of 16 mmhg may be insignificant if the baseline value was 13 mmhg, where it may cause organ injury if the baseline value was 6 mmhg. unfortunately, the baseline iap value is usually unknown and this effect is difficult to quantify. in situations where exposure to iah has already been prolonged (e.g., several days, in cases of delayed iah diagnosis), organ dysfunction may not be reversible as quickly or fully as in more acute situations. we hypothesize that interventions aimed at lowering iap are unlikely to have an immediate beneficial effect on organ function in this context, especially when iah has caused or contributed to cellular organ injury (e.g., acute tubular necrosis). this highlights the importance of iap monitoring in at-risk patients to avoid delayed diagnosis [22] . on the other hand, one measurement of elevated iap does not constitute a definite diagnosis of iah/acs (as highlighted by the definitions in box 1). repetitive measurements are more likely to ascertain true iap values and unmask potential measurement errors. mild elevation of iap, measured at one time point, is unlikely to cause organ dysfunction and seldom warrant immediate intervention, but should lead to repeated iap measurement. the second element of the triangle to consider is the resultant degree of organ dysfunction thought to be secondary to iah and the rapidity with which it occurred. many experimental studies have shown that subclinical organ injury develops at levels of iap previously deemed to be safe (iap between 12 and 15 mmhg), but as iap increases, organ dysfunction will become more pronounced and a dose-dependent relationship between iap and organ dysfunction has been demonstrated in many studies [23] . one of the key features of acs is organ dysfunction and the absence of organ dysfunction should raise doubts about the reliability of the measurement or the interpretation of the iap value. the most extreme and urgent form of organ dysfunction in patients with acs is the inability to ventilate, which requires urgent action. another very frequent form of iah-induced organ dysfunction is iah-induced acute kidney injury (aki) [24] . there is extensive experimental evidence that aki occurs at iap levels as low as 12 mmhg [25] . in patients with acs, aki is usually firmly established with anuria and need for renal replacement therapy (rrt) unless early intervention is used to prevent this [25] . organ dysfunction is not limited to the respiratory or renal system and may include hemodynamic instability, metabolic failure, gastrointestinal failure, and even intracranial hypertension [26] . often multiple organ systems will fail, and the clinical picture can mimic many conditions (e.g., septic shock, hypovolemia) associated with multiple organ dysfunction syndrome (mods). compartment pressures can also be increased in more than one compartment and this has been referred to as the polycompartment syndrome [27] . the speed at which organ function deteriorates and the time-dependent relationship with the increase in iap are important elements to consider. a sudden increase in intra-abdominal volume, causing a sudden increase in iap with subsequent organ dysfunction, warrants more aggressive treatment than a situation where a condition frequently associated with mods is diagnosed concurrently with iah and organ dysfunction. indeed, in many conditions that are associated with iah, the pathophysiology of the underlying disease (e.g., severe trauma, severe acute pancreatitis, or burns) may cause severe organ dysfunction and the exact role of increased iap superimposed on this "primary" organ injury may be difficult to estimate. baseline organ dysfunction (i.e., before iah was present) as well as dynamics between concurrent increase in iap and deterioration of organ function may offer a clue. the third element to consider in iah management is the etiology of the elevated iap, which allows selection of the best possible treatment option. the course of disease also needs to be considered. an initial increase in iap up to 18 mmhg after elective abdominal hernia repair may be well tolerated [28] and could be just observed, whereas the same value of iap in a patient with severe acute pancreatitis and shock still needing massive fluid resuscitation to preserve organ perfusion presents a high risk for developing acs and needs immediate attention and measures (e.g., sedation, muscle relaxation) to control the iap. all reasonable attempts should be made to ascertain the underlying disease leading to elevated iap before starting treatment. knowledge of the patient's medical history and present condition and a full general and abdominal clinical examination usually offer the first clues. directed imaging, such as ultrasound or computed tomography (ct), may also be necessary. a plethora of risk factors for iah/acs has been described, but they can be largely divided into three categories: increased intraabdominal volume, decreased abdominal compliance, and a combination of both [13] . this can be caused by increased intraluminal or extraluminal volume within the abdominal cavity. the presence of increased intraluminal volume can be suspected based on the clinical circumstances and diagnosed with medical imaging techniques if indicated (e.g., gastric distention after gastroscopy due to gas insufflation, added colonic volume in clostridium difficile colitis [29] , or severe constipation). increased extraluminal volume may accumulate freely in the abdominal cavity or localized in abdominal collections. free abdominal air, fluid, or blood can be diagnosed easily by bedside ultrasound and can be evacuated by percutaneous catheter drainage. extraluminal abdominal collections are mostly associated with underlying abdominal diseases (e.g., pancreatitis, abdominal sepsis, or abdominal hematoma) and usually require abdominal ultrasound or ct imaging for accurate diagnosis and treatment. tissue edema-often in a context of resuscitation or fluid overload-may be another cause of increased extraluminal volume, without any discernible collections. in rare cases, iah/acs may be caused by increased native solid organ volume (e.g., splenomegaly or in solid organ transplants [30] , e.g., in children receiving adult organs [31] ). abdominal wall compliance is a measure of the ease of abdominal expansion, which is determined by the elasticity of the abdominal wall and diaphragm [32] . when abdominal wall compliance is decreased, any increase in intra-abdominal volume is much more likely to produce a significant increase in iap. risk factors for decreased abdominal wall compliance can be divided into three categories, including those related to (1) body anthropomorphism and habitus (e.g., age, morbid obesity); (2) abdominal wall (e.g., burn eschars, rectus sheath hematoma, tight sutures or bandages, ventral hernia repair, prone positioning); and (3) comorbidities (e.g., capillary leak due to sepsis, burns, trauma, or pancreatitis) [33] . large-volume fluid resuscitation, usually related to systemic inflammatory syndrome and biomediator activation, is one of the most important risk factors for the development of iah/ acs, due to its combined effects of increased intra-abdominal volume (both intraand extraluminal due to ascites formation, gut edema, and ileus) and decreased abdominal wall compliance due to tissue edema of the abdominal wall. respiratory cycle-related variations in iap have been found to linearly increase with end-expiratory iap and reflect abdominal wall compliance [34] . the first two elements of the triangle (pressure and impact) will determine whether or not active attempts to decrease iap should be considered, in what timeframe these attempts should produce a clinically relevant result, and what level or invasiveness (and possibility of complications) is required. the third element (cause) will determine which treatment option will most likely produce the desired result. at the bedside, three critical questions should be asked once iah/acs has been diagnosed (fig. 3) . why intervene: the decision to intervene will be guided by the presence of organ dysfunction caused by a relevant increase in iap in a patient who has been diagnosed with a condition that may be associated with iah and in which an intervention is expected to have a beneficial impact on iap as well as on organ function. the iap value, the evolution of iap over time, and the degree of organ dysfunction are the most important considerations. however, the measured iap value should be interpreted carefully. if iap is elevated in semiconscious or fully awake patients and organ function is normal or improving, techniques to reduce iap are probably less warranted and may cause unnecessary complications. if iap is normal after analgesia/sedation, iah is unlikely to be a contributing factor to organ dysfunction. if iap remains increased, an underlying cause of iah is likely and additional diagnostic and/or therapeutic interventions are warranted. when to intervene: the urgency of an intervention in the setting of iah/acs depends on the measured iap value, the rate of iap increase, and the degree of organ dysfunction. in most situations, starting stepwise management should not be delayed and some situations require immediate invasive intervention. in general, in patients with primary acs, intervention is more urgent than in patients with secondary acs where the clinician has more time to intervene. if adequate oxygenation and/or ventilation cannot be maintained despite optimal ventilator settings, or circulation is severely compromised despite adequate fluid resuscitation and vasopressor support, immediate decompression may be required-irrespective of the other interventions. if organ function is slowly deteriorating along with a gradually increasing iap, using a technique expected to have a slower effect on iap may be considered, fig. 3 elements to be considered in decision-making for management of intra-abdominal hypertension (iah). acs abdominal compartment syndrome, iap intra-abdominal pressure if the potential for serious complications can be avoided by this strategy. how to intervene: the method of choice for treating iah will be guided by both the cause that led to the iah and the degree of organ dysfunction. knowing the cause of iah can help predict the effect of a specific intervention on iap, both in magnitude and time to effect. the degree and dynamics of organ dysfunction should be considered to determine the desired decrease in iap and the time allowed to achieve it. many techniques to decrease iap have been described and interventions may be aimed at lowering intra-abdominal volume (intra-or extraluminal volume), improving abdominal compliance, or both. evacuation of excess volume from the gastrointestinal tract can be accomplished by prokinetics and/or enemas. decompression of the gastrointestinal tract by nasogastric and/or rectal tubes or endoscopic decompression can be performed quickly and safely, but only the most proximal and distal parts of the gastrointestinal tract are accessible for easy intervention [8] , thereby limiting their expected effectiveness in some patients. iah/acs due to small bowel dilatation may be difficult to treat noninvasively. even if surgery is not required for treatment of the underlying condition, decompressive laparotomy may be necessary, especially as the combination of abdominal visceral edema and increased iap poses a significant risk for bacterial translocation or even bowel ischemia [35] . percutaneous catheter drainage can be used as a definitive treatment in some cases (e.g., ascites in liver cirrhosis [36] , burn patients with acs [37] ), but can also be used as a temporary measure in cases where investigation of the underlying disease is ongoing but organ dysfunction requires urgent decompression (e.g., decompression of pneumoperitoneum before evaluation for gastrointestinal tract perforation [38] ) or after definitive treatment of the underlying condition to treat any residual iah/acs (e.g., evacuation of free abdominal blood after endovascular aortic reconstruction for ruptured aortic aneurysm). this is a direct challenge to the classical adage that a diagnosis of overt acs equals the need for decompressive laparotomy while, even in extreme circumstances, the etiology of acs should be considered. as an example, several cases of acs due to acute massive pneumoperitoneum, successfully treated with needle decompression, have been published [38] . some conditions associated with impaired abdominal wall compliance can be easily corrected and enable fast and significant decrease in iap. burn eschars can be treated with escharotomy [39] , tight bandages can be released, and body position can be changed [13] . for other causes of decreased abdominal wall compliance, fast release is not possible or not desirable (e.g., release of a tight hernia repair). in these cases, other techniques to improve abdominal wall compliance can be attempted (such as analgesia and/or sedation [40] , neuromuscular blockers [41] , and changing body position [42] ) when indicated. since small changes in intra-abdominal volumes can lead to significant changes in iap in patients with decreased abdominal wall compliance, bedside ultrasound and removal of moderate amounts of ascites may offer relief of iah/acs, even if the main etiology of iah is decreased abdominal wall compliance not amenable to nonsurgical treatment. decompressive laparotomy will decrease intra-abdominal volume in relation to the abdominal cavity and abdominal wall compliance and is as such the ultimate treatment for acs. however, the consequences are considerable and even with improved open abdomen management techniques this should-based on current knowledge-only be reserved for treatment failures [10] [11] [12] . however, treatment failures should be identified swiftly when they occur and both the decision to proceed to decompressive laparotomy and the execution of that decision should not be delayed if the patient's condition warrants urgent intervention. the anesthesiologist and/or intensivist should be aware that decompressive laparotomy can be a severe ischemiareperfusion event, especially when iap has been elevated for some time, and patients may require supportive measures to tolerate the intervention. after decompressive laparotomy, patients should still be treated according to the medical management principles, especially in terms of controlling fluid balance and improving abdominal compliance, in order to facilitate primary fascial closure. the success of this approach has been demonstrated by cheatham et al. [43] . iap should be monitored closely after decompressive laparotomy in order to prevent recurrent acs [44] . this chapter focuses on the treatment of iah/acs in terms of treatment aimed at reducing iap. it is important to realize that the presence of iah/acs may lead to changes in general icu management [45] . respiratory management is affected since studies have shown that higher ventilation pressures (both peep and plateau pressures) can be used safely in patients with increased iap and may be warranted in order to maintain alveolar recruitment [46] . elevated iap has profound effects on the cardiovascular system and the microcirculation; it changes normal values for hemodynamic monitoring and can mimic a state of fluid responsiveness [47] . administration of a fluid bolus may temporarily improve tissue perfusion although fluid resuscitation is a major risk factor for (progression of) iah/acs [48] . since iah/acs can have an impact on practically all organ systems, it should be a consideration in all aspects of supportive icu management [49] , although a complete discussion on this topic is beyond the scope of this manuscript. secondary iah/ acs is mainly an iatrogenic disease related to fluid overload after resuscitation; therefore, a more restrictive fluid management approach with limitation of fluid intake or fluid removal with diuretics or rrt with net ultrafiltration may have a beneficial effect on outcomes [50] . in 2013, the wsacs published evidence-based guidelines on the definitions, diagnosis, and treatment of iah and acs. even with the implementation of these guidelines, making bedside decisions regarding the management of individual patients with iah/acs remains difficult, because of the wide variety of conditions associated with iah/acs, the broad spectrum of associated organ dysfunction, and the large number of treatment options available to decrease iap. in this chapter, we provide a clinical framework that provides insight into how to use the guidelines when managing a specific patient in daily practice. the key message is that treatment should not be based solely on the degree of iah, but also on the severity and dynamics of organ dysfunction as well as the etiology of iah/acs. in general, the higher the iap, the faster and more pronounced the rise in iap and the more severe or deteriorating the organ dysfunction, the prompter and more aggressive treatment of iah that is warranted. therefore, frequent re-evaluation, taking into account the progression of iah and course of disease and organ dysfunction, is necessary. if the underlying cause is well controlled and general condition is improving, the further course of iah can usually be observed before initiating aggressive treatment. if there is underlying ongoing inflammation and fluid resuscitation continues, it is unlikely that iah will decrease and more aggressive measures should be considered early. results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. i. definitions the measurement of intra-abdominal pressure as a criterion for abdominal re-exploration incidence, risk factors, and outcomes of intra-abdominal hypertension in critically ill patients-a prospective multicenter study (iroi study) what's new in medical management strategies for raised intra-abdominal pressure: evacuating intra-abdominal contents, improving abdominal wall compliance, pharmacotherapy, and continuous negative extraa-bdominal pressure the abdominal compartment syndrome: evolving concepts and future directions results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. ii. recommendations nonoperative management of intra-abdominal hypertension and abdominal compartment syndrome intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the world society of the abdominal compartment syndrome respiratory functions of burn patients undergoing decompressive laparotomy due to secondary abdominal compartment syndrome decompressive laparotomy for abdominal compartment syndrome-a critical analysis effect of decompressive laparotomy on organ function in patients with abdominal compartment syndrome: a systematic review and meta-analysis decompressive laparotomy for abdominal compartment syndrome the role of abdominal compliance, the neglected parameter in critically ill patients-a consensus review of 16. part 2: measurement techniques and management recommendations the role of abdominal compliance, the neglected parameter in critically ill patients-a consensus review of 16. part 1: definitions and pathophysiology determining normal values for intra-abdominal pressure what is normal intraabdominal pressure and how is it affected by positioning, body mass and positive end-expiratory pressure morbid obesity causes chronic increase of intra-abdominal pressure it's high time for intra-abdominal hypertension guidelines in pregnancy after more than 100 years of measuring pressures renal resistive index and renal function before and after paracentesis in patients with hepatorenal syndrome and tense ascites abdominal contributions to cardiorenal dysfunction in congestive heart failure the significance of intra-abdominal pressure in neurosurgery and neurological diseases: a narrative review and a conceptual proposal the duration of intra-abdominal hypertension strongly predicts outcomes for the critically ill surgical patients: a prospective observational study intra-abdominal hypertension and abdominal compartment syndrome intra-abdominal hypertension and acute renal failure in critically ill patients renal implications of increased intra-abdominal pressure: are the kidneys the canary for abdominal hypertension? current insights in intra-abdominal hypertension and abdominal compartment syndrome the polycompartment syndrome: a concise stateofthe-art review permissible intra-abdominal hypertension following complex abdominal wall reconstruction fulminant clostridium difficile enteritis causing abdominal compartment syndrome renal allograft compartment syndrome: an underappreciated postoperative complication surgical complications after intestinal transplantation in infants and children-uk experience the neglected role of abdominal compliance in organ-organ interactions abdominal compliance: a bench-to-bedside review integration of inspiratory and expiratory intra-abdominal pressure: a novel concept looking at mean intraabdominal pressure gut barrier dysfunction in critically ill surgical patients with abdominal compartment syndrome effects of plasma expansion with albumin and paracentesis on haemodynamics and kidney function in critically ill cirrhotic patients with tense ascites and hepatorenal syndrome: a prospective uncontrolled trial a pilot study comparing percutaneous decompression with decompressive laparotomy for acute abdominal compartment syndrome in thermal injury abdominal compartment syndrome caused by tension pneumoperitoneum in a scuba diver effects of escharotomy as abdominal decompression on cardiopulmonary function and visceral perfusion in abdominal compartment syndrome with burn patients results of a pilot study on the effects of propofol and dexmedetomidine on inflammatory responses and intra-abdominal pressure in severe sepsis the effect of neuromuscular blockers in patients with intra-abdominal hypertension the impact of body position on intra-abdominal pressure measurement: a multicenter analysis is the evolving management of intra-abdominal hypertension and abdominal compartment syndrome improving survival recurrent abdominal compartment syndrome: an inciting factor of the second hit phenomenon fluid therapy and perfusional considerations during resuscitation in critically ill patients with intra-abdominal hypertension ventilation in patients with intraabdominal hypertension: what every critical care physician needs to know intra-abdominal hypertension is responsible for false negatives to the passive leg raising test principles of fluid management and stewardship in septic shock: it is time to consider the four d's and the four phases of fluid therapy icu management of the patient with intraabdominal hypertension: what to do, when and to whom? fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank drs. bart authors' contributions jdw wrote concept and first draft. mlngm and idl reviewed and edited the manuscript. all authors read and approved the final manuscript. publication costs were funded by the authors.availability of data and materials not applicable.ethics approval and consent to participate not applicable competing interests mlngm is a member of the medical advisory board of pulsion medical systems (now fully integrated in getinge, solna, sweden) and serenno medical (tel aviv, israel), consults for baxter, maltron, convatec, acelity, spiegelberg and holtech medical. none of the remaining authors have any potential conflict of interest related to the main topic of this article.author details 1 key: cord-005496-cnwg4dnn authors: gutierrez, guillermo title: artificial intelligence in the intensive care unit date: 2020-03-24 journal: crit care doi: 10.1186/s13054-020-2785-y sha: doc_id: 5496 cord_uid: cnwg4dnn this article is one of ten reviews selected from the annual update in intensive care and emergency medicine 2020. other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. further information about the annual update in intensive care and emergency medicine is available from http://www.springer.com/series/8901. the past century has witnessed a massive increase in our ability to perform complex calculations. the development of the transistor in the 1950s, followed by the silicone integrated circuit, accelerated those capabilities and gave rise to what is commonly known as moore's law. according to this principle, the number of transistors packed into a dense integrated circuit doubles every 2 years. the corollary is that computation speed also doubles at 2-year intervals. figure 1 is a graphical interpretation of moore's law, showing an exponential increase in computational power, in terms of calculations per second that can be purchased with $1000 (constant us, 2015) . according to that graph, computing power has increased by a factor of 10 18 from the mechanical analytical engine of the early 1900s to today's core i7 quad chip found in personal laptop computers. the growth in computing power was made possible by the relentless downsizing of integrated circuits, with some components being produced in the sub-100 nm range. as we approach the physical limits of silicone chip downsizing, other materials are being developed. a likely candidate is the carbon nanotube, composed of a single sheet of carbon atoms arranged in a hexagonal pattern. when rolled into itself, the sheet becomes a tube approximately 2 nm in diameter, capable of forming different circuit elements. this nascent technology, along with the development of quantum computing, assures the durability of moore's law well into the future. as processors grew in power, and personal computers became ubiquitous appliances, the stage was set for the development of the internet, a digital network that morphed from the arpanet, a communication structure designed by the u.s. advanced research projects agency (arpa) to transfer information among computers located at remote distances. the internet promoted the free dissemination of software and provided the impetus for computer scientists to develop powerful algorithms aimed at simulating human intelligence. according to the encyclopedia britannica, artificial intelligence (ai) refers to a system "endowed with the intellectual processes characteristic of humans, such as the ability to reason, discover meaning, generalize, or learn from past experience." ai computer systems are able to perform tasks normally requiring human intelligence and that are considered "smart" by humans. ai systems act on information, such as controlling a self-driving automobile or influencing consumer shopping decisions. in the area of medicine, ai has been used in drug discovery, personalized diagnostics and therapeutics, molecular biology, bioinformatics, and medical imaging. ai applications are also capable of discerning patterns of disease by scrutinizing and analyzing massive amounts of digital information stored in electronic medical records. in a recent proposal aimed at regulating ai software in medical devices, the u.s. food and drug administration states that "artificial intelligence-based technologies have the potential to transform healthcare by deriving new and important insights from the vast amount of data generated during the delivery of healthcare every day" [1] . human intelligence is defined by the mental capability to think abstractly, use reason to solve problems, make plans, comprehend complex ideas, and learn from experience [2] . much of human intelligence involves pattern recognition, a process that matches a visual or other type of stimuli, to similar information stored in our brains. although endowed with abstract thinking and capable of sublime leaps in imagination, humans have a limited capacity for memory. it is estimated that the brain cannot store more than four "chunks" of short-term memory at any one time [3] . moreover, humans find it difficult to think in terms of n-dimensional spaces or visualize patterns embedded into large quantities of data. conversely, computers have vast memory storage, excel at handling multidimensional problems and can discern even small or "fuzzy" associations within massive data collections. the use of computers to guide the treatment of critically ill patients is not a new concept. with uneven results, computerized systems have been proposed in the past to monitor icu patients [4] , manage patients on mechanical ventilators [5, 6] , guide care in patients with acute respiratory distress syndrome (ards) [7] , and manage arterial oxygenation [8] . these early computer systems were programmed with highly specific and sequential if/then/else logical expressions that assessed the validity of a condition based on accepted physiological principles and/or clinical experience (fig. 2 ). according to these expressions, if a given condition was judged to be "true," then the program executed instruction 1, else, it executed instruction 2. ai is based on a fundamentally different approach to traditional computer programming. instead of instructing the computer to evaluate a given condition, or to perform a specific task according to detailed programmed instructions, ai algorithms, in a manner similar to the way children absorb knowledge, learn from exposure to numerous examples. ai algorithms establish their own rules of behavior and can even improve on their "intelligence" by incorporating additional experiences resulting from the application of these rules. machine learning is a subset of ai in which machines learn or extract knowledge from the available data, but do not act on the information. machine learning combines statistical analysis techniques with computer science to produce algorithms capable of "statistical learning." broadly speaking, there are two types of machine learning structures: supervised and unsupervised (fig. 3) . the objective of supervised machine learning is to develop an algorithm capable of predicting a unique output when provided with a specific input. in other words, the machine is shown examples of input (x) and its corresponding output (y), such that y = f(x). machine learning is predicated on large sets of data containing myriad examples that relate one or several input variables to a single output. the expectations are that the resulting algorithm will deliver accurate predictions when exposed to new and never before seen data. supervised learning requires a great deal of human effort when building large datasets to train and test the algorithm. there are two major types of supervised learning: regression and classification. most clinicians are familiar with regression analysis, a statistical technique producing a mathematical expression relating one input variable to another (linear regression) or many input variables to one dependent variable (multiple regression). in regression analysis, the output is a continuous function of the input. in other words, the predicted variable will change in concert with the input variables. regression is used commonly to test hypotheses involving causal relationships, with the choice of model being based on its significance and goodness of fit. classification supervised learning is a form of pattern recognition designed to predict a single, nonnumerical output, or "class," from a predefined list of possibilities. classifier algorithms are trained with many lines of data, with each line having several input variables and one desired output. for example, a model designed to identify a breed of dog may be trained with data listing their traits or characteristics, e.g., height, type of hair, and length of tail. each line will be associated with a specific breed. once trained, the model can be asked to predict the dog breed when given new set of input variables. two important steps are needed to build a classifier model. the first is to establish the number of classes the model will be required to identify. the second is to identify the number of variables required to describe the classes. fewer variables and classes require less training data and result in simpler and more accurate models. the simplest classification model is the binary kind, in which the model is asked to choose between a "yes" and a "no" answer. classes may consist of physical objects (chair, table, etc.), medical conditions (e.g., sepsis, ards, chronic obstructive pulmonary disease [copd], etc.), clinical or physiological observations (e.g., different types of arrhythmia or ventilator asynchronies). each class is associated with a number of input variables common to all classes. in machine learning parlance, input variables are known as "features," with each line of data, or "instance," containing several features and a single class. let us say we want to develop a classifier algorithm to identify five different kinds of animal (fig. 4) . in this example, each line of data has one animal class and several features to describe the animal's characteristic, such as sea or land dwelling, fish or mammal. this is a very simple example having only one instance per class. the model, therefore, would be totally inadequate if its purpose were to differentiate among different dog or cat breeds. in that case, many more instances would be needed to describe different types of dogs and cats. the more specific one wishes to be, the more features are needed to describe the classes. on the other hand, increasing the number of features results in complex models that require greater computing power and longer time to run, a condition termed "the curse of dimensionality." an important guiding principle in machine learning is the truism that "less is best." in mathematical terms, a feature matrix contains n features and m instances, and it is associated with an m length classification vector: perhaps the most important step in developing a machine learning model is to have a clear definition of the problem and to determine its suitability for machine learning. the next step is to determine the size of the feature matrix and the classification vector (fig. 5) . whereas humans develop generalized concepts on the basis of just a few examples, training a machine learning algorithm requires large quantities of data. the creation of a large feature matrix with its classification vector is accomplished by gathering as many instances as possible. once satisfied that we have collected an adequate number of examples to be presented to the computer, we split the feature matrix into a "training" dataset, for model development, and a "test" dataset. the data are split by a random process that assigns instances from the original data to each dataset. a common practice is to use 70% or 80% of the data for training and the remainder for testing. the purpose of the "test" dataset is to assess the algorithm's accuracy when exposed to never before seen data. accuracy is defined as the percentage of correct answers made by the algorithm on the unknown "test" dataset. should accuracy fall below a chosen expected value, we can choose to gather more "training" data or to use another type of machine learning algorithm altogether. several types of classifier algorithms may be used to create the machine learning model. among them are decision trees, random forests, k-nearest neighbors, and many others (fig. 3) . a popular type of classifier algorithm is the neural network, modeled on the way human neurons are thought to process information. the basic element of the neural network, the perceptron, produces a single binary output from several inputs. a neural network results from the interacting of several perceptrons. advanced machine learning systems encompassing several layers of stacked complex neural networks are called deep learning. it is beyond the purpose of this chapter to describe the theory and application of these algorithms (listed in fig. 3 ), but the reader interested in pursuing this line of investigation can access "scikit-learn" (https://scikitlearn.org/stable/), an open source machine learning library written with the python programming language (https://www.python.org/). this library of programs makes it relatively easy to develop classification supervised machine learning algorithms. when building a classifier model, it is imperative to generalize its utility to make accurate predictions using both the "training" and the "test" datasets. one should beware of models of high complexity that may conform closely to the "training" set, but have poor accuracy when applied to the "test" dataset, a phenomenon called "overfitting." in this type of machine learning, no instructions are given to the algorithm on how to process the data. instead, the computer is asked to extract knowledge from a large set of unclassified data with no known output or a set of rules. given the lack of label information, a major challenge for the investigator when evaluating an unsupervised algorithm is how to determine the utility of the results, or whether the right output has been achieved. unsupervised algorithms, however, can be very useful in exploratory attempts to understand large collections of data. the techniques most commonly used are clustering, anomaly detection, and dimensionality reduction. in clustering, algorithms are asked to identify or partition large data sets into subsections and patterns sharing similar characteristics. in anomaly detection the algorithm is asked to detect atypical patterns in the dataset, such as searching for outliers. dimensionality reduction is useful when analyzing data having many features, or dimensions. these algorithms may be able to present the data in a simpler form, summarizing its essential characteristics and making it easier for humans or other machine learning algorithms to understand. an important point to keep in mind is that no machine learning algorithm, regardless of its accuracy, is the only possible choice for a model. other algorithms may be capable of providing a good fit and derive additional useful inferences from the data. for those wishing to delve deeper into the development of machine learning models, a good source of information is the book by müller and guido [9] and the website (https://www.geeksforgeeks.org/learning-model-building-scikit-learn-pythonmachine-learning-library/). there are numerous opportunities in the hospital setting to apply ai. unsupervised machine learning techniques have been used to explore massive amounts of data encoded in electronic medical records. models have been developed to obtain important information in a patient's chart [10] and identify high-cost patients [11] . supervised machine learning algorithms, given their potential for automated pattern recognition of images, have proven their utility in radiology [12] and histopathology [13] . machine learning has been used extensively in the fields of surgery, as it pertains to robotics [14] , in cardiology [15] for early detection of heart failure [16] , and in cancer research to classify tumor types and growth rates [17] . although the introduction of machine learning to the icu is in its infancy, several studies have already been published describing the application of this technology in the management of the critically ill patient. some have used large population datasets to predict length of stay, icu readmission and mortality rates, and the risks of developing medical complications or conditions such as sepsis and ards. other studies have dealt with smaller datasets of clinical and physiological data to aid in the monitoring of patients undergoing ventilatory support. houthooft et al. [18] trained a support vector machine model to forecast patient survival and length of stay using data from 14,480 patients. the model's area under the curve (auc) for predicting a prolonged length of stay was 0.82. this is in contrast to a clinical study showing the accuracy of physicians to be only 53% when predicting icu length of stay [19] . a hidden markov model framework applied to physiological measurements taken during the first 48 h of icu admission also predicted icu length of stay with reasonable accuracy [20] . the problem of icu readmission was investigated with a neural network algorithm applied to the medical information mart for intensive care iii (mimic-iii) database. this is an open source, freely available database collected from patients treated in the critical care units of the beth israel deaconess medical center between 2001 and 2012. the algorithm was able to identify patients at risk of icu readmission with 0.74 sensitivity and auc of 0.79 [21] . awad et al. [22] applied several machine learning algorithms, including decision trees, random forest, and naïve bayes to 11,722 first admission mimic-ii data to predict icu mortality. features included demographic, physiological, and laboratory data. these models outperformed standard scoring systems, such as apache-ii, sequential organ failure assessment (sofa), and simplified acute physiology score (saps), a finding that was confirmed by the same group in a follow-up study using time-series analysis [23] . a swedish system using artificial neural networks applied to >200,000 first-time icu admissions also showed superior performance in predicting the risk of dying when compared to saps-3 [24] . machine learning models have also been proposed to predict mortality in trauma [25] and pediatric icu patients [26] . the abovementioned icu survival models, while offering improved performance when compared to standard mortality prediction scoring systems, are somewhat cumbersome to use, require a large number of variables and have yet to be tested prospectively. yoon et al. [27] developed a method to predict instability in the icu based on logistic regression and random forest models of electrocardiogram (ekg) measures of tachycardia, reporting an accuracy of 0.81 and auc of 0.87. the publication of the study is accompanied by an excellent and highly recommended editorial by vistisen et al. [28] that thoroughly analyzes the strengths and pitfalls of machine learning methods as predictors of complications in the icu. a recent study applied a random forest classifier to over 200,000 electronic health records of hospitalized patients to predict the occurrence of sepsis and septic shock. although the algorithm was highly specific (98%), it only had a sensitivity of 26%, severely limiting its utility [29] . other studies have been published describing the use of machine learning models in generating patient-specific risk scores for pulmonary emboli [30] , risk stratification of ards [31] , prediction of acute kidney injury in severely burned patients [32] and in general icu populations [33] , prediction of volume responsiveness after fluid administration [34] and identification of patients likely to develop complicated clostridium difficile infection [35] . whereas present day mechanical ventilators work exceedingly well in delivering air to diseased lungs, they are "feed-forward" or open loop systems where the input signal, or mode of ventilation, is largely unaffected by its output, the adequacy of ventilation. as such, ventilators lack the capacity to assess the patient's response to the delivered breath. a desirable solution is the development of the autonomous ventilator, a device that could monitor the patient's response to ventilation continuously, while adjusting ventilatory parameters to provide the patient with a comfortable, optimally delivered breath. although we are far from this ideal device, significant strides are being made toward making it into a reality. over the past decade, there has been considerable interest in detecting and classifying patient-ventilator asynchrony, a phenomenon indicating the degree of coupling or response of the patient to ventilatory support [36] . machine learning methods of detecting patient-ventilator asynchrony have been based on morphological changes of the pressure and flow signals. chen et al. [37] developed an algorithm to identify ineffective efforts from the maximum deflection of the expiratory portion of airway pressure and flow. ineffective effort was present in 58% of the 24 patients enrolled in their study. analysis of 5899 breaths yielded sensitivity and specificity for the detection of ineffective efforts >90%. an algorithm developed by blanch at al [38] . compared a theoretical exponential expiratory flow curve to actual flow tracings. a deviation exceeding 42% was considered indicative of ineffective effort. they compared the predictions of the algorithm in a random selection of 1024 breaths obtained from 16 patients, to those made by five experts and reported 91.5% sensitivity and 91.7% specificity with 80.3% predictive value. as proof-of-concept, this group also reported monitoring airway signals in 51 mechanically ventilated patients and were able to predict the probability of an asynchrony occurring from one breath period to the next using a hidden markov model [39] . the system used in these trials has been commercialized as better care®, and it is capable of acquiring, synchronizing, recording, and analyzing digital signals from bedside monitors and mechanical ventilators [38] . rhem et al. [40] and adams et al. [41] developed a set of algorithms to detect two types of asynchrony associated with dynamic hyperinflation, double triggering, and flow asynchrony. based on a learning database of 5075 breaths from 16 patients, they developed logical operators to recognize double triggering based on bedside clinical rules. dynamic hyperinflation was identified from the ratio of exhaled to inhaled tidal volume. the algorithms were validated with data drawn from another patient cohort (n = 17), resulting in sensitivity and specificity >90%. sottile at al [42] . evaluated several types of machine learning algorithms, including random forest, naïve bayes, and adaboost on data recorded from 62 mechanically ventilated patients with or at risk of ards. they chose 116 features based on clinical insight and signal description and were able to determine the presence of synchronous breathing, as well as three types of patientventilator asynchrony, including double triggering, flow limited and ineffective triggering, with an auc >0.89. the authors did acknowledge that their algorithm does not identify all types of patient-ventilator asynchrony, in particular premature ventilator terminated breaths, or cycling asynchronies. gholami et al. [43] trained a random forest classifier algorithm from a training data set produced by five experts who evaluated 1377 breath cycles from 11 mechanically ventilated patients to evaluate cycling asynchronies. patients were ventilated with pressurecontrolled volume ventilation. the model accurately detected the presence or absence of secondary synchrony with a sensitivity of 89%. mulqueeny et al. [44] used a naïve bayes machine learning algorithm with 21 features, including measures of respiratory rate, tidal volume, respiratory mechanics and expiratory flow morphology to a dataset of 5624 breaths manually classified by a single observer, resulting in an accuracy of 84%, but a sensitivity of only 59%. loo et al. [45] trained a convolutional neural network with 5500 abnormal and 5500 normal breathing cycles aimed at developing an algorithm capable of separating normal from abnormal breathing cycles, reporting 96.9% sensitivity and 63.7% specificity. the accuracy of a machine learning algorithm is judged by its ability to correctly predict the unseen test dataset. models are created and tested with instances culled from the same data population, and it is common to find reports of algorithms having very high accuracy scores in the machine learning literature. given a judicious selection of features, a sufficiently large number of instances, and a wise choice of algorithm, the most likely outcome will be a highly accurate model. if the data are true and verifiable, the model's predictions are also bound to be reliable. on the other hand, when a model trained with untested or faulty data is presented with data drawn from the same population, the predictions are likely to be accurate but totally unreliable. as some have succinctly put it, rubbish in, rubbish out. this begs the question of what are the limits of model reliability. whereas ai is able to consider numerous variables and minimize human bias in data classification, it cannot insure model reliability. therefore, the greatest challenge when creating a clinical machine learning model lies in identifying the gold standard to be used in the classification. a great deal of what we see and do in medicine is highly subjective, and unanimity of opinion is seldom found among intensivists. for example, a study [46] on interobserver reliability of clinicians in diagnosing ards according to the berlin definition found only a moderate degree of reliability (kappa = 0.50). the main driver of the variability was the interpretation of chest radiographs. similar findings were noted in clinicians evaluating optic disk photographs for glaucoma (kappa 0.40-0.52) [47] . it is therefore unlikely that model reliability in the icu will ever exceed 60-70%, even in the best of hands. experienced intensivists excel at collecting, classifying, and analyzing snapshots of clinical information to expeditiously reach a diagnosis and decide on treatment options. in the data-intensive environment of today's icus, however, intensivists must cope with a relentless flow of information, some of it useful, most of it not. according to a thoughtful essay by alan morris [48] , intensivists must contend with no less than 236 variables when caring for patients on ventilatory support. the ability to catalog, correlate, and classify these variables on a continuous basis lies well beyond the capabilities of even the most knowledgeable and perceptive of clinicians. the judicious application of ai technology can be of assistance in helping us deal with information overload. machine learning algorithms have been used to analyze data stored in electronic medical records to predict icu mortality and length of stay. they also have furthered our understanding of populations who may be at risk of disease progression or likely to experience medical complications. these retrospective studies, useful as they may be in the early identification and stratification of patients, represent only the low-lying fruit in ai research. a more difficult task, but perhaps one with far greater potential, is the development of intelligent machine learning monitors capable of continuously assessing the human response to critical illness with a high degree of certainty. the development of such monitors will provide the knowledge and experience needed for the creation of the semi-autonomous icu, an environment where intelligent machines provide most of the care delivered today by humans. the full potential of ai will be realized once it becomes a trustworthy clinical adjunct to intensivists. by helping us cope with information overload, ai endowed machines may allow our faculties of reflection, imagination, and compassion to come to the fore when caring for fellow humans in distress. the future of ai in the icu is indeed bright. as with all new technologies, there will be zealots and pharisees, ups and downs, elations and disappointments, as well as thorny ethical quandaries. i have no doubt, however, that ai is here to stay, and it behooves us to become familiar with this technology for the betterment of our patients. proposed regulatory framework for modifications to artificial intelligence/ machine learning (ai/ml)-based software as a medical device (samd) mainstream science on intelligence: an editorial with 52 signatories, history, and bibliography chunks in expert memory: evidence for the magical number four integrated computer systems for monitoring of the critically ill assessment of the ability to manage patients on mechanical ventilators using a computer model a microprocessor based feedback controller for mechanical ventilation computerized management of patient care in a complex, controlled clinical trial in the 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are unable to accurately predict length of stay at admission: a prospective study improving length of stay prediction using a hidden markov model analysis and prediction of unplanned intensive care unit readmission using recurrent neural networks with lon short term memory early hospital mortality prediction of intensive care unit patients using an ensemble learning approach predicting hospital mortality for intensive care unit patients: time-series analysis artificial neural networks improve and simplify intensive care mortality prognostication: a national cohort study of 217,289 first-time intensive care unit admissions machine learning models of survival prediction in trauma patients a deep learning model for real-time mortality prediction in critically ill children predicting tachycardia as a surrogate for instability in the intensive care unit predicting vital sign deterioration with artificial intelligence or machine learning a machine learning algorithm to predict severe sepsis and septic shock: development, implementation, and impact on clinical practice development and performance of the pulmonary embolism result forecast model (perform) for computed tomography clinical decision support machine learning for patient risk stratification for acute respiratory distress syndrome artificial intelligence and machine learning for predicting acute kidney injury in severely burned patients: a proof of concept machine learning versus physicians' prediction of acute kidney injury in critically ill adults: a prospective evaluation of the akipredictor machine learning for the prediction of volume responsiveness in patients with oliguric acute kidney injury in critical care using machine learning and the electronic health record to predict complicated clostridium difficile infection patient-ventilator asynchrony during assisted mechanical ventilation detecting ineffective triggering in the expiratory phase in mechanically ventilated patients based on airway flow and pressure deflection: feasibility of using a computer algorithm validation of the better care® system to detect ineffective efforts during expiration in mechanically ventilated patients: a pilot study predicting patient-ventilator asynchronies with hidden markov models creation of a robust and generalizable machine learning classifier for patient ventilator asynchrony development and validation of a multialgorithm analytic platform to detect off-target mechanical ventilation the association between ventilator dyssynchrony, delivered tidal volume, and sedation using a novel automated ventilator dyssynchrony detection algorithm replicating human expertise of mechanical ventilation waveform analysis in detecting patient-ventilator cycling asynchrony using machine learning automated detection of asynchrony in patient-ventilator interaction mat-nor mb. a machine learning model for real-time asynchronous breathing monitoring interobserver reliability of the berlin ards definition and strategies to improve the reliability of ards diagnosis agreement among clinicians in the recognition of patterns of optic disk damage in glaucoma human cognitive limitations. broad, consistent, clinical application of physiological principles will require decision support publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none.author's contributions single author review by guillermo gutierrez, md, phd who has read and approved of the final manuscript. availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. key: cord-000498-absjerdt authors: hagau, natalia; slavcovici, adriana; gonganau, daniel n; oltean, simona; dirzu, dan s; brezoszki, erika s; maxim, mihaela; ciuce, constantin; mlesnite, monica; gavrus, rodica l; laslo, carmen; hagau, radu; petrescu, magda; studnicska, daniela m title: clinical aspects and cytokine response in severe h1n1 influenza a virus infection date: 2010-11-09 journal: crit care doi: 10.1186/cc9324 sha: doc_id: 498 cord_uid: absjerdt introduction: the immune responses in patients with novel a(h1n1) virus infection (nva(h1n1)) are incompletely characterized. we investigated the profile of th1 and th17 mediators and interferon-inducible protein-10 (ip-10) in groups with severe and mild nva(h1n1) disease and correlated them with clinical aspects. methods: thirty-two patients hospitalized with confirmed nva(h1n1) infection were enrolled in the study: 21 patients with nva(h1n1)-acute respiratory distress syndrome (ards) and 11 patients with mild disease. one group of 20 patients with bacterial sepsis-ards and another group of 15 healthy volunteers were added to compare their cytokine levels with pandemic influenza groups. in the nva(h1n1)-ards group, the serum cytokine samples were obtained on admission and 3 days later. the clinical aspects were recorded prospectively. results: in the nva(h1n1)-ards group, obesity and lymphocytopenia were more common and ip-10, interleukin (il)-12, il-15, tumor necrosis factor (tnf)α, il-6, il-8 and il-9 were significantly increased versus control. when comparing mild with severe nva(h1n1) groups, il-6, il-8, il-15 and tnfα were significantly higher in the severe group. in nonsurvivors versus survivors, il-6 and il-15 were increased on admission and remained higher 3 days later. a positive correlation of il-6, il-8 and il-15 levels with c-reactive protein and with > 5-day interval between symptom onset and admission, and a negative correlation with the pao(2):fio(2 )ratio, were found in nva(h1n1) groups. in obese patients with influenza disease, a significant increased level of il-8 was found. when comparing viral ards with bacterial ards, the level of il-8, il-17 and tnfα was significantly higher in bacterial ards and il-12 was increased only in viral ards. conclusions: in our critically ill patients with novel influenza a(h1n1) virus infection, the hallmarks of the severity of disease were il-6, il-15, il-8 and tnfα. these cytokines, except tnfα, had a positive correlation with the admission delay and c-reactive protein, and a negative correlation with the pao(2):fio(2 )ratio. obese patients with nva(h1n1) disease have a significant level of il-8. there are significant differences in the level of cytokines when comparing viral ards with bacterial ards. originating from mexico and spreading initially in the united states and canada, a novel influenza a(h1n1) virus infection (nva(h1n1)) of swine origin spread globally during spring 2009 to mid-february 2010. rates of hospitalization and death have varied widely according to country [1] . among hospitalized patients 9 to 31% have been admitted to intensive care units (icus) where the rate of death was 14 to 46% [2] [3] [4] [5] [6] . in romania the pandemic wave lasted from september 2009 to february 2010, reaching a peak in december. the romanian ministry of health reported 7,008 confirmed cases of nva(h1n1) influenza, the death rate being 1.9%. primary influenza pneumonia had a high mortality rate during pandemics not only in immune-compromised individuals and patients with underlying co-morbid conditions, but also in young healthy adults [7] . during nva(h1n1) virus infection, experimental and clinical studies have identified dysregulated systemic inflammation as an important pathogenetic mechanism correlating with severity and progression of the disease [8, 9] . the role of most immune responses in controlling and clearance of h1n1 influenza a or its contribution to severe respiratory compromise is not well known. to and colleagues found higher plasma levels of proinflammatory cytokines and chemokine in the group of patients with acute respiratory distress syndrome (ards) caused by viral a(h1n1) influenza, throughout the initial 10 days after symptom onset [8] . bermejo-martin and colleagues found that mediators involved in the development of th17 cells (il-6, il-8, il-9, il-17), th1 cells (tnfα, il-15, il-12p70) and type ii interferon (ifnγ) had high systemic levels in hospitalized patients with nva(h1n1) influenza [9] . the detrimental or beneficial role of these cytokines in severe illness is not known. the aim of our study was to further investigate the profile of th1 and th17 mediators and interferoninductible protein-10 (ip-10), an innate-immunity mediator, as early host response in a group of critical and noncritical hospitalized patients with nva(h1n1) from cluj-napoca, romania, and to correlate them with the clinical aspects. the study was performed between october 2009 and february 2010 in the icus of the emergency county clinical hospital and of the teaching hospital of infectious diseases, cluj-napoca, romania. thirty-two patients hospitalized with nva(h1n1) infection were enrolled in the study: 21 patients with nva(h1n1)-ards, and 11 patients with nva(h1n1)mild disease. additionally, 20 patients with bacterial sepsis-ards were included and served to compare the cytokine levels between the nva(h1n1)-ards group and the bacterial sepsis-ards group. the study protocol was approved by the ethics committee for clinical research of the university of medicine and pharmacy 'iuliu hatieganu' cluj napoca and the hospital authority. informed consent was obtained from each patient or their legal representative. the inclusion criteria were age > 16 years, symptoms compatible with influenza and confirmed nva(h1n1) virus, bacterial severe sepsis with ards, and informed consent. the exclusion criteria were age < 16 years, known infection by human immunodeficiency virus, patients with other respiratory viral infections, bacterial sepsis without ards-syndrome, and refusal to consent. the control group included 15 healthy volunteers without chronic or acute disease. data were recorded prospectively by investigators at each hospital. the following data were recorded: age, sex, pregnancy, underlying diseases (chronic obstructive pulmonary disease, asthma, diabetes, chronic heart failure, chronic renal failure, cirrhosis, immunosuppression), obesity defined as body mass index > 30, and the time in days from symptom onset to hospital admission. hematological, biochemical and microbiological results were included in the database. the extension of lung infiltrates on chest x-ray scan was registered as the number of quadrants involved. the severity and prognosis of the illness was assessed in adults using the acute physiology and chronic health evaluation ii (apache ii) score and the sepsis-related organ failure assessment (sofa) score. ards was defined using the 1994 american-european consensus conference definitions [10] . the pulmonary dysfunction score was based on the pao 2 :fio 2 ratio, ranging from 0 to 3 where grade 0 represented a ratio less or equal to 250; grade 1, a ratio ranging from 250 to 175; grade 2, a ratio ranging from 100 to 175; and grade 3, a ratio less or equal to 100 [11] . a(h1n1) influenza virus presence was confirmed by testing nasopharyngeal swabs or bronchoalveolar lavage specimens with real-time pcr (commercial kits: full velocity sybr green qrt-pcr/superscript iii platinum one-step quantitative rt-pcr taqman; invitrogen corporation, carlsbad, california, usa) at the national influenza centre of cantacuzino institute, bucharest, romania. in patients with nva(h1n1)-mild disease, the serum samples were taken on hospital admission. in patients with nva(h1n1)-ards infection, the serum samples were taken on admission to the icu and 3 days later to determine cytokine kinetics. the installation of ards, either viral or bacterial, in the course of the disease determined the time of admission to the icu. in patients with bacterial sepsis-related ards, the serum samples were taken on admission to the icu. the enrolled patients and the healthy volunteers gave whole blood, which was clotted for 30 minutes at 37°c and stored at -70°c until use. the resulting serum was used for cytokine determination. seven different serum cytokines (il-6, il-8, il-12p70, il-15, il-17, tnfα and ifn-γ) were measured with luminex 200 (luminex corporation, austin, tx, usa) using a multiplex cytokine kit along with the assay performed in accordance with the manufacturer's instructions (r&d systems, minneapolis, mn, usa). additionally, we used elisa kits for quantitative determination of the two cytokines il-9 and ip-10 (quantikine; r&d systems). subjects were stratified into three groups: 11 patients with nva(h1n1)-mild disease, 21 patients with nva (h1n1)-ards, and 20 patients with bacterial sepsis-ards. descriptive statistics included means and standard deviations or medians and interquartile ranges for continuous variables of normal and non-normal distributions. clinical and biochemical characteristics and cytokine levels were compared. the fisher exact test and the chi-square test were used for categorical variables. the mann-whitney u test was used for nonparametric variables. the wilcoxon test (nonparametric test) was used to compare two paired groups. the association between nonparametric variables was determined by the spearman correlation coefficient (r). any value of p < 0.05 was considered statistically significant. graphpad prism version 5.03 software for windows (graphpad software, la jolla, california, usa) was used. a total of 32 patients with confirmed nva(h1n1) infection and 20 patients with bacterial sepsis-ards were enrolled over the study period. their demographic, co-morbidities and clinical characteristics are presented in table 1 . patients in the nva(h1n1)-ards group were significantly older than those in the nva(h1n1)-mild disease group (median age 42 years vs. 33 years, p = 0.009). obesity was more common in the nva(h1n1)-ards group. the median interval between onset of illness and admission was 6 days (interquartile range 3.5 to 8.5) in the nva(h1n1)-ards group and 2 days (interquartile range 2 to 3) in the mild disease group (p < 0.001) ( table 1 ). all the patients with nva(h1n1) virus infection presented symptoms of acute respiratory viral infection on admission. the median length of hospital stay was higher in the nva(h1n1)-ards group compared with the mild disease group (11 days vs. 6 days, p < 0.001). all patients with nva(h1n1) virus infection received oseltamivir on admission: the standard dose (150 mg/day) was administered for patients with mild disease, and a higher dose (300 mg/day) was used for nva(h1n1)-ards patients. during the icu hospitalization, critical patients with influenza virus infection (ards) received corticosteroid therapy (hydrocortisone or methylprednisolone). in agreement with our protocol, empirical antibiotics were started on admission. among 21 patients with nva(h1n1)-ards, four developed acute renal failure requiring renal replacement therapy, two developed secondary bacterial pneumonia and three developed pneumothorax (table 1 ). ten patients from the nva(h1n1)-ards group received non-invasive ventilation and 11 patients received mechanical ventilation. pregnancy was another risk factor for nva(h1n1)-ards infection and icu admission (3/21 cases; table 1 ). two pregnant women were in the third trimester and one was in the second trimester. no underlying disease was noted. the range interval after symptom onset and icu admission was 3 to 7 days. caesarean delivery was necessary in two cases. all pregnant women required respiratory support (two invasive and one noninvasive) during hospitalization and all survived. seven patients died in the nvh1n1-ards group. histopathological changes were similar in all cases: tracheitis, bronchitis with focal squamous metaplasia, necrotizing bronchiolitis, emphysema, extensive diffuse alveolar damage associated with alveolar hemorrhage and marked hyaline membrane formation, fibrosis and granulocyte pulmonary infiltrates. pulmonary thromboemboli with focal infarcts were observed in three cases. the lymphocyte count was significantly lower in the nva(h1n1)-ards group than in the mild disease group (p = 0.011) ( table 2 ). comparing laboratory abnormalities on hospital admission we found that patients with nva(h1n1)-ards were more likely to have elevated levels of serum lactate dehydrogenase, alanine and aspartate aminotransferase (p < 0.001, p = 0.049 and p < 0.001, respectively) than patients with nva(h1n1)mild disease ( table 2) . twenty patients with bacterial sepsis-ards were included to compare the cytokine levels in viral and bacterial ards. immune suppression (six patients with cancer) was more common in the bacterial sepsis-ards group (p = 0.044). the mean (standard deviation) apache ii score, sofa score and pao 2 :fio 2 ratio were similar in both groups ( table 1 ). the leukocyte count, c-reactive protein and procalcitonin levels were higher in the bacterial ards group than in the nva (h1n1)-ards group (p = 0.047, p = 0.05 and p < 0.001, respectively) ( table 2) . the results of the cytokine profile are shown in figure 1 . at admission, only il-6, il-12, ip-10 and tnfα were significantly higher in the mild disease group than in the control group. except for il-17 and ifnγ, all cytokine levels were higher in critical patients with nva (h1n1)-ards than in the control group. compared with the mild disease group, significantly higher levels of il-6, il-8, il-15 and tnfα were found in the nva (h1n1)-ards group (p < 0.001, p < 0.001, p < 0.001 and p < 0.05, respectively). compared with controls, the levels of il-6, il-8, il-9, il-15, il-17, ip-10 and tnfα were significantly elevated in the bacterial sepsis-ards group. levels of il-8, il-17 and tnfα were significantly higher in the bacterial-ards group versus the nva (h1n1)-ards group (p = 0.05, p = 0.004 and p = 0.011, respectively; figure 1 ). patients with pandemic influenza virus (severe ards and mild disease) were stratified according to the interval between symptom onset and admission. levels of il-6, il-8, il-15 and ifnγ were significantly higher in patients with delayed admission, > 5 days after symptom onset (p = 0.006, p = 0.037, p = 0.013 and p = 0.027, respectively) ( table 3 ). serum cytokine levels over time (3 days after admission and antiviral treatment) showed a decrease of il-6, ip-10, tnfα, ifnγ and il-17 in critical patients with nva (h1n1)-ards (table 4 ). serum cytokine levels over time in nva(h1n1)-ards survivors showed a significant decrease of il-6, ip-10 and tnfα (table 5 ). in nonsurvivors versus survivors from the nva(h1n1)-ards group, the levels of il-6 and il-15 on admission and 3 days after were significantly higher ( table 6 ). il-17 was higher in nonsurvivors 3 days after admission (table 6) . correlation between cytokine levels and clinical or laboratory characteristics in patients with confirmed nva(h1n1) infection was determined by spearman correlation coefficient. we found significant correlation of il-6, il-8 and il-15 levels with c-reactive protein (r = 0.67, p < 0.001; r = 0.5, p = 0.003; and r = 0.48, p = 0.005, respectively), with pao 2 :fio 2 ratio (r = -0.556, p = 0.001; r = -0.574, p < 0.001; and r = -0.614, p < 0.001, respectively) and with interval between symptom onset and hospital admission (r = 0.51, p = 0.002; r = 0.41, p = 0.019; and r = 0.48, p = 0.004, respectively). il-8 was significantly higher (p = 0.013) in obese versus nonobese patients with nva(h1n1) infection. in this study we presented the cytokine profiles following nva(h1n1) infection in 32 hospitalized patients (11 mild and 21 severe disease) and the cytokine profiles found in 20 cases of bacterial sepsis. the patients with severe nva(h1n1) disease were younger than the patients with bacterial sepsis (no statistical significance). similarly to other study groups, we found that obesity was more common in the nva (h1n1) ards group, suggesting it may be a risk factor for complications and admission to the icu [2, 5, 6] . laboratory findings in the same group of patients include lymphocytopenia and elevation in levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and creatinine -as in other patient groups with novel influenza virus infection [4, 6] . in contrast, the bacterial-ards group presented no lymphocytopenia, lower elevation in serum liver enzymes and higher levels of c-reactive protein and procalcitonin. no significant differences were found between bacterial and viral ards groups in sofa and apache ii scores at admission. the pulmonary histopathological findings in nva(h1n1)-ards nonsurvivors were similar to other fatal cases of nva(h1n1) virus infection [12, 13] . installation of ards in the course of the disease was the moment of blood sampling for cytokine measurements. there was a difference regarding the time of symptom onset and hospital admission between the severe and mild groups of nva(h1n1) disease that could affect the comparison of cytokine levels between the two groups. for this reason we not only compared the cytokine levels between mild and severe disease, but also mixed the patients with nva(h1n1)-mild and severe disease and compared the level of cytokines according to the interval between symptom onset and admission (first interval 1 to 5 days, second interval 6 to 14 days). we found that not all cytokines had the same behavior against the time of symptom onset and admission. the pattern of immune response in patients with nva (h1n1) virus infection is incompletely characterized. cd4 + t cells are known to play an important role in the initiation of immune responses by providing help to other cells. t-helper cells could be divided into subsets: th1, th2 and th17. th1 cells mainly develop following infections by intracellular bacteria and some viruses [14] . the mediators involved in the development of th1 are il-12, ifnγ, il-15, il-18 and tnfα. il-12 bridges the early nonspecific innate immunity and the subsequent antigen-specific adaptative immunity [15] . il-12 was shown to inhibit apoptosis of t cells [16] and of dendritic cells [17] . alveolar macrophages have a functional il-12 receptor, and virus-infected macrophages in the presence of il-12 might be protected from apoptosis limiting viral clearance [18] . apoptosis of virus-infected cells was shown to be an effective mechanism for viral clearance [19] . bermejo-martin and colleagues reported more significant il-12 results in the critical a(h1n1) group of patients [9] . in our study, il-12 is significantly higher in the nva (h1n1)-mild disease group and in the nva(h1n1)-ards group versus the control group and is not significantly higher in the bacterial ards group. il-15 plays a critical role in protecting cd8 + t cells from apoptosis during the contraction phase following microbial infection [20, 21] . the cd8 + t cells surviving in the presence of il-15 might be pathogenic in lung injury following highly pathogenic influenza a virus infection [22] . il-15 activates the effector function of memory phenotype cd8 + cells [23] . in our study, il-15 is significantly higher in the nva(h1n1)-ards group versus the nva(h1n1)-mild disease group, but without significant difference in the nva(h1n1)-ards versus bacterial-ards groups. similar to our results, il-15 was a hallmark of critical illness in the hong kong and spanish nva(h1n1) cytokine studies [8, 9] . il-15 is significantly higher at admission (p1) and 3 days later (p2) in the nva(h1n1)-ards group for nonsurvivors versus survivors, so it might be pathogenic in lung injury influenza a virus infection. similarly, to and colleagues found il-15 significantly higher in critical a(h1n1) patients and very significant in the a(h1n1)-ards death group [8] . ifnγ is a cytokine of innate and adaptative immunity. its major functions are activation of macrophages, differentiation of th1 from t cells, inhibition of the th17 pathway and control of intracellular pathogens [24] . bermejo-martin and colleagues found high systemic levels of ifnγ in hospitalized patients with nva(h1n1) [9] . in contrast, in the present study there were no differences between the control and study groups. the ifnγ level over time in the nva(h1n1) ards group was higher at admission than 3 days later, without significant difference between survivors versus nonsurvivors. tnfα is a cytokine of innate immunity. the principal cellular targets and biologic effects include activation of endothelial cells, neutrophil activation, fever, liver synthesis of acute phase proteins, muscle and fat catabolism, and apoptosis of many cell types. in our study, we found highly increased tnfα levels in the nva(h1n1)mild disease, nva(h1n1)-ards and bacterial ards groups compared to the control group. tnfα is significantly higher in nva(h1n1)-ards versus nva(h1n1)mild disease, with similar results being found by to and colleagues and bermejo-martin and colleagues [8, 9] . this cytokine is also significantly increased in bacterial-ards versus nva(h1n1)-ards. for the groups of patients with nva(h1n1), according to the time interval between symptom onset and hospital admission, there were no significant differences found for il-12 and tnfα levels, but there were significant differences for il-15 and ifnγ, levels being higher when the time interval was between 6 and 14 days. none of our patients were on oseltamivir medication between symptom onset and admission. th17 cells are effective in host defense against certain pathogens and tissue inflammation. th17 mediators for the development of th17 cells are il-6, transforming growth factor beta, il-8, il-9, il-17, il-1 and il-23. il-6 is a cytokine of innate immunity, its principal targets being the liver cells, the β cells and the naïve t cells [25] . despite the apparently beneficial role that macrophages play in controlling early viral replication, several reports have demonstrated a more deleterious effect of these cells in influenza a viral infections by excessive inflammation in the lung attributed to il-6 and tnfα [26] . in our study, il-6 is increased in nva(h1n1)-ards versus nva(h1n1)-mild disease. similarly, il-6 and il-15 constituted a hallmark of critical illness in the hong kong and spanish nva(h1n1) cytokine studies [8, 9] . in the nva(h1n1)-ards group, the il-6 serum level is significantly higher at admission than 3 days later. in the same group, il-6 is significantly higher in nonsurvivors versus survivors at admission and 3 days later, which seems to further contribute to pulmonary damage and death. we found positive correlations between il-6, il-15 and il-8 levels and a longer than 5 days interval between symptom onset and admission, as well as with c-reactive protein, but a negative correlation with the pao 2 :fio 2 ratio, indicating the severity of the disease. il-8 is a chemokine of innate immunity. the chemokine's principal biologic effect is chemotaxis, being a major chemokine for neutrophil activation, and migration into tissues [24] . in our study, il-8 is highly significant in the nva(h1n1)-ards and ards bacterial groups versus the control group, but is not significant in mild disease. in contrast, il-8 was increased in both critical and noncritical nva(h1n1) hospitalized patients in the spanish and hong kong studies. in our study, il-8 is higher in nva(h1n1)-ards versus nva(h1n1)-mild disease and in bacterial ards versus nva(h1n1)-ards. the obese patients with nva(h1n1) disease had a significant level of il-8. plasma il-8 levels are increased in normoglycemic obese subjects, related to fat mass and the tnfα system [27] . ip-10 is a chemokine of innate immunity, and macrophages and dendritic cells are the principal cell source. we found a higher level of ip-10 in nva(h1n1)-mild disease, nva(h1n1)-ards and bacterial-ards groups versus the control group, and no other differences between groups. in the nva(h1n1)-ards group, the ip-10 level is higher at admission than 3 days after admission because of the survivors' cytokine profile. an increased level of ip-10 was found in the spanish group as early response to nva(h1n1) infection in both hospitalized and mild patient disease, as in the present study, while in the hong kong group ip-10 was significantly higher in critical patients only. in our study, ip-10 levels in nva(h1n1)-ards nonsurvivors remained higher at admission and 3 days later, being not significantly correlated with the clinical outcome. emphysema was one of our hystopathological findings and thus it might be speculated that a high level of ip-10 in nonsurvivors could be correlated with emphysema. ip-10 released by lung cd41 and cd81 t cells stimulates alveolar macrophage production of matrix metalloproteinase-12, which digests lung elastin [28, 29] . il-17 is a cytokine of adaptative immunity. principal cellular targets include endothelial cells with increased chemokine production and macrophages with increased chemokine and cytokine production. this cytokine's principal biologic effect is proinflammatory [24, 25] . in the present study il-17 is significantly higher in the bacterial ards group versus the control group and is higher in the bacterial ards group versus the nva(h1n1)-ards group. no significant differences between nva(h1n1)-mild disease versus controls and between nva(h1n1)-ards versus controls were found. in the nva(h1n1)-ards group, il-17 was higher at admission and lower 3 days later. in the spanish study the il-17 level was increased in hospitalized noncritical patients, and in the hong kong study no differences between groups were found, similar to the present study. il-9, like il-6, is a th2 cytokine that induces differentiation of th17 cells and has anti-inflammatory properties. il-9 is a cytokine of current interest associated with allergic th2 responses and is a key modulator of antiviral immunity [30] . in our study il-9 is significantly higher in the h1n1-ards group versus the control group, and is not significantly increased in mild disease -in contrast to the spanish study, where il-9 was increased in both critical and noncritical hospitalized patients. regarding the behavior of th17 mediators in nva (h1n1) groups of patients according to the time interval between symptom onset and admission, there were no differences for il-9, il-17 and ip-10 and there were significant differences for il-6 and il-8, the levels being higher when the interval was between 6 and 14 days. all our patients with ards disease were on corticosteroid treatment, because deficient corticosteroid-mediated downregulation of inflammatory cytokine transcription in ards patients is associated with disease progression and mortality. many studies reported that prolonged corticosteroid treatment was associated with a significant reduction in markers of systemic inflammation [31, 32] . in the present study the blood samples for cytokine measurements were taken at admission for the bacterial-ards group of patients, and at admission and 3 days later for the nva(h1n1) group of patients -for this reason, corticosteroid could not significantly affect cytokine levels. the small number of patients enrolled in the mild disease group is one of our study limitations. among hospitalized patients with mild flu-like syndrome, only those with risk of severe complications and of secondary outbreaks in the exposed population were sampled for real-time pcr. on the contrary, the laboratory of the national influenza centre of cantacuzino institute, bucharest was overwhelmed, being the only centre for influenza pcr diagnosis. another limitation is the exclusion of children, an important group with nva (h1n1) virus infection. in our critically ill patients with nva(h1n1) virus infection we found increased levels of some cytokines: ip-10, tnfα, il-15, il-12, il-6, il-8 and il-9. the hallmarks for the severity of the disease were il-6, il-15, il-8 and tnfα. we found a positive correlation of il-6, il-15 and il-8 with the admission delay and c-reactive protein and a negative correlation with the pao 2 :fio 2 ratio. the obese patients with nva(h1n1) disease had a significant level of il-8. there were significant differences in the level of cytokines when comparing viral ards with bacterial ards. • in the influenza-related ards group, the levels of il-6, il-8, il-9, il-12, il-15, ip-10 and tnfα are significantly increased versus the control group. in the bacterial sepsis-ards group, levels of il-6, il-8, il-9, il-15, il-17, ip-10 and tnfα are also increased versus the control group. when comparing these two groups, the levels of il-8, il-17 and tnfα are significantly higher in bacterial ards versus viral ards, and il-12 is increased only in viral ards whereas il-17 is increased only in bacterial ards. when comparing the mild nva (h1n1) and critical ards influenza a groups, il-6, il-8, il-15 and tnfα are significantly higher in critical ards patients being hallmarks of disease severity. • the serum levels of il-15, il-6, il-8 and ifnγ according to the interval between symptom onset and admission in hospitalized nva(h1n1) patients are significantly higher when this interval is longer than 5 days. • in nonsurvivors versus survivors from the nva (h1n1)-ards group, il-6 and il-15 are increased at admission and stay higher 3 days later -which seems to further contribute to pulmonary damage and death. • there is a positive correlation of il-6, il-8 and il-15 levels with c-reactive protein and with > 5-day interval between symptom onset and hospital admission, and a negative correlation with the pao 2 :fio 2 ratio. • the obese patients versus nonobese patients with nva(h1n1) infection have a significant level of il-8. writing committee of the who consultation on clinical aspects of pandemic (h1n1) 2009 influenza: clinical aspects of pandemic 2009 influenza a (h1n1) virus infection h1n1) working group: factors associated with death or hospitalization due to pandemic 2009 influenza a(h1n1) infection in california pandemic influenza a (h1n1) virus hospitalizations investigation team: hospitalized patients with 2009 h1n1 influenza in the united states critically ill patients with 2009 influenza a(h1n1) in mexico the anzic influenza investigators: critical care services and 2009 h1n1 influenza in australia and new zealand critically ill patients with 2009 influenza a(h1n1) infection in canada clinical review: primary influenza viral pneumonia pandemic h1n1 study group: delayed clearance of viral load and marked cytokine activation in severe cases of pandemic h1n1 2009 influenza virus infection th1 and th17 hypercytokinemia as early host response signature in severe pandemic influenza definition, mechanisms, relevant outcome, and clinical trial coordination lung injury severity scoring in the era of lung protective mechanical ventilation: the pao 2 /fio 2 ratio pulmonary pathologic findings of fatal 2009 pandemic influenza a/h1n1 viral infections lung pathology in fatal novel human influenza a(h1n1) infection romagnani s: t-cell subsets (th1 versus th2) interleukin 12 a key immunoregulatory cytokine in infection applications il-12 decreases activation-induced cell death in human naïve th cells costimulated by intercellular adhesion molecule-1.i. il-12 alters caspase processing and inhibits enzyme function cytokine-mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the bcl-2 family of proteins positive regulatory role of il-12 in macrophages and modulation by ifn-gamma influenza a virus-induced apoptosis in bronchiolar epithelial (nci-h292) cells limits pro-inflammatory cytokine release il-15 promotes the survival of naïve and memory phenotype cd8 + t cells il-15 regulates cd8 + t cell contraction during primary infection interleukin-15 is critical in the pathogenesis of influenza a virus-induced acute lung injury il-15 mimics t cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in cd8 + memory t cells interleukin-17 and type 17 helper t cells th17 cells: effector t cells with inflammatory properties innate immune control and regulation of influenza virus infections plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-α system chronic obstructive pulmonary disease: molecular and cellular mechanisms an immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema il-9 regulates pathology during primary and memory responses to respiratory syncytial virus infection prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome. evidence for inadequate endogenous glucocorticoid secretion and inflammationinduced immune cell resistance to glucocorticoids corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review clinical aspects and cytokine response in severe h1n1 influenza a virus infection the present work was possible thanks to the financial support for reagent and kit acquisition, obtained from the university of medicine and pharmacy 'iuliu hatieganu' cluj-napoca, romania. the authors would like to thank to all of the nurses, residents and attendings for their special care to the patients with nva(h1n1) influenza virus infection. authors' contributions nh and as designed the study, coordinated patient recruitment, supervised laboratory works and wrote the article. dng and so performed cytokine profiling and wrote the report. dsd, esb and mma collected clinical and laboratory data, and wrote the report. cc assisted in the design of the study and assisted in writing the paper. mml, rlg and cl supervised clinical aspects, participated in patient recruitment. rh contributed to the statistical analysis. mp provided pulmonary histopathological analysis. dms assisted in the design of the study, coordinated patient recruitment, analyzed and interpreted the data. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord-000705-w52dc97h authors: ríos, fernando g; estenssoro, elisa; villarejo, fernando; valentini, ricardo; aguilar, liliana; pezzola, daniel; valdez, pascual; blasco, miguel; orlandi, cristina; alvarez, javier; saldarini, fernando; gómez, alejandro; gómez, pablo e; deheza, martin; zazu, alan; quinteros, mónica; chena, ariel; osatnik, javier; violi, damian; gonzalez, maria eugenia; chiappero, guillermo title: lung function and organ dysfunctions in 178 patients requiring mechanical ventilation during the 2009 influenza a (h1n1) pandemic date: 2011-08-17 journal: crit care doi: 10.1186/cc10369 sha: doc_id: 705 cord_uid: w52dc97h introduction: most cases of the 2009 influenza a (h1n1) infection are self-limited, but occasionally the disease evolves to a severe condition needing hospitalization. here we describe the evolution of the respiratory compromise, ventilatory management and laboratory variables of patients with diffuse viral pneumonitis caused by pandemic 2009 influenza a (h1n1) admitted to the icu. method: this was a multicenter, prospective inception cohort study including adult patients with acute respiratory failure requiring mechanical ventilation (mv) admitted to 20 icus in argentina between june and september of 2009 during the influenza a (h1n1) pandemic. in a standard case-report form, we collected epidemiological characteristics, results of real-time reverse-transcriptase--polymerase-chain-reaction viral diagnostic tests, oxygenation variables, acid-base status, respiratory mechanics, ventilation management and laboratory tests. variables were recorded on icu admission and at days 3, 7 and 10. results: during the study period 178 patients with diffuse viral pneumonitis requiring mv were admitted. they were 44 ± 15 years of age, with acute physiology and chronic health evaluation ii (apache ii) scores of 18 ± 7, and most frequent comorbidities were obesity (26%), previous respiratory disease (24%) and immunosuppression (16%). non-invasive ventilation (niv) was applied in 49 (28%) patients on admission, but 94% were later intubated. acute respiratory distress syndrome (ards) was present throughout the entire icu stay in the whole group (mean pao(2)/fio(2 )170 ± 25). tidal-volumes used were 7.8 to 8.1 ml/kg (ideal body weight), plateau pressures always remained < 30 cmh(2)o, without differences between survivors and non-survivors; and mean positive end-expiratory pressure (peep) levels used were between 8 to 12 cm h(2)o. rescue therapies, like recruitment maneuvers (8 to 35%), prone positioning (12 to 24%) and tracheal gas insufflation (3%) were frequently applied. at all time points, ph, platelet count, lactate dehydrogenase assay (ldh) and sequential organ failure assessment (sofa) differed significantly between survivors and non-survivors. lack of recovery of platelet count and persistence of leukocytosis were characteristic of non-survivors. mortality was high (46%); and length of mv was 10 (6 to 17) days. conclusions: these patients had severe, hypoxemic respiratory failure compatible with ards that persisted over time, frequently requiring rescue therapies to support oxygenation. niv use is not warranted, given its high failure rate. death and evolution to prolonged mechanical ventilation were common outcomes. persistence of thrombocytopenia, acidosis and leukocytosis, and high ldh levels found in non-survivors during the course of the disease might be novel prognostic findings. on april 2009, a novel influenza a (h1n1) virus emerged in mexico and spread rapidly across the world [1, 2] . as of 17 june 2010, more than 214 countries had reported confirmed cases of infection with pandemic 2009 influenza a (h1n1) virus, including at least 18,156 deaths [3] . unlike seasonal influenza, in which hospitalizations occur among patients younger than 2 and older than 65 years, or in those with underlying diseases [4] , this novel virus affected otherwise healthy young and middle-aged adults and obese individuals [2, 5] . patients with previous respiratory disease, immunocompromised hosts and pregnant women were affected as frequently as with seasonal influenza [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] . although a mild form of the disease was prevalent, it soon became evident that the 2009 influenza a (h1n1) virus could also provoke severe, acute respiratory failure requiring admission to the intensive care unit (icu) for mechanical ventilation [16] , which was reflected in the severe pathological injury found at autopsy [17] . the argentinian population was greatly affected during the pandemic, with a total of 1,390,566 cases of influenza-like illness requiring 14,034 hospitalizations. of the 11,746 confirmed cases of patients infected with the new strain, 617 died [18] . this represents a death rate per infection of 4.3% in hospitalized cases; an intermediate figure compared to 3.6% in brazil, 1.2% in chile, and approximately 6% in uruguay, colombia and venezuela [19] . it should be noted that these numbers reflect great uncertainty, particularly with regard to case diagnosis. lack of testing of mild disease and difficulties due to laboratory overload have also been well described [15, 20] . these general problems have been acknowledged by experts [21] . the severity of disease was rapidly perceived by health authorities and scientific societies. hence, a committee of experts of the argentinian society of intensive care medicine decided to focus on the most acutely ill patients: those presenting with diffuse viral pneumonitis requiring mechanical ventilation. they designed an epidemiological study, recently-published, to determine risk factors and outcomes [15] ; this is one of many series up to the present that have described epidemiological and clinical aspects of the 2009 influenza a (h1n1) pandemic [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] . there remains, however, a paucity of data published on physiological evolution during icu stay [22] . this present study, concurrently planned with the first by the same committee of experts, thus aims to provide such information. our objectives were: first, to characterize alterations of oxygenation, respiratory mechanics and the use of mechanical ventilation; second, to explore compliance with protective lung ventilation; and, finally, to assess the evolution of laboratory findings and organ dysfunctions throughout the course of the disease. this was a multicenter, inception cohort study that included patients aged > 15 years admitted to the icu with a previous history of influenza-like illness, evolving to acute respiratory failure that required mechanical ventilation during the 2009 winter in the southern hemisphere. these patients had confirmed or probable disease caused by the 2009 influenza a (h1n1) virus and were included in the registry of cases of the argentinian society of intensive care medicine (sati), created to characterize local aspects of the pandemic. on 27 june 2009, a form to collect online epidemiological data was posted on the official sati website. a detailed description and analysis of this information was recently published [14] . there was also an optional, more comprehensive casereport form to complete, developed by experts of the sati's respiratory committee for recording certain prespecified variables throughout icu stay, which included mechanical ventilation (mv), respiratory mechanics, oxygenation, blood chemistry and organ failure variables. this information was collected over 10 days and is analyzed in the present study. patients were characterized as confirmed, probable or possible cases of 2009 influenza a (h1n1) [20] according to the findings in the respiratory samples collected on admission. some specimens, however, were not analyzed because laboratories soon became overloaded, especially at the beginning of the pandemic. as of 25 september 2009, the weekly update of the ministry of health reported that in patients ≥5 years with influenzalike illness, the 2009 influenza a (h1n1) virus had displaced other respiratory viruses in 93.4% of the samples processed [23, 24] . as a result of this, probable and suspected cases were considered as caused by the novel virus and were so included in the study. we collected dates of hospital and icu admission, and of mv onset; demographics; risk factors for influenza a; actual weight; height; severity of illness (acute physiology and chronic health evaluation ii, apache ii), organ failures (sequential organ failure assessment, sofa); type of mv used, as noninvasive (niv) and invasive; and date of intubation. ideal body weight (ibw, ml/kg) and body mass index (bmi) were calculated; obesity was defined as a bmi > 30. at mv onset (day 0) and on days 3, 7 and 10, until death or discharge, whichever occurred first, we recorded: (1) mv-related variables. (2) mv modes: volume-controlled ventilation (vcv); pressure-controlled ventilation (pcv); bilevel mode; pressure support ventilation (psv); other. (3) tidal volume (vt, in ml/kg of ibw) (4) pressures: peak, plateau pressures, total positive end-expiratory pressure (peep) and driving pressure (plateau pressure -peep), in cmh2o. the main outcome measure was hospital mortality; secondary outcomes were length of mv, of icu (losicu) and of hospital (loshosp) stays. in case of missing observations, local study coordinators were contacted to provide the corresponding values. proportions were calculated as percentages of existing data. no assumptions for missing data were made. statistical analysis was performed with spss 17.0 (spss inc., chicago, il, usa). data were analyzed for the entire population; for the subgroups of survivors vs. non-survivors; and for patients receiving niv on admission vs. those who did not. descriptive statistics used were: mean ± standard deviations (sd) and median and 25-75% interquartile ranges (iqr) for continuous data of normal and non-normal distribution, respectively; and percentages for categorical data. differences between subgroups were analyzed with unpaired t test, mann-whitney u test, and chi-square tests, as appropriate. a p-value of <.05 was considered statistically significant. a kaplan-meier curve was constructed to evaluate survival over the follow-up period. over time, normally distributed data were analyzed with two-way repeated measures of anova. at the pre-specified time points, differences within the entire group and subgroups, and between subgroups, were tested using paired and unpaired t tests, respectively. in non-normally distributed data, differences over time within the entire group and the subgroups were analyzed with friedman's and wilcoxon tests. comparisons between subgroups at the pre-specified time points were tested with mann-whitney u test. the bonferroni correction was used to adjustments for multiple comparisons. the local institutional review boards waived the need for informed consent, given the general lack of knowledge on the clinical and outcome characteristics of the ongoing pandemic and to the non-interventional study design. general characteristics (table 1) between 6 june and 28 august 2009, the sati's online registry included 337 patients admitted to 35 icus with confirmed/probable/possible diffuse viral pneumonitis caused by influenza a (h1n1), with acute respiratory failure requiring mv (14) . of these, 178 consecutive patients admitted to 20 icus were followed over time, and are presented in this study. to address any potential concern that unconfirmed cases could belong to a different population of patients, we performed a sensitivity analysis of clinical and outcome characteristics data after exclusion of these patients. the results of this analysis did not differ from those of the primary assessments, so the 178 patients are considered for evaluation. briefly, patients were middle-aged, with no gender preponderance; they had a history of symptoms of nearly one-week duration and were ventilated at 1 [0 to -2] day after hospital admission. pre-existent respiratory diseases, obesity, and diseases causing immunosuppression were the most frequent comorbid conditions; and prevalence of pregnancy was higher than in the general population, as expected [25] . non-survivors were sicker on admission; duration of previous symptoms was longer; and organ failures were more severe. obesity and immunosuppression were significantly more frequent as predisposing conditions. ninety-three patients survived (52%) (see figure 1 ). (table 2) during the study period, the entire group had vt values between 7.8 to 8.1 ml/kg of ibw, with plateau pressures remaining always < 30 cmh 2 o. non-survivors displayed a trend towards lower vt and higher plateau pressures, which differed significantly from survivors only at day 7. intermediate peep levels were used, and decreased in survivors from day 3 onwards. driving pressures were similar over time in all patients; only at admission did non-survivors exhibit higher values. pao 2 /fio 2 increased significantly over time in all patients and in survivors. it remained, however, < 200 in the whole group throughout the entire icu stay due to non-survivor values. non-survivors displayed significantly lower pao 2 /fio 2 at all time points. lung infiltrates (in quadrants) peaked at day 3 (3.1 ± 1.0 vs. 2.9 ± 1 at day 0, p < 0.01) and then decreased during the study in the entire group, especially at day 10 (2.8 ± 1.1, p < 0.83 vs. day 0), which reflected the improvement in survivors (3.1 ± 1.0 at day 3 vs. 2.9 ± 1.0 at day 10, p < 0.01). in figure 2 , the utilization of ventilation modes and rescue therapies in the entire group are shown. briefly, pcv use equaled vcv at day 10, preceded by deterioration in oxygenation and respiratory mechanics: pao 2 / fio 2 78 ± 24 vs. 128 ± 33, (p = 0.03); paco 2 44 ± 4 vs. 35 ± 3 mmhg (p = 0.04); ph 7.29 ± 0.03 vs. 7.39 ± 0.05 (p = 0.05), and plateau pressures of 30 ± 2 vs. 25 ± 3 cmh 2 o (p = 0.03). recruitment maneuvers became significantly more common in non-survivors at day 3 (46%, vs. 29% in survivors; p = 0.03), as did prone positioning (24%, vs. 14%; p = 0.001). after that, only prone positioning remained significantly more used in nonsurvivors (at day 7: 38%; vs. 14%, p = 0.004; and at day 10: 25%; vs. 5%, p = 0.02). six patients received tracheal gas insufflation; only one survived. neuromuscular blockers were prescribed in 18% of patients on admission; and their use was subsequently more frequent in non-survivors (day 3: 14% vs. 8%, p = 0.02; and day 7: 14% vs. 8%, p = 0.04). the main causes of death were refractory hypoxemia (64%); followed by multiorgan dysfunction syndrome (15%) and shock (10%). prolonged mechanical ventilation and long icu and hospital stays were frequent (table 1) . tracheostomy was performed in 29 patients (16%) at day 14 [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] . acid-base variables and fluid balance (table 3) arterial ph increased over time in the whole cohort and in both subgroups, perhaps secondary to general resuscitation measures. despite this, non-survivors displayed significantly lower ph at all time points, owing to changes in base excess on days 0 and 3, and to pco 2 elevations thereafter. respiratory rates remained unchanged, only increasing at day 10 in non-survivors; nevertheless, this corresponded to the highest pco 2 values, indicating the more severe respiratory compromise. bicarbonate paralleled ph behavior. changes in fluid balance did not show clear trends: only at day 10 they decreased significantly, expressing survivors' behavior. forty-nine patients (28%) underwent a trial of niv on admission; they were significantly less ill and had a lower incidence of immunosuppression. oxygenation and outcome variables were similar to those of patients not receiving niv. sixty-one percent of patients (n = 30) receiving niv survived; duration of niv was of 8 (2 to 18) hours. there were no differences between survivors and nonsurvivors in the duration of the procedure, or in the type of interface or respirator used. of note, most patients on niv (46 out of 49; 94%) had to be intubated and ventilated invasively for hypoxemic failure. characteristics associated to niv success/failure are shown in table 5 . niv was also used for treating post-extubation respiratory failure in 12 of 178 patients (7%), with success (reintubation not needed) in 8 cases (66%). the most consistent changes over time were found in platelet count, which increased significantly in the whole cohort (p < 0.000 for days 3, 7 and 10 vs. day 0), secondary to elevations in survivors. at all time points, platelets differed between survivors and non-survivors. conversely, white blood cell count showed a progressive creatine-kinase and markers of liver injury (alanine/ aspartate aminotransferases, serum bilirubin; not shown) were mildly elevated and displayed no substantial changes. on the contrary, lactate-dehydrogenase levels were significantly higher in non-survivors throughout the study. creatinine levels were stable over the period, but were significantly higher in non-survivors on days 0 and 3. finally, sofa score diminished over time in all patients (p < 0.000 for days 7 and 10 vs. day 0), as a result of the decrease in survivors. sofa was significantly lower in survivors throughout the study. in figure 3 , the differences between survivors and non-survivors are displayed. we report on a large, prospective cohort of 2009 influenza a (h1n1) patients that were mechanically ventilated for acute respiratory failure due to diffuse pneumonitis during the pandemic in argentina. though most were middle-aged, previously healthy adults, patients with preexistent lung disease, immunosuppression, obesity and pregnancy were also affected. mortality was high and evolution to chronic critical illness was common, as shown by prolonged mechanical ventilation, high needs of tracheostomy, and lengthened icu and hospital stays. patients had characteristically a history of protracted symptoms and displayed severe compromise of oxygenation compatible with ards throughout the study period, which only improved in survivors. at all time points, pao 2 /fio 2 differed significantly between survivors and non-survivors, requiring higher fio 2 and peep in this last subgroup. yet the levels of applied peep were only in the intermediate range, similar to mean values of 8.7 cmh 2 o of peep in an international study on mechanical ventilation [26] , which may explain the relatively high fio 2 used in our study. driving pressures were similar in both subgroups most of the time, suggesting an intention to limit alveolar excursion as part of a protective strategy. it is striking that, as has been described in similar studies on mechanical ventilation performed during the 2009 influenza a (h1n1) pandemic [6, 7] , tidal volumes used were between 7.5 and 8.3 ml/kg ibw, certainly higher than the 6 ml/kg demonstrated as being lungprotective [27] . indeed, barriers to implementing lowtidal volume have been identified and might explain physician behavior [28] . despite this, plateau pressures did remain below 30 cmh 2 o [29] , indicating that lung compliance might have been preserved. perhaps clinicians focused on plateau pressures rather than on tidal volumes [30] since it still remains unclear which should be limited to avoid ventilator-induced lung injury [31] . we, like others [6, 7, 32, 33] , could not find differences in utilized tidal volumes between survivors and non-survivors. even so, non-survivors tended to display lower values, probably reflecting physician efforts to intensify protective ventilation strategies in the most severely compromised. some researchers [34, 35] have suggested that allowing higher tidal volumes in a population of young and previously healthy patients with strong ventilatory drive might reveal an attempt to restrain heavy sedation and neuromuscular blocker use. notwithstanding this, we believe that these findings may also represent clinicians' inadequate prescription, as described in other scenarios [36] . not unexpectedly, vcv was the most common ventilator mode used. pcv use increased throughout the study period, peaking at day 10. this is in contrast with the recently identified trend towards decreased pcv utilization. transition to pcv mode was associated with preceding physiological worsening, so clinicians might have perceived pcv utilization as part of a global lungprotective strategy [37] . refractory hypoxemia was the main cause of death. as in other studies [6, 7, 11] , rescue therapies were frequently applied, with utilization highest 72 hours after admission. recruitment maneuvers and prone positioning were the primary adjuvants utilized; ecmo and hfov are currently not available in argentina. a table 3 oxygenation and acid-base variables, and fluid balance in all patients, and in survivors and non-survivors. prolonged mechanical ventilation course was frequent as reported elsewhere [6] . niv was the first ventilation approach in 28% of cases, with 94% later requiring invasive ventilation, as has been documented in other studies [6, 7, 11] . these common experiences should caution against delaying proper ventilatory support in this group, given that rapid deterioration is common. a recent meta-analysis suggests that niv does not decrease the need for intubation, so evidence to support its use in severe ards is questionable [38] . in our study, improved outcomes with niv could be due to milder disease, evidenced by apache ii. the small number of patients that were not intubated precludes a statistical analysis; however, they were younger, with less severe disease and better oxygenation. significant changes in fluid balance were late and reflected changes in survivors. negative fluid balances could never be obtained, perhaps suggesting a continuing need for hemodynamic support: 72% of patients presented with shock [14] . on the whole, fluid balances remained between those achieved by "liberal" and "conservative" strategies of the fluids and catheters treatment trial, depending on the day evaluated [39] . thus far, it is not clear whether the negative fluid balance has a causal role in improving outcome in ali/ards, or if it simply expresses the global recovery of patients. another important finding was that arterial ph consistently and significantly differed between survivors and non-survivors, as described elsewhere [40, 41] . during the first 72 hours acidosis had a major metabolic component, likely as a sign of hemodynamic impairment. after the first week, respiratory acidosis ensued, indicating either the effects of protective ventilation, or merely deterioration due to progressive shunt, profound ventilation/perfusion mismatch and increased deadspace. with respect to blood chemistry, the usual findings of thrombocytopenia, leukocytosis and mildly elevated creatine-kinase blood levels were present [21, 42] . regrettably, the lymphocyte count was not recorded. in viral infections, thrombocytopenia occurred frequently. although the mechanisms by which the 2009 influenza a (h1n1) virus causes thrombocytopenia are unknown, its lack of resolution is a marker of poor prognosis. both leukocytosis and leucopenia have been found in hospitalized patients with 2009 influenza a (h1n1) [2, 43] ; in our study, persistent leukocytosis was associated with increased mortality. ldh elevations have been previously described in fatal cases [2] , which corresponded to our finding of higher ldh levels in non-survivors at all time points. such elevations have also been reported in seasonal influenza [44] . in experimental studies, increased ldh is a marker of human fetal membrane cell apoptosis induced by influenza virus [45] . finally, multiorgan failure was frequent, and predictably more severe in non-survivors. this study has several strengths: first, the clinical characteristics and time course of pandemic 2009 influenza a (h1n1) are thoroughly described and analyzed. second, data were collected prospectively in consecutive patients and with a standardized casereporting form, representing a large, nationwide cohort. third, temporal patterns of mechanical ventilation use, acid-base and blood chemistry variables, as well as fluid balance and organ failures, are carefully analyzed. prognostic implications are highlighted. finally, we present the largest experience with niv use during the pandemic. study limitations include the focus on mechanically ventilated patients, excluding less severe cases also admitted to the icu. many cases could not be confirmed because laboratories were overwhelmed with clinical samples, which is also described elsewhere [7, 14] . data about transmission to healthcare workers were not recorded, especially regarding niv. currently, most information about its use during an epidemic relies upon expert opinion [46] . in 178 patients with diffuse viral pneumonitis caused by the 2009 influenza a (h1n1) virus admitted to the icu and followed over time, ards was the rule, requiring high ventilation support and frequent use of rescue therapies. death, organ failures, and evolution to prolonged mechanical ventilation were common. in most cases, noninvasive ventilation failed to prevent endotracheal intubation. finally, elevated ldh levels, lack of recovery of platelet count and persistent acidosis and leukocytosis in non-survivors behaved as prognostic findings. • in 2009 influenza a (h1n1) patients, hospital admission with prompt indication of mechanical ventilation -a marker of severe disease -was associated with a history of symptoms of nearly one-week duration. • an initial niv trial was not effective to avoid intubation in most patients; thus, this ventilation approach should likely be discarded in this setting. • mortality and morbidity were frequent: death was common and was mainly caused by persistent, refractory hypoxemia. prolonged mechanical ventilation and icu and hospital stays were typical. • ph, platelet count, ldh and sofa differed significantly between survivors and non-survivors over time. lack of recovery of platelet count and persistence of leukocytosis might be markers of poor prognosis. • every effort should be done to increase adherence to protective ventilation in the real world. abbreviations ali: acute lung injury; ards: acute respiratory distress syndrome; bmi: body mass index; cxr: plain chest x-ray film; ibw: ideal body weight; icu: intensive care unit; ldh: lactate dehydrogenase assay; los: length of stay; mv: mechanical ventilation; niv: non-invasive ventilation; pao2/fio2: relation between patient arterial po 2 and inspired oxygen fraction used; pcv: pressure-controlled ventilation; peep: positive end-expiratory pressure; psv: pressure support ventilation; rr: respiratory rate; rt-pcr: real-time reversetranscriptase-polymerase-chain-reaction; sati: argentinian society of intensive care; sofa: sequential organ failure assessment; vcv: volumecontrolled ventilation; vt: tidal volume. the registry of the argentinian society of intensive care department intensive care, hospital general de agudos velez sarsfield, calderón de la barca 1550, (c1407ahh) department critical care department intensive care, hospital lagomaggiore, gordillo s/n 16 department intensive care mar del plata, argentina. 19 intensive care unit, hospital universidad abierta interamericana, portela 2975, (c1069aab) group on influenza: pneumonia and respiratory failure from swine-origin influenza a (h1n1) in mexico pandemic (h1n1) 2009 -update 104. weekly update influenza-associated hospitalizations in the united states intensive care patients with severe novel influenza a (h1n1) virus infection-michigan critically ill patients with 2009 influenza a (h1n1) infection in canada critically ill patients with 2009 influenza a (h1n1) in mexico critical care services and 2009 h1n1 influenza in australia and new zealand pandemic influenza a (h1n1) virus hospitalizations investigation team: hospitalized patients with 2009 h1n1 influenza in the united states h1n1) working group: factors associated with death or hospitalization due to pandemic 2009 influenza a(h1n1) infection in california intensive care adult patients with severe respiratory failure caused by influenza a (h1n1) in spain influenza a pandemics: clinical and organizational aspects: the experience in chile national influenza a 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volume in mechanical ventilation: the importance of considering predicted body weight pressure-and volume-limited ventilation strategy group: evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome the multicenter trail group on tidal volume reduction in ards: tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome mechanical ventilation in critically ill patients with 2009 influenza a (h1n1) mechanical ventilation in critically ill patients with 2009 influenza a (h1n1) the finnali study on acute respiratory failure: not the final cut effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome is there a role for noninvasive ventilation in acute respiratory distress syndrome? a meta-analysis the national heart, lung, and blood institute acute respiratory distress syndrome (ards) clinical trials network: comparison of two fluidmanagement strategies in acute lung injury metabolic correlates of oxygen debt predict posttrauma early acute respiratory distress syndrome and the related cytokine response osatnik j: incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome swine influenza (h1n1) pneumonia: clinical considerations influenza pneumonia: a descriptive study lactate dehydrogenase leakage as a marker for apoptotic cell degradation induced by influenza virus infection in human fetal membrane cells should noninvasive ventilation be considered a high-risk procedure during an epidemic? on the role of non-invasive (niv) to treat patients during the h1n1 influenza pandemic lung function and organ dysfunctions in 178 patients requiring mechanical ventilation during the influenza a (h1n1) pandemic the authors declare that they have no competing interests. key: cord-031033-v4yetn4f authors: martin-loeches, ignacio; dickson, robert; torres, antoni; hanberger, håkan; lipman, jeffrey; antonelli, massimo; de pascale, gennaro; bozza, fernando; vincent, jean louis; murthy, srinivas; bauer, michael; marshall, john; cilloniz, catia; bos, lieuwe d. title: the importance of airway and lung microbiome in the critically ill date: 2020-08-31 journal: crit care doi: 10.1186/s13054-020-03219-4 sha: doc_id: 31033 cord_uid: v4yetn4f during critical illness, there are a multitude of forces such as antibiotic use, mechanical ventilation, diet changes and inflammatory responses that could bring the microbiome out of balance. this so-called dysbiosis of the microbiome seems to be involved in immunological responses and may influence outcomes even in individuals who are not as vulnerable as a critically ill icu population. it is therefore probable that dysbiosis of the microbiome is a consequence of critical illness and may, subsequently, shape an inadequate response to these circumstances. bronchoscopic studies have revealed that the carina represents the densest site of bacterial dna along healthy airways, with a tapering density with further bifurcations. this likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. though bacterial dna density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. the dogma of lung sterility also violated numerous observations that long predated culture-independent microbiology. the body’s resident microbial consortia (gut and/or respiratory microbiota) affect normal host inflammatory and immune response mechanisms. disruptions in these host-pathogen interactions have been associated with infection and altered innate immunity. in this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome and ventilator-associated pneumonia. the normal microbiota is the ecological communities of commensal, symbiotic and pathogenic microorganisms whilst the microbiome comprises all of the genetic material within a microbiota (the entire collection of microorganisms in a specific niche, such as the human gut). this can also be referred to as the metagenome of the microbiota [1, 2] . approximately 100 billion microorganisms are found in the body due to recent discoveries in molecular analysis such as next-generation sequencing (ngs) and whole metagenome shotgun sequencing (wmgs); there is an increasing body of evidence pointing towards the dysbiosis that is often defined as an 'imbalance' in the microbial community that is associated with disease [3] [4] [5] . a microbiome is shaped by multiple factors including the resident flora of the animate or inanimate vicinity and the external forces that modulate this flora [6] . it becomes a changeable reflection of diversity, and so its study can provide valuable insights into the factors that drive that diversity [7] . just as the study of global climate or the roots of language requires input from around the world, so the interpretation of the microbiome of an individual or a group of patients needs comprehensive comparative data to generate insight [8, 9] . the variability of the host microbiome-either in an individual patient over time in response to the pressures of illness [10] or in a geographically localized population in response to environmental-can yield important insight into factors that can be manipulated to improve clinical outcomes. such factors include risk of infection, emergence of resistance, spread from the environment, host susceptibility and even the resilience of the health care system [11] . in this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome (ards) and ventilator-associated pneumonia (vap). though for years textbooks taught that 'the normal lung is free from bacteria', this dogma was generally repeated without citation or argument [12] . in retrospect, this claim of lung sterility was remarkable: virtually no environment on earth exists that is so extreme in temperature, ph, salinity or nutrient scarcity that microbial communities cannot be detected [13] . yet for more than a century, it was taken as fact that the warm, wet mucosa of the lower respiratory tract-mere inches below the microbial reservoir of the pharynx-is an exception to this rule [14] [15] [16] [17] [18] . each individual has a unique microbiota profile that plays many specific functions in host nutrient metabolism, maintenance of structural integrity and protection against pathogens. there is not a unique optimal microbiota composition as it can be different for each individual [19, 20] . thus, the 'revolution' in culture-independent microbiology has merely confirmed with certainty what has long been inferred indirectly: human lungs are constantly exposed to environmental bacteria. to date, more than 30 studies have used sensitive, culture-independent techniques to study lung bacteria in healthy volunteers, and none has failed to detect a distinct bacterial signal [21] . the viability of bacteria in healthy lungs has been confirmed via advanced cultivation [22] and indirectly validated via correlation with healthy alveolar immune tone in humans and mice [23, 24] . some of the confusion regarding the existence of lung microbiota reflects flawed parallels with the lower gut microbiome, which represents a wholly different ecosystem with radically different ecologic forces. whereas the gut lumen is densely populated by dense communities' bacteria, lung microbiota is scarce and associated with mucosal surfaces. whereas gut communities are relatively stable dayto-day, reflecting stable selective pressure on resident bacteria, lung communities are in constant turnover, with their identities and burdened determined by the relative balance of immigration (via microaspiration and mucosal dispersion) and elimination (via cough and mucociliary clearance). whereas the gut microbiome is nutrient-rich and characterized by intense metabolic competition amongst dense communities, the lung microenvironment is nutrient-poor, and the primary competition is between immigrating pharyngeal microbes and locally calibrated alveolar and airway host defences attempting to minimize their outgrowth [24, 25] . these ecologic differences between the lower gut and the lungs erode somewhat in conditions of acute and chronic disease: the influx of mucus and proteinrich oedema provide nutrient sources for bacteria, and once-transient bacteria become resident, shaped by selective pressure. further confusion arose via misinterpretation of clinical culture protocols, which have been optimized for detection of respiratory pathogens, not the 'background' microbiota of uninfected patients. sequencing-based studies have revealed that the normal microbiota of healthy lungs closely resembles that of the oropharynx [26] [27] [28] and, whilst commonly cultured, are routinely dismissed by clinical microbiology laboratories as 'normal oral flora'. bronchoscopic studies have revealed that the carina represents the densest site of bacterial dna along healthy airways, with a tapering density with further bifurcations [28] . this likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. though bacterial dna density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. bacterial communities within the lungs of healthy volunteers are relatively homogenous; the bacteria of a given individual's right middle lobe far more closely those of the same individual's left upper lobe than do other individuals' right middle lobe (i.e. intraindividual similarity is greater than interindividual similarity) [27] . how to study the lung microbiome? high densities of bacteria are always present on the skin, in the mouth, and in the upper respiratory tract. for this reason, it is important to avoid contamination with commensal bacteria from other sites when taking samples for investigation of the lower respiratory tract microbiome [29, 30] . since samples from the lower respiratory tract may have a low biomass, it increases the risk for contamination that can occur at any time from sampling to sequencing [31, 32] . the first molecular techniques used for studying the bacterial microbiome in humans were based on 16s rrna gene sequencing many years ago which is an appropriate method to assess diversity on taxonomic levels above species level. a limitation of 16s rrna gene sequencing is that whilst bacteria can normally be identified on genus and family level, species identification usually requires simultaneous evaluation of several genes [33] [34] [35] . newer technology of whole genome sequencing and metagenomics has shown better definition of the gut microbiome and what has currently been shown of the lung microbiome will also be significantly updated by these newer sequencing technologies [36] [37] [38] . an important matter is that when studying the lung microbiome, the pathogens and host response needs to be simultaneously studied by molecular methods, for instance, microbial metagenomics and transcriptomics. langelier et al. [39] performed in almost 100 patients with acute respiratory failure (arf) metagenomic nextgeneration sequencing (mngs) on endotracheal aspirates (eta) and simultaneously assessed pathogens, the airway microbiome and the host transcriptome. this study found that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome and host transcriptome represents a new tool for diagnosis in lower respiratory tract infections (lrti). the progress in molecular microbiology has developed very fast in the last years and several rapid technologies will provide biological signals taking into account the interaction of the host (e.g. via digital enzyme-linked immunosorbent assay (elisa) [40] ) and the microbes (e.g. via nanorod-pcr [41] ). another technology is microgas chromatography for the analysis of bacterial function and virulence and metabolic indices of the host response on exhaled breath [42, 43] . the field of lung microbiome is no longer limited by the speed of sequencing, processing, or measurement, but rather our ability to make sense of the highdimensional data we generate. ards is a complication of critical illness characterized by protein-rich pulmonary oedema, hypoxaemia and alveolar inflammation. alveolar inflammation, damage and subsequent oedema may be initiated by a change in pulmonary microbiome, or a change in lung microbiome may be initiated by an alveolar nutrient available after the onset of oedema [2] . even though ards is traditionally not considered to be related to microbial changes in the lung, these physiological considerations resulted in the hypothesis that pathogenic bacteria may be present in the lung of patients with ards. kyo et al. [44] analysed the lung microbiome from the bronchoalveolar lavage fluid (balf) of patients with ards found that lung bacterial burden (16s rrna gene copy numbers tended to be increased) tended to be increased, and the alpha diversity (copy numbers and relative abundance of betaproteobacteria) was significantly decreased in ards patients. in an experimental mouse model of lung injury following abdominal sepsis induced by cecal ligation and puncture, the lung microbiome was enriched with gut bacteria [3] . how did these bacteria get there? it is hypothesized that bacteria can translocate from the gut into the lymphatic system and portal circulation during critical illness [4] . if so, these changes should also be observed in patients on the icu. indeed, enrichment of gut bacteria was also observed in balf from ards patients [3] . gut bacteria and more specifically enterobacterieae enrichment in patients with ards were confirmed in a second observational cohort study [5] . both studies were performed in a selective cohort of patients with potential biases of prolonged antibiotic exposure before measurement. in a more recent study conducted in europe, patients who were treated with selective decontamination of the digestive tract (sdd) during admission at the icu, but were not treated with antibiotics prior to icu admission, validated the specific enrichment of enterobacterieae in the lungs of ards patients [45] . taken together, the current body of evidence suggests that amplification of enterobacterieae in the lung is strongly associated with ards. this association is not sufficiently explained by potential confounders such as geographical location of sampling, exposure to antibiotic therapy, amplification protocols or exact definitions of ards. the evidence for consistent dysbiosis in lung microbiome is actually stronger for ards than for most other respiratory diseases, where other microbes are enriched in different studies. however, no causal link between dysbiosis of the lung microbiome and development of lung injury has been established. this link needs to be further explored before we can conclude that lung microbiome dysbiosis is a potential target for treatment (fig. 1) . in ecological terms, pneumonia can be described as the collapse of local microbiome diversity and the emergence of a dominant pathogen [46] . several studies have therefore hypothesized that the lung changes considerably during nosocomial lower respiratory tract infections. some critically ill patients can develop pneumonia due to their clinical condition such as patients with ischaemic stroke and/or with loss of neurological control of the respiratory system. these clinical conditions can be associated to reduced airway clearance and increased bacterial translocation and therefore can develop more often respiratory infections [47] . so, the more appropriate question is 'do patients that develop pneumonia have more dysbiosis of the lung microbiome than mechanically ventilated icu patients who do not develop pneumonia'? two studies addressed this problem. the first included consecutive patients at risk for pneumonia with a duration of mechanical ventilation of more than 7 days [48] . endotracheal aspirates were performed every third day and the microbial composition was evaluated with 16s sequencing. there was a small, but significant increase in the change in beta-diversity (change in diversity of species from one environment to another) in patients who went on to develop pneumonia as compared to patients who did not develop any signs of infection and were not colonized by any bacteria according to traditional bacterial cultures. the composition of the microbiome in these patients also showed a slight enrichment of pseudomonadales. a second study conducted had a similar design and showed no difference in the change of microbiome during mechanical ventilation between patients who did and did not develop pneumonia [49] . as discussed in the accompanying editorial, the results from these studies have elegantly shown that it is time to let go of any simplistic view of vap pathogenesis [10] . one conclusion might be that lrti cannot simply be defined as a collapse of bacterial ecology as this is present also in part of the patients without pneumonia who do not show any signs of pneumonia. one could also argue that the studies did not sample the alveolar space and additional studies with balf are needed to confirm or discard these findings. furthermore, evaluation of microbial composition may be more useful in establishing the presence of a pathogen in patients who already have a clinical suspicion of pneumonia. indeed, with pre-test probability, metagenomics may provide valuable information on the pathogen causing pneumonia [11] . future studies have to consider these possibilities before we disregard the lung microbiome in nosocomial pneumonia. in the critically ill, changes in the microbiome in all habitats, including the lungs, are particularly striking. due to the devastating consequences of untreated severe infections, broad eradication is accepted as lesser evil and collateral damage on beneficial or commensal microbes is generally accepted. however, the potential long-term consequences of unwarranted side effects on the microbiome warrant a reassessment of the microbiome as a diagnostic or even therapeutic target. for example, dysbiosis of the gut microbiome itself has been described as a predictive factor for late-onset neonatal sepsis [50] suggesting that the microbiome can serve at least as a biomarker to predict ensuing nosocomial infection. moreover, albeit solid data are still missing to support interventions to restore a healthy microbiome, the strategy holds promise to impact on incidence and outcome of nosocomial infection and ensuing organ injury, including ards [51, 52] . in the light of a better understanding of off-target effects of broad-spectrum antibiotics on the microbiome, the liberal administration of antibiotics must be discussed against more sophisticated interventions to treat the bacterial infection (non-antibiotic therapies such as bacteriophages) or manipulation of the microbiome to make the residing communities more resilient (for example probiotics). in particular, the need to combine multiple anti-infective compounds in the light of diagnostic uncertainty might outweigh the benefit of early source control and explain controversial results for aggressive antibiotic strategies. for instance, in a before-andafter study hranjec et al. reported that the subgroup with least benefit from 'calculated' broad-spectrum antibiotics were patients presenting with septic shock, i.e. those in which the current paradigm would expect the highest need to initiate early anti-infective therapy [53] . thus, a holistic approach taking the microbiome into consideration carries the potential to initiate a paradigm shift in the treatment of infections in the icu. as discussed in the previous paragraphs, the lung dysbiosis seems to be common in the icu and enrichment of gut bacteria might be an important contributor to the development of lung injury and infection (fig. 2) . the relationship between gut and lung microbiome is described as the gut-lung axis [54] . because the gut microbiome can be targeted directly or indirectly with therapeutic interventions, this is an area of active study. investigations have thus far fallen into two specific pathways-first, using probiotics to help restore a premorbid microbiome, or second, to use antibiotics through an sdd approach to target specific families of organisms so as to alter the microbiome in possibly beneficial ways. further novel pharmacologic options that have direct gut microbiome modifying effects are also under development, including faecal transplantation as a possible novel treatment for microbiota dysregulation (considering the immune system during faecal microbiota transplantation for clostridioides difficile infection [55] and for the decolonization of antibioticresistant bacteria in the gut [56] ). one of the major challenges of studying the effect of these interventions is the huge variability in the gut microbiome of critically ill patients, even during the first days of icu admission [57] . furthermore, any beneficial effect of these interventions on the microbiome has yet to be assessed formally in a prospective, large-scale, randomized manner. attempting to attribute a causal impact of microbiome modifications upon clinical outcomes has been difficult to tease out as to whether changes in the microbiome are merely surrogates of some other mechanistic pathway that leads to improved clinical outcomes [58] . fundamentally, probiotics in critical illness aim to provide bacteria that may have been eradicated during the pre-and early phases of critical illness [59] . this eradication may be through administering antibiotics early in critical illness, which have been shown to greatly modify the gut microbiome [60] . alternatively, the mere onset of critical illness-be it sepsis, ards or any number of conditions, is associated with alterations of the gut fig. 2 island model for the development of lung injury based on sites of dysbiosis microbiome, which may be independent of antibiotic administration [61] . regardless, the stated goal of probiotic administration is to restore a pre-morbid microbiomeprimarily to the gut, but partially to other microbiome communities through generalized cross-talk [62] . through yet-unknown mechanisms, administering lactobacillus or bifidobacterium species through a probiotic may increase the diversity of microbial species in the gut, although more studies with rigorous outcome determinations are required [63] . in the critically ill, randomized studies and meta-analyses of randomized trials demonstrate a possible benefit of probiotic administration on the outcome of ventilator-associated pneumonia, without a difference in mortality [64, 65] , with a major challenge being a lack of standardization in dosing and composition of probiotic products [66] . larger scale studies are nearing completion and further data on the impact of microbiome modifications are forthcoming in the years ahead [59] . selective digestive decontamination, a regimen of prophylactic antibiotic administration, has been shown in small series to result in important alterations in gut microbiota, when compared with controls [67] . these changes are typically related to increasing selection for resistant organisms and decreased microbiome diversity, per a number of different metrics. given a possible benefit on patient mortality in some randomized trials [68, 69] , exploring the specific impact of this strategy on the microbiome, and related clinical outcomes, is a vital area for further study. additionally, given burgeoning evidence of crosstalk between the lung and gut microbial communities, the impact of either of these strategies on the non-gut microbiome communities in the critically ill patient remains under-investigated. given the apparent conflicting goals of sdd and probiotic administration in the critically ill as it relates to the microbiome, the role of co-administration may be difficult to conceive. however, most currently used sdd regimens are unlikely to affect the administered probiotic agent, and this may be a strategy for further investigation in targeted patients [70] . both sdd and probiotics appear to mediate their effect on patientrelated outcomes through reducing the incidence of ventilator-associated pneumonia, speaking to a crucially under-investigated relationship between the two microbiome communities and host immunology, a tantalizing area for future research. novel pharmacologic agents have also been suggested as modifiers for the gut microbiome but have yet to be formally tested in the critically ill. butyrate, a large bowel microbial fermentation product, is being investigated in pre-clinical trials as a specific modifier of gut-derived regulatory t cells [71] . administering a sialic acid analogue is being investigated as to whether it may reduce the burden of antibiotic-associated pathogens such as c. difficile by altering metabolic pathways [72] . older drugs such as metformin may have a role, with their demonstrated effects on altering the gut microbiome in patients with diabetes [73] . the lung microbiome is clearly more difficult to target than the gut microbiome due to the lack of routine administration of bacteria and bacterial products into the airways. the low biomass environment may also cause the lung microbiome to be more prone to infection induced by the introduction of, for example, probiotics. therefore, direct intervention in the lung microbiome may be sought via the alteration of regional growth conditions via the availability of nutrients or through immunomodulation. an example is the administration of macrolides in chronic obstructive pulmonary disease (copd): there is a selection for anti-inflammatory microbial metabolites and an alteration of the lung microbiome [74] . all of these possible interventions speak to the importance of achieving a better understanding of the gut-lung axis in critical illness. as this understanding evolves, the possibility of personalizing interventions for individual microbiome communities, or widespread initiation of interventions such as sdd or probiotics, would be possible. whilst patient-to-patient or staff-to-patient transmission of infection occurs within the intensive care unit, most nosocomial infections in critically ill patients arise through the invasion of normal host defences by bacteria and fungi that have become a part of an altered microbiome-either by changes in numbers or by the incorporation of species from the environment [75] . the hospital environment itself acquires a microbiome that reflects the patients that have been in it, and environmental reservoirs such as sinks, plumbing, work surfaces, and equipment can become reservoirs of resistant organisms that can infect the critically ill [76] . the inherent variability of the microbiome, therefore, provides an opportunity to study not only the individual patient, but also the forces in the environment that shape patient's outcome, and to identify specific opportunities where the persistence and transmission of pathogens can be prevented or minimized. because of the high prevalence of nosocomial infection, the environmental concentration of causative pathogens and the multiple risk factors for exposure, the icu provides a unique opportunity for intensive study of the microbiome and its role in the establishment and transmission of resistant organisms. with the emergence of new models of global acute care research collaboration through the international forum for acute care trialists (infact; www.infactglobal.org), and the launch of an infact initiative to leverage icu data to understand variability in patterns of resistance through the antimicrobial resistance in intensive care (amric) initiative. in previous years, we believed that the normal lung was free from bacteria. certainly, some features in the respiratory tract such as temperature, ph and nutrients were not beneficial for microbial growth. during critical illness, antibiotic use, mechanical ventilation, diet changes and inflammatory responses can bring the microbiome to dysbiosis. with the use of molecular techniques, we have had the opportunity to study the lung microbiome and not only in the microbial aspect but also in the responses from the host. one of the most important aspects to better determine the physiopathology of host-pathogen interaction in pulmonary complications such as ards and va-lrti is the gut-lung axis. further study of patients with disease in the respiratory tract will help us to better determine microbial diversity and constitution when comparing healthy and diseased 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metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug randomised, double-blind, placebo-controlled trial with azithromycin selects for antiinflammatory microbial metabolites in the emphysematous lung hospital-associated microbiota and implications for nosocomial infections investigation of a multiyear multiple critical care unit outbreak due to relatively drugsensitive acinetobacter baumannii: risk factors and attributable mortality publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. key: cord-010697-0eutz8xy authors: roumy, aurélien; liaudet, lucas; rusca, marco; marcucci, carlo; kirsch, matthias title: pulmonary complications associated with veno-arterial extra-corporeal membrane oxygenation: a comprehensive review date: 2020-05-11 journal: crit care doi: 10.1186/s13054-020-02937-z sha: doc_id: 10697 cord_uid: 0eutz8xy veno-arterial extracorporeal membrane oxygenation (va-ecmo) is a life-saving technology that provides transient respiratory and circulatory support for patients with profound cardiogenic shock or refractory cardiac arrest. among its potential complications, va-ecmo may adversely affect lung function through various pathophysiological mechanisms. the interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response which may increase pulmonary vascular permeability and promote the sequestration of polymorphonuclear neutrophils within the lung parenchyma. also, va-ecmo increases the afterload of the left ventricle (lv) through reverse flow within the thoracic aorta, resulting in increased lv filling pressure and pulmonary congestion. furthermore, va-ecmo may result in long-standing pulmonary hypoxia, due to partial shunting of the pulmonary circulation and to reduced pulsatile blood flow within the bronchial circulation. ultimately, these different abnormalities may result in a state of persisting lung inflammation and fibrotic changes with concomitant functional impairment, which may compromise weaning from va-ecmo and could possibly result in long-term lung dysfunction. this review presents the mechanisms of lung damage and dysfunction under va-ecmo and discusses potential strategies to prevent and treat such alterations. veno-arterial extracorporeal membrane oxygenation (va-ecmo) is a life-saving technology providing respiratory and circulatory support in patients with refractory cardiogenic shock or cardiac arrest [1] and which may give time to plan future therapeutic decisions such as the insertion of long-term cardiac assist devices or heart transplantation (htx) [2] . notwithstanding its potential benefits, va-ecmo remains associated with significant morbidity and mortality [1] . this is partly due to the patients' critical condition, but also to complications related to va-ecmo, notably renal failure, sepsis, bleeding, thromboembolism, limb ischemia, and multiorgan failure [3, 4] . va-ecmo-induced pulmonary complications are much less recognized, except from the pulmonary congestion related to left ventricle pressure overload induced by retrograde va-ecmo flow within the thoracic aorta [5] . beside this particular aspect, several additional mechanisms may contribute to lung damage and dysfunction in the setting of va-ecmo. the latter may be assimilated to a simplified cardiopulmonary bypass (cpb) circuit, and both techniques share common pitfalls with respect to lung physiology. cpb may alter pulmonary function after cardiac surgery by promoting an inflammatory response via biomaterial-dependent and biomaterial-independent factors, the collapse of lungs during the procedure, the shunting of pulmonary circulation, and the phenomenon of lung reperfusion injury which takes place once cpb is weaned [6] . during va-ecmo, although such processes are attenuated, they still occur at different stages of support and at various degrees, and they may persist for days or weeks. in such conditions, the combination of a chronic inflammatory response, pulmonary congestion, and lung ischemia could foster a wealth of morphological and functional alterations which could interfere with patient's recovery and compromise the overall planned therapeutic strategy. in this review, we discuss the pathophysiological mechanisms and potential clinical implications of the pulmonary complications associated with va-ecmo. the induction of a systemic inflammatory response syndrome (sirs) by the contact of blood with biomaterial is a typical consequence of extracorporeal circulation [7] . while extensively studied in the field of cpb, this is also witnessed during va-ecmo, as recently reviewed [8] . in addition, patients undergoing va-ecmo are critically ill and suffer from profound cardiogenic shock, which by themselves contribute to the development of sirs [9] . the lung is a major target of inflammatory injury in the context of sirs, owing to its extensive capillary bed and the presence of abundant immune cells within the lung parenchyma. therefore, the occurrence of sirs in the context of ecmo provides a highly favorable environment for the development of acute lung injury [10, 11] . the main mechanisms triggering the inflammatory response to biomaterials are presented below. blood contact with va-ecmo circuitry activates the contact system (cs) and the complement system ( fig. 1) . cs generates kallikrein [12] , which activates monocytes fig. 1 main va-ecmo-induced mechanisms of lung damage and dysfunction. left side: sirs is initiated by the blood contact with the circuitry surface. it activates humoral cascades, platelets, and leukocytes, leading eventually to ec injury and activated pmn sequestration into the lung parenchyma. right side: ec injury favors fluid infiltration into both alveolar space and lung parenchyma, leading to pulmonary edema, which is aggravated by the increase of pulmonary vein pressure. alveolar edema and decreased pulmonary artery perfusion lead to lung parenchymal ischemia which in turn maintains chronic inflammation and promotes neoangiogenesis and fibrosis generation and polymorphonuclear cells (pmns), and triggers the intrinsic coagulation cascade, resulting in the rapid generation of thrombin and fibrin within the systemic circulation [13] . thrombin activates platelets and endothelial cells (ecs) and induces the secretion of pro-inflammatory mediators and growth factors, such as interleukin-6 (il-6), interleukin-8 (il-8), or platelet-derived growth factor (pdgf) [13] . the extrinsic coagulation pathway is activated to a lesser extent, mainly through the release of tissue factor (tf) by activated monocytes and ecs. cs also generates bradykinine [12] , which activates ecs and leukocytes, and elicits hemodynamic alterations including systemic vasodilation and pulmonary vasoconstriction [14] . complement activation occurs via the alternative pathway, generating the anaphylatoxins c3a and c5a, which activate ecs. c5a is also a potent mediator of leukocyte chemotaxis. a peak of complement activation occurs within 1-2 h of ecmo onset, followed by a progressive decreases over the next 2 to 3 days [15] . the humoral response triggered by blood-biomaterial interaction comprises the release of multiple cytokines [16] . whereas a balance between pro-and anti-inflammatory cytokines is reached several hours after va-ecmo initiation [17] , an initial imbalance in favor of pro-inflammatory tnf-α, il-1β, and il-6 leads to the activation of ecs and promotes the release of multiple inflammatory proteins by the liver such as fibrinogen, complement, and c-reactive protein. tnf-α plays a major role in the amplification of the early inflammatory response, by upregulating proinflammatory cytokines and prostaglandin synthesis, activating pmns and ecs, and stimulating reactive oxygen species (ros) production [18, 19] . platelets are activated by contact with the tubing surface and by thrombin and complement. activated platelets foster the generation of pro-inflammatory cytokines, thromboxane a2 (txa2), platelet-activating factor (paf), pselectin, and serotonin. txa2 induces ecs activation and local vasoconstriction, while serotonin and p-selectin promote pmn-endothelial interactions [20] . platelet activation is maximal at the initiation of va-ecmo and progressively decreases over hours to days but remains persistent [21] . ec activation leads to their detachment from the basal membrane and disassembly of tight junctions, increasing vascular permeability with the development of sub-endothelial edema [22] . moreover, activated ecs display an upregulated expression of adhesion molecules favoring pmn adhesion and transendothelial migration [23] , and they also release cytokines, tissue factor, and ros. circulating pmns, monocytes, and macrophages are spontaneously activated by tubing surfaces [24] . furthermore, pmns are activated by complement, histamine, serotonin, and paf, which facilitate their adhesion to ecs, diapedesis, tissue infiltration [25] , and the release of cytotoxic mediators, including proteases, cytokines, and ros. at variance with cpb, va-ecmo is generally maintained over several days. the initial significant sirs gradually decreases [15, 17] , mostly through the progressive build-up of counter-regulatory mechanisms leading to compensatory anti-inflammatory response and of possible biomaterial inactivation [26] . still, a delayed persisting inflammatory response can be observed several days after va-ecmo implementation, whose underlying mechanisms may involve the presence of low concentration of endotoxin within the circulation, which may sustain complement activation, cytokine release, and ros generation, to elicit a sepsis-like inflammation [27, 28] . the low-level inflammatory response induced by pulmonary low flow is another potential mechanism (see below). some potential therapies have been proposed to downregulate inflammation and possibly improve lung outcome in this setting. the replacement of a silicon oxygenator by a poly-methyl pentene oxygenator has been associated with reduced radiological signs of pulmonary inflammation on chest x-ray [29] , while the administration of steroids in patients undergoing va-ecmo has been associated with shortened mechanical ventilation time, although without any survival benefit [30] . pathophysiology peripheral (femoro-femoral) va-ecmo provides a non-physiological blood flow promoting significant hemodynamic perturbations (fig. 1 ). the retrograde reinjection of blood into the thoracic aorta increases lv afterload and impedes aortic valve opening, while increasing myocardial oxygen demand [31] . in the setting of cardiogenic shock, these disturbances may worsen lv performance and dramatically reduce lv stroke volume [31, 32] . in addition, if lv residual function is insufficient to permit aortic valve opening, progressive lv distension will occur, due to persisting venous return through pulmonary and bronchial veins into the left atrium and through thebesian veins into the lv, with concomitant increase of lv end-diastolic pressure. at worst, stagnation of blood within dilated left cardiac chambers may favor the formation of clots and induce pulmonary vein thrombosis [33] . pulmonary congestion develops consecutively to the passive upstream transmission of elevated lv pressure [34] . lung extravascular water accumulation is potentiated by the increased vascular permeability in the context of va-ecmo-induced sirs. the magnitude of afterload increase, lv distension, and pulmonary congestion is dependent on several parameters, including va-ecmo flow, systemic vascular resistance, and lv residual function [31, 35] . pulmonary congestion may jeopardize lung parenchymal cell oxygenation through two mechanisms. firstly, interstitial edema increases the thickness of the alveolarcapillary barrier, hence the diffusion distance for oxygen between alveoli and parenchymal cells, whose oxygenation primarily depends on oxygen diffusing from alveolar spaces [36] . secondly, alveolar edema results in a marked reduction of local alveolar po 2 (pao 2 ). alveolar epithelial cells, normally exposed to pao 2 above 100 mmhg, are sensitive to hypoxia from pao 2 below 50 mmhg, which may occur in alveoli flooded by pulmonary edema [37] . alveolar hypoxia can destabilize intercellular junctions, impair barrier permeability, impede alveolar fluid clearance and surfactant production by pneumocytes, induce local vasoconstriction and neoangiogenesis, and finally trigger local and systemic inflammation [37] [38] [39] . therefore, pulmonary congestion during va-ecmo creates a vicious circle in which va-ecmoinduced sirs and lv pressure overload promote pulmonary edema, leading to alveolar hypoxia which maintains sirs [37] . alveolar hemorrhages are another frequent consequence of the combination of pulmonary congestion and the requirement of anticoagulation during ecls. even if massive hemoptysis is rare [40] , local alveolar hemorrhages are frequent and sustain local inflammatory changes [41, 42] . chest x-ray is the simplest exam to assess pulmonary congestion, although its interpretation is complicated by frequently associated abnormalities, such as pneumonia, atelectasis, or alveolar hemorrhages. chest ultrasound is an effective and reliable alternative method to assess interstitial edema, pleural effusion, and parenchymal consolidation [43] . echocardiographic examination is mandatory, as it may show left heart dilation and indirect signs of cardiac congestion, such as spontaneous contrast echoes or the presence of "sludge" in heart chambers, as well as the absence of aortic valve opening [44] . hemodynamic monitoring using pulmonary artery catheter (pac) has been associated with improved survival in cardiogenic shock [45] , notably in the context of mechanical cardiac support. pac is particularly helpful to identify patients with cardiac distension, by demonstrating elevated left-sided filling pressure [46] . it has been shown that combining a value of pulmonary artery diastolic pressure > 25 mmhg (as a surrogate of pulmonary capillary wedge pressure) with evidence of pulmonary edema on chest x-ray could identify patients with subclinical lv distension [47] . although these data need further validation, pac is now advocated by most experts to help manage patients under va-ecmo [48] . severe pulmonary congestion during va-ecmo is associated with a dismal prognosis, and its treatment is mandatory [5, 49] . inotropic agents increase cardiac contractility, promote aortic valve opening, and reduce lv dilation and filling pressure. reducing va-ecmo flow to decrease lv afterload, as long as residual lv ejection is present and peripheral perfusion maintained, should also be considered. the insertion of an intra-aortic balloon pump (iapb) is a further option to decrease lv afterload. as demonstrated by bréchot et al., iabp in combination with va-ecmo versus va-ecmo alone is independently associated with less frequent hydrostatic pulmonary edema and a shorter duration of mechanical ventilation [50] . a recent meta-analysis found concomitant iabp to reduce in-hospital death and length of stay [51] . if previous steps fail to reduce pulmonary edema, the left heart chambers must be directly unloaded ("vented"), either by percutaneous atrial transseptal approach or by using a venting cannula inserted into the left atrium or the lv apex by surgical or trans-aortic approach [52] . in addition, the catheter-mounted microaxial pump impella® (abiomed, danvers, ma) may represent a further efficient device to permit lv unloading [52] . eliet et al. have recently observed that impella® not only decreases lv diastolic diameter but also increases pulmonary flow [53] . these different modalities of cardiac unloading during va-ecmo have been the matter of several extensive recent reviews [52, 54] . the lung is characterized by a dual circulation, comprising the pulmonary circulation, which supplies the alveoli for gas exchange, and the bronchial circulation, which conveys oxygen and nutrients to the airways, but not alveoli, whose oxygen supply is almost exclusively provided by direct diffusion from the alveolar spaces [39] . bronchopulmonary anastomoses allow collateralization between these two circulations. in case of chronic decrease of pulmonary blood flow (e.g., in chronic thromboembolic disease or pulmonary stenosis), the bronchial flow may increase from 1 to 30% of the cardiac output, permitting to compensate this decrease and participate to gas exchange, providing a kind of "rescue flow" to the ischemic areas [55, 56] . as depicted in fig. 1 , venous blood during va-ecmo is derived from the vena cava and the right atrium through the venous canula, resulting in a reduction of right ventricle (rv) filling, pulmonary blood flow, and pulmonary arterial pulsatility [31] . in a porcine model, vardi et al. demonstrated that the pulmonary capillary blood flow decreases dramatically as the va-ecmo flow increases [57] . moreover, in case of pulmonary congestion (see above), the upstream transmission of increased left atrial pressure reduces the transpulmonary perfusion gradient. ventilation with high positive end-expiratory pressure (peep) might also impede pulmonary blood flow by compression of alveolar vessels [58] . several additional mechanisms, including alveolar hypoxia, reduction of local no production, and the actions of inflammatory mediators can promote vasoconstriction and the subsequent increase of pulmonary vascular resistance, with a reduction of pulmonary blood flow [59] . it is also noteworthy that blood flow through the bronchial arteries (bas) is also reduced during va-ecmo, due to attenuated pulsatility of the systemic circulation (which supplies the bas). this can further limit blood supply to ischemic areas within the congested lung [60] . eventually, these various hemodynamic changes may lead to hypoperfusion of the entire pulmonary vasculature, which, superimposed to alveolar hypoxia, can promote a state of global, persistent lung ischemia. the best way to overcome such alterations is, of course, the withdrawal of va-ecmo. if this is not possible, va-ecmo flow may be reduced to maintain partial pulmonary perfusion. in early experimental studies in pigs, prolonged (18 h) ecmo at full support (with no residual pulmonary blood flow) promoted massive pulmonary parenchymal damage [61] , which was not observed at a residual pulmonary blood flow reaching 25% of the systemic cardiac output [62] . an additional strategy relies in the upgrading of va-ecmo to a hybrid system of veno-veno-arterial support, with an additional cannula inserted into the jugular vein, which provides oxygenated blood within the pulmonary arteries. this approach is sometimes used to treat the harlequin syndrome (see below), but has not yet been evaluated to prevent lung injury during va-ecmo. although no dedicated study has specifically focused on pulmonary histological consequences of va-ecmo, data from animal models and small human necropsy series have reported several pathological alterations. koul et al. maintained 6 pigs under total cpb for 18 h before weaning. all the animals died within the next 4 h, and on histological examination, more than 80% of the pulmonary parenchyma displayed edema, hyaline membranes, alveolar hemorrhages, thrombi, and focal necrotic changes [61] . in another experimental study exploring the effects of long-term va-ecmo without anticoagulation, mizuno et al. succeeded to maintain a goat up to 5 months under va-ecmo with a pulmonary blood flow reduced to 40%. at autopsy, diffuse interstitial fibrosis and swelling of endothelial cells with thickening of their basal membrane were noted [63] . in humans, ratliff et al. reported postmortem findings in 4 patients undergoing va-ecmo for 7 to 12 days. in two patients, diffuse lung fibrosis was noted, together with liquefaction necrosis of the lower lobes. the authors hypothesized that the combination of an increase in metabolically active cell mass together with partial pulmonary shunting concurred to establish ischemic areas with subsequent necrosis [64] . in an autopsy series of 23 infants supported by va-ecmo, chou et al. reported hyaline membrane formation, interstitial and intra-alveolar hemorrhages, and reactive hyperplasia of epithelial and smooth muscle cells, developing already after 2 to 3 days of va-ecmo support, whereas interstitial fibrosis was noted beyond 7 days [41] . to sum up, va-ecmo appears mostly associated with signs of protein-rich edema, alveolar hemorrhages, tissue necrosis, and fibrosis, which are reminiscent of the damage noted in the acute respiratory distress syndrome. these changes are likely the result of the combination of inflammatory injury, pulmonary congestion, and hypoxia, with the progressive development of epithelialendothelial injury, increased vascular permeability, and interstitial collagen deposition [65] . furthermore, some degree of angiogenesis and vascular remodeling may also play some role, as alveolar hypoxia and chronic ischemia (typical of long-lasting va-ecmo) can activate several pro-angiogenic cascades in alveolar cells, relying on the hypoxia-inducible factor family or the resistin-like molecule-α [37] . such alterations could result in longterm changes in pulmonary vascular physiology, with possible detrimental consequences on the right ventricle. pulmonary dysfunction during va-ecmo the impaired pulmonary function induced by va-ecmo may require long-lasting mechanical ventilation (mv) which may further alter the lung through ventilatorinduced lung injury (vili). although there is presently no consensus regarding optimal ventilator settings for mv during va-ecmo, the principles of lung-protective ventilation should be applied [66] . furthermore, prolonged mv increases the risk of ventilator-associated pneumonia (vap), which occurs in up to 74% of patients under ecmo, as recently reviewed [67] , with risk factors including an age > 65 years, a higher sofa score on admission, and a history of copd or hypertension [68] . causative microorganisms comprise primarily gram-negative bacilli, with pseudomonas aeruginosa isolated in 18-25% of cases [67] . diagnosis of vap may be particularly troublesome, as the usual criteria of vap are difficult to interpret in the setting of ecmo, and a high clinical index of suspicion coupled to early microbiological sampling are major clues to diagnosis [67] . treatment of vap on ecmo is challenging, notably because of the alterations of antibiotic pharmacokinetics occurring in this setting, and frequent therapeutic drug monitoring is therefore recommended [69] . preventive measures to reduce the risk of vap include primarily the reduction of mv duration. in this regard, a strategy of early extubation and awake ecmo support is emerging as a promising strategy [70] . in properly selected patients, such strategy not only significantly reduces the incidence of vap [70] , but also permits active mobilization, reduces the overall rate of complications, and increases survival [71] . the prototypical consequence of va-ecmodependent impairment of lung function is the development of the "harlequin syndrome," reflecting the opposing flows from the heart (antegrade, poorly oxygenated blood flow) and from the peripheral ecmo (retrograde, highly oxygenated blood flow), resulting in differential hypoxia (upper body hypoxemia, lower body normo/ hyperoxemia). the level of mixing of the two flows within the aorta is termed the "watershed," which can be identified in contrast-enhanced ct scan of the chest (fig. 2) . the harlequin syndrome may be treated by increasing va-ecmo flow or adding a venous injection cannula either as a hybrid ecmo (veno-veno-arterial ecmo, fig. 3 ) or as pure veno-venous ecmo if the function of the heart allows withdrawal of the arterial cannula. another option consists of switching the arterial cannulation site from femoral to axillary or central (aorta) location, in order to avoid the retrograde flow from the peripheral femoral cannula [72] . finally, bronchoscopy with bronchial hygiene may be considered routinely in order to maximize chances of successful weaning from va-ecmo when cardiac function recovers [73] . pulmonary dysfunction after weaning from va-ecmo va-ecmo-induced lung alterations may only appear after weaning and the restoration of physiological pulmonary artery blood flow. in a series of 55 patients who underwent long-term mechanical assist device implantation under va-ecmo (l-vad, bi-vad, or total artificial heart), boulate et al. noticed that 27% of patients develop acute lung injury (ali) few hours after restoration of pulmonary blood flow, with a significant impact on mortality. the authors hypothesized that chronic lung ischemia during va-ecmo support could promote alveolar frailty and that the sudden restoration of an antegrade pulsatile pulmonary blood flow creates a massive pulmonary bed overload responsible of ali [74] . accordingly, one of the identified risk factors of ali in this study was the occurrence of a pulmonary edema during the week preceding the implantation of the mechanical device, featuring a preexisting lung frailty. this form of ali is reminiscent of reperfusion pulmonary edema, a well-known and described condition that occurs after reperfusion of a chronic low pulmonary blood flow situation, as in correction of tetralogy of fallot [75] or pulmonary endarteriectomy for chronic embolism [76] . such reperfusion pulmonary edema relies both on ischemia-induced chronic inflammation and reperfusion injury that involves similar mechanisms than those described above [77] . fig. 2 the watershed. a axial. b sagittal. contrast in the aorta indicates blood flow from the va-ecmo arterial cannula, whereas absence of contrast within the ascending aorta indicates blood flow from the native heart. the level of blood mixing in the thoracic aorta represents the va-ecmo watershed (arrows) in order to help the decision-making process in patients under va-ecmo, chen et al. developed a risk factorcalling score (rfss) to select patients eligible for l-vad or htx. the rfss has 5 items and 16 points, 7 of which are allocated to pulmonary dysfunction. a rfss > 7 predicted a poor outcome, which emphasizes the relative burden of pulmonary dysfunction in the outcome of patients under va-ecmo in a bridge strategy [78] . it is currently unknown whether lung damage and dysfunction induced by va-ecmo have an impact on long-term outcome, the more so that many unrelated factors may interfere with such outcome, such as prolonged icu stay, previous health condition, or reduced lv ejection fraction. a few studies focused on long-term health-related quality of life (hrql) in va-ecmo survivors after cardiogenic shock. combes et al. questioned 28 va-ecmo survivors about their hrql via the short-form 36 questionnaire (sf-36). mean va-ecmo duration and follow-up were respectively 7 days (5 to 10) and 11 months (3 to 39). in comparison to sex-and agematched controls, va-ecmo survivors disclosed significantly lower role-physical score and a trend to a lower physical function, even though most patients recovered a good cardiac function with mean lvef 51% or underwent htx [79] . these results were confirmed by other studies showing lower sf-36 values of physical functioning and role-physical scores in va-ecmo survivors compared to standard population [80, 81] . these data however do not give any information with respect to the potential long-term burden of pulmonary alterations associated with va-ecmo, and future studies should be designed to address this issue, for example by performing delayed lung functional tests in long-term survivors of va-ecmo. va-ecmo elicits several pathophysiological disturbances which may significantly impact on lung integrity and function. first, the rapid development of a systemic inflammatory response with pulmonary involvement is an unavoidable consequence of the artificial va-ecmo circuitry. second, due to retrograde blood flow within the thoracic aorta, peripheral va-ecmo has the propensity to increase lv afterload, which may favor the congestion of alveoli already affected by the ongoing inflammation. third, persistent lung ischemia due to the partial shunting of the pulmonary circulation and reduced pulsatility of the bronchial circulation may elicit further cytotoxicity within the whole lung parenchyma. limited evidence from human observational studies and animal models indicates that va-ecmo support for more than a few days may lead to severe structural changes of the lung parenchyma and interstitial fibrosis, which could result in long-term functional limitation. 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contributor in writing manuscript. all authors contributed to the content of this paper and critically reviewed the final manuscript. ar edited individual contributions and finalized the manuscript. all authors read and approved the final manuscript. lucas liaudet is supported by a grant from the swiss national fund for scientific research (nr 310030_162629).availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare they have no competing interests. key: cord-003995-53115c1c authors: guerci, philippe; bellut, hugo; mokhtari, mokhtar; gaudefroy, julie; mongardon, nicolas; charpentier, claire; louis, guillaume; tashk, parvine; dubost, clément; ledochowski, stanislas; kimmoun, antoine; godet, thomas; pottecher, julien; lalot, jean-marc; novy, emmanuel; hajage, david; bouglé, adrien title: outcomes of stenotrophomonas maltophilia hospital-acquired pneumonia in intensive care unit: a nationwide retrospective study date: 2019-11-21 journal: crit care doi: 10.1186/s13054-019-2649-5 sha: doc_id: 3995 cord_uid: 53115c1c background: there is little descriptive data on stenotrophomonas maltophilia hospital-acquired pneumonia (hap) in critically ill patients. the optimal modalities of antimicrobial therapy remain to be determined. our objective was to describe the epidemiology and prognostic factors associated with s. maltophilia pneumonia, focusing on antimicrobial therapy. methods: this nationwide retrospective study included all patients admitted to 25 french mixed intensive care units between 2012 and 2017 with hospital-acquired s. maltophilia hap during intensive care unit stay. primary endpoint was time to in-hospital death. secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy. results: of the 282 patients included, 84% were intubated at s. maltophilia hap diagnosis for duration of 11 [5–18] days. the simplified acute physiology score ii was 47 [36–63], and the in-hospital mortality was 49.7%. underlying chronic pulmonary comorbidities were present in 14.1% of cases. empirical antimicrobial therapy was considered effective on s. maltophilia according to susceptibility patterns in only 30% of cases. delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. survival analysis did not show any benefit from combination antimicrobial therapy (hr = 1.27, 95%ci [0.88; 1.83], p = 0.20) or prolonged antimicrobial therapy for more than 7 days (hr = 1.06, 95%ci [0.6; 1.86], p = 0.84). no differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between monoversus polymicrobial s. maltophilia hap (p = 0.273). the duration of ventilation prior to s. maltophilia hap diagnosis and icu length of stay were shorter in patients with monomicrobial s. maltophilia hap (p = 0.031 and p = 0.034 respectively). conclusions: s. maltophilia hap occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival. trial registration: clinicaltrials.gov, nct03506191 stenotrophomonas maltophilia is one of the 10 most frequently isolated pathogens responsible for hospitalacquired pneumonias (haps) in intensive care unit (icu) patients in western countries [1, 2] , representing approximately 5% of positive pulmonary samples. previous studies identified several risk factors for developing s. maltophilia hap in critically ill patients, such as prolonged icu hospitalization associated with invasive procedures, extended periods of mechanical ventilation, or exposure to broad-spectrum antibiotics [3] [4] [5] . therefore, s. maltophilia pneumonia occurs preferentially in patients with the poorest prognosis [6, 7] . however, these studies were conducted from heterogeneous and small cohorts of patients. the severity of s. maltophilia hap and antimicrobial therapy modalities were sparsely reported [3, 4] . hence, data are lacking to draw recommendations on the optimal therapeutic strategies against s. maltophilia pneumonia. we undertook a large nationwide multicenter retrospective study with the main objective to demonstrate that modalities of antibiotic therapy, including empirical antimicrobial choice, whether a combination therapy was used, or the duration of the therapy, would influence in-hospital mortality. secondary objectives were to describe the characteristics of icu patients with s. maltophilia hap and to draw prognostic factors of these pneumonias. the medical records of patients who experienced s. maltophilia pneumonia from january 2012 to january 2017 were collected from 25 icus of the french society of anaesthesia & intensive care medicine (sfar) and azurea networks [8] . participating centers and casemixes are listed in additional file 1. the collected data involved both icu and hospital stays. follow-up was stopped either after hospital discharge or death, whichever occurred first. all patients aged over 18 years who were admitted to the participating icus and presenting with a documented diagnosis of s. maltophilia pneumonia during their icu stay were eligible. the patient's files were extracted through french hospital discharge database containing individual records of all hospital stays using international classification of disease (icd-10) for the terms "stenotrophomonas maltophilia" and "pneumonia." in addition, icu medical charts were cross-checked with microbiology laboratoryspecific information systems to ensure exhaustivity. each medical record was analyzed by local investigators to determine if clinical, biological, and/or radiological signs of s. maltophilia hap were present, thus excluding respiratory tract colonizations (defined as a positive respiratory sample without clinical, biological, and/or radiological signs of s. maltophilia pneumonia). in case of uncertainty, consensus was obtained between local infectious disease specialists and study coordinators (pg, ab) to clarify s. maltophilia hap cases. pneumonia was defined as follows: (i) new or progressive lung infiltrate, (ii) temperature > 38°c or < 36.5°c, leukocyte count > 12,000 μl −1 or < 4000 μl −1 , purulent endotracheal aspirate or sputum, (iii) positive respiratory sample (see below), and (iv) decline in oxygenation [9, 10] . hap was defined as a pneumonia not incubating at the time of hospital admission and occurring 48 h or more after admission. ventilator-associated pneumonia (vap) was defined as a pneumonia occurring 48 h or more after tracheal intubation [9] . the clinical cure of s. maltophilia pneumonia was defined by the absence of pneumonia criteria 48 h after antimicrobial therapy cessation. treatment failure was defined as a failure of first-line treatment or death attributable to s. maltophilia pneumonia. recurrence was defined as the onset of new pneumonia criteria associated with a positive respiratory sample with s. maltophilia after the initial pneumonia was considered successfully cured. empirical antimicrobial therapy was defined as the first agents prescribed for the initial treatment of hap (effective or not on s. maltophilia) finally diagnosed as being caused by s. maltophilia. empirical antimicrobial therapy was considered as effective if the s. maltophilia strain cultured from the respiratory sample was susceptible to at least one of the antimicrobial agents. combination therapy was defined as the administration of at least two antimicrobial agents a priori (before s. maltophilia hap has been confirmed, usually within 48 h) or a posteriori (after s. maltophilia hap has been confirmed) effective on the s. maltophilia strain for more than 24 h. usual demographic variables were collected, including previous hospital stays and previous exposure to antimicrobial therapies (agents and durations). simplified acute physiology score ii (sapsii) and the sequential organ failure assessment (sofa) score were assessed. on the day of s. maltophilia hap diagnosis, the sofa score was collected, as well as the number and type of invasive devices inserted. the severity of hypoxemia was graded according to the berlin acute respiratory distress syndrome (ards) criteria [11] . requirements for highflow nasal oxygen therapy, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ecmo) were reported. empirical antimicrobial therapy and secondary adaptations were recorded, as were durations. in case of s. maltophilia isolation, the culture was considered to be positive (either mono-or polymicrobial infection) with the following cutoff: (1) for minimally contaminated lower respiratory tract sample with quantitative culture, the threshold was 10 4 colony-forming units (cfu)/ml for bronchoalveolar lavage (bal) and the cutoff was 10 3 cfu/ml for protected specimen brush (psb) or protected (plugged) telescoping catheter (ptc); (2) nonprotected sample (endotracheal aspirate, eta) with quantitative culture (10 5 cfu/ml); or (3) sputum bacteriology with quantitative culture (10 7 cfu/ml) [12] . s. maltophilia identification characteristics (date of isolation and type of respiratory tract sampling) and antimicrobial susceptibility testing were independently performed by each microbiology laboratory. ast was performed on isolates using disk diffusion or automated testing methods according to guidelines and breakpoints established by the european committee on antimicrobial susceptibility testing (eucast) [13] . data were collected and managed using research electronic data capture (redcap) software [14] . the database was approved by the institutional review board of the sfar (irb00010254-2015-010), which waived the need for signed informed consent of the participants, in accordance with the french legislation on noninterventional studies [15] . the study was declared on clinicaltrials.gov (nct03506191). this manuscript was written in accordance with the strobe statement for the reporting of observational studies in epidemiology. the results are expressed as the number of patients (%) for categorical variables and mean (± standard deviation) or median [iqr] for continuous variables. prognostic factors associated with time to in-hospital death were studied using the cox proportional hazard model. time to in-hospital death was calculated from the diagnostic date of s. maltophilia to death. the follow-up was censored at discharge from the icu and/ or the hospital. baseline prognostic factors were age, saps ii, mechanical ventilation at diagnosis, vap, duration of mechanical ventilation before the diagnosis, sofa score at diagnosis, bacteremia, mono/polymicrobial pneumonia, use of empirical antimicrobial therapy, and use of empirical antimicrobial therapy effective against s. maltophilia. other antimicrobial therapyrelated variables were not defined as baseline and were thus entered in the model as time-dependent variables, including time elapsed between sample and effective antimicrobial therapy, use of effective combination antimicrobial therapy, and duration of effective antimicrobial therapy against s. maltophilia (monotherapy or combination therapy). baseline and time-dependent variables associated (p < 0.05) with outcome in the univariate analysis and that were present at the diagnosis were considered for the multivariate model, and the final model was selected using backward stepwise regression (p < 0.05). hazard ratios (hr) were calculated accordingly with their 95% confidence intervals (ci). we compared the time to in-hospital death between patients who received or not an empirical antimicrobial therapy effective against s. maltophilia using propensity score framework. the variables used for propensity score estimations were age, sex, sofa score at diagnosis, saps ii, and the icu length of stay before pneumonia diagnosis. the two groups of patients were matched using a 1:1 nearest neighbor matching algorithm with replacement, using a caliper of 0.2 of the standard deviation of the propensity score on the logit scale [16] . covariate balance between the two groups was assessed after matching, and we considered an absolute standardized difference (asd) less than 0.1 as evidence of balance [17] . then, time to in-hospital death was compared between matched groups using a cox proportional hazard model. the 95% confidence intervals of the estimated hazard ratio (empirical antimicrobial therapy yes vs no) were estimated using robust standard error [18] . significance was defined as p values < 0.05. statistical tests were two-sided. statistical analyses were performed using r 3.5.0 (r foundation for statistical computing, http://www.r-project.org/, vienna, austria). of the 102,316 patients admitted to the 25 icus within the study period, 282 (0.27%) with a s. maltophilia pneumonia were included (fig. 1 ). our population was predominantly male (69.9%), with an age of 65 [56-74] years, mostly admitted for medical reasons (59.2%) or emergent surgery (29.4%). severity at admission was illustrated by sofa score (8 [5] [6] [7] [8] [9] [10] [11] ) and sapsii (47 ). icu and hospital lengths of stay were 32 and 54 days, respectively. the overall in-hospital mortality rate was 49.7% (table 1 ). there was no difference in trends of patient inclusion and distribution over years. 48 patients had been hospitalized in the icu for 11 [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] days at the time of onset of s. maltophilia pneumonia. forty patients (14.2%) presented with a chronic underlying pulmonary disease. other characteristics of patients are described in table 1 , and invasive devices are reported in additional file 2: table s1 in the online data supplement. characteristics of s. maltophilia hap are described in table 2 . briefly, 41.6% of s. maltophilia pneumonias were monomicrobial and 80.8% were vap. blood culture was concomitantly positive in only 7.1% of cases. microbiological diagnosis methods for isolation of s. maltophilia are presented in additional file 3: table s2 in the online data supplement. patients with s. maltophilia vap had a duration of mechanical ventilation before the onset of pneumonia of 11 [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] days. s. maltophilia pneumonia-related septic shock was present in 123 patients (43.6%) within 48 h of s. maltophilia hap (septic shock attributed to pneumonia by clinicians and without other identified cause in the post hoc analysis). among these patients who developed septic shock, 38 (30.8%) did not receive initial empirical antimicrobial therapy. forty-nine percent of patients fulfilled moderate or severe ards criteria. the description of antimicrobial therapy modalities is reported in table 3 . before the onset of s. maltophilia pneumonia, patients received 3 [2] [3] [4] prior antimicrobial therapies for at least 5 consecutive days in icu. empirical antimicrobial therapy was a posteriori effective against s. maltophilia in 30.1% of cases. the duration of effective antimicrobial therapy on s. maltophilia was 11 [7] [8] [9] [10] [11] [12] [13] [14] [15] days. a combination of antimicrobials effective against s. maltophilia was used in 59.4% of patients for 7 [5] [6] [7] [8] [9] [10] [11] [12] days. ast of s. maltophilia strains is presented in fig. 2a . trimethoprim-sulfamethoxazole (tmp-smx) (88.1%) and ticarcillin-clavulanate (73.3%) remained highly active against more than two thirds of s. maltophilia strains. the main antimicrobial therapies prescribed to treat s. maltophilia hap after identification were tmp-smx (29%), ciprofloxacin (25%), and ticarcillin-clavulanate (24%) (fig. 2b) . treatment failure occurred in 65 patients (23.1%). recurrence of s. maltophilia pneumonia was diagnosed in table 4 ). the subsequent occurrence of a septic shock was significantly associated with an increased risk of death (hr = 3.070, 95%ci [1.9; 5.0], p < 0.0001). neither the duration of treatment nor the use of combination therapy directed against s. maltophilia was associated with the primary endpoint (table 4 ). other commonly reported risk factors for s. maltophilia hap (i.e., immunosuppression, chronic obstructive pulmonary disease (copd), prior antimicrobial therapy) were not statistically associated with time to in-hospital death. in multivariate analysis, only age (hr = 1.02, 95% ci [1.01; 1.04], p = 0.001) and sofa score at s. maltophilia pneumonia diagnosis (hr = 1.1, 95%ci [1.06; 1.15], p < 0.001) were associated with in-hospital death ( table 4 ). subsequent septic shock was not included in the multivariate analysis because it was a consequence and not present at the diagnosis of s. maltophilia. the results were similar when only considering vap in our cohort (n = 228) (additional file 5: table s4 ). finally, we performed a statistical analysis based on a propensity score to evaluate the effect of an empirical antibiotic therapy effective on s. maltophilia on the primary endpoint (additional file 6: table s5 ). after matching, we compared 48 patients who received appropriate empirical antibiotic therapy versus 222 who did not (additional file 7: table s6 ). this analysis confirmed the previous results (hr = 0.891, 95%ci [0.498-1.593], p = 0.697). the aforementioned results remained unchanged when considering only monomicrobial s. maltophilia pneumonia (n = 117) (hr = 1.08, 95%ci [1.01; 1.15], p = 0.021 for sofa score at s. maltophilia pneumonia diagnosis). comparisons of characteristics and outcomes between mono-and polymicrobial s. maltophilia hap are provided in table 5 . no differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono-versus polymicrobial s. maltophilia hap. a similar number of vap occurred in both groups, 91 (77.8%) versus 136 (82.9%) (p = 0.280) for mono-and polymicrobial hap respectively. the duration of ventilation prior to s. maltophilia hap diagnosis and icu length of stay were shorter in patients with monomicrobial s. maltophilia hap. herein, we report the largest cohort study of critically ill patients developing s. maltophilia hap. regarding the large screening, the prevalence of s. maltophilia hap remained very low. the majority of s. maltophilia hap was vap and occurred in patients ventilated for more than 10 days and previously exposed to several antimicrobial therapies. the mortality rate of these patients remained high, but surprisingly, the treatment delay in adequate antimicrobial therapy targeting s. maltophilia was not found to be associated with mortality. this observation may be the result of (i) a low virulence of the pathogen, (ii) the underlying condition of the critically ill patient being more contributive to the outcome than s. maltophilia hap itself, or (iii) a 24-to 48-h delay in the treatment of s. maltophilia hap had no real impact. finally, if sap-sii and sofa score were independently associated with mortality, no specific pneumonia or antimicrobial therapy-related factors impacted the outcome. our study population shares common features with previously published reports [3, 4, 6, 7, [19] [20] [21] [22] [23] . indeed, s. maltophilia pneumonia develops in high-risk phenotypes patients, i.e., long icu/hospital length of stay and duration of mechanical ventilation. despite a mortality rate of approximately 50%, it is difficult to delineate direct attributable mortality of s. maltophilia hap from mortality linked to underlying diseases [24] . indeed, the prolonged icu length of stay preceding s. maltophilia isolation and the number of prior antimicrobial therapies suggest noticeable patient frailty and complicated medical history. these factors have been associated to high mortality in patients with resistant bacteria in icu [25] . s. maltophilia hap could also be perceived as a final previous studies that included a small number of patients [3, 4, 6, [19] [20] [21] [22] [23] [26] [27] [28] [29] [30] [31] suggested that immunecompromised conditions, copd, prior cardiac surgery, or prior antimicrobial therapy were risk factors for s. maltophilia hap. conversely, our large series of mixed icu patients did not confirm these elements. this implies that the involvement of s. maltophilia in late onset hap should be considered and be kept in mind by all critical care physicians. however, in our series, initial antimicrobial therapy inactive against s. maltophilia was not a risk factor for in-hospital mortality, arguing against a systematic coverage of s. maltophilia by empirical antimicrobial therapy in this setting. although the prolonged duration of antimicrobial treatment is a well-known risk factor for emergence of multidrug resistant (mdr) bacteria [32] , it did not appear to be discriminant in our study, irrespective of the class of antimicrobial agent previously administered. these results are in accordance with previously published literature on continuation or de-escalation of beta-lactam antibiotics and emergence of mdr [31] . indeed, different regimens were used in our population, with various durations of treatment before s. maltophilia hap diagnosis without apparent consequences on s. maltophilia emergence and susceptibility profiles. soubirou et al. found that the increase in use of antimicrobial class was an independent predictor of s. maltophilia emergence in vap [33] . it is however conceivable that some patients of our cohort may be colonized with other non-fermenting gram-negative bacilli. actually, almost 20% of patients had copd or chronic respiratory insufficiency and might be regularly exposed to antibiotics. nseir et al. and saugel et al. reported 63% and 25% respectively incidence of copd patients with s. maltophilia pneumonia [3, 4] . despite clinical signs of hap, only 59% of patients readily received empirical antimicrobial therapy (additional file 4: table s3 ). this highlights the variable implementation and adherence to antimicrobial bundles of care and stewardship programs [34] [35] [36] . pathmanathan et al. previously reported no measurable impact of antibiotic therapy in patients without evidence of consolidation which suggests colonization [23] . in our study, colonization was excluded. although it is currently suggested to start antibiotics early in patients with suspected vap [37] , physicians may have been expecting a definitive identification with the resistance profile of microorganisms possibly involved to restrain the use of broad-spectrum antibiotics, especially in patients previously exposed to several antibiotic regimens. tracheobronchitis and pneumonia may also be hard to be differentiated and need time to be distinguished. of note, the interplay between resistance and virulence remains complex [38] . in these patients already exposed to several series of antimicrobial therapies, with an extended hospital length of stay, the likelihood of mdr bacteria involvement was very high. moreover, due to its natural resistance to multiple antimicrobial agents, only one third of empirical antimicrobial therapies was actually effective against s. maltophilia. conversely to other authors [39] , but in accordance with studies on pseudomonas aeruginosa vap, the delayed administration of effective antimicrobial treatment was not statistically associated with increased mortality [40, 41] . the duration of s. maltophilia hap antimicrobial therapy is still subject to debate. the comparison of short (< 8 days) versus prolonged (8 days and greater) antibiotic course could not properly be investigated in our study because of its design. chastre et al. demonstrated that an 8-day course of antibiotic therapy for vap was not inferior to a longer duration, but only 0.8% of patients had an s. maltophilia vap [42] . however, it was suggested that patients infected with difficult-to-treat pathogens, immunocompromised patients, and patients at high risk for relapse may require a longer duration of antibiotic therapy. in our study, we identified neither the duration of antimicrobial treatment nor the combination of antibiotic therapies as significant risk factors for in-hospital death. low virulence of s. maltophilia strains may partially explain these findings. in a recent retrospective study focused on the interest of combination therapy, shah et al. reported that combination of antibiotic therapies yielded similar clinical efficacy and resistance development compared to monotherapy [43] . optimal antimicrobial against s. maltophilia hap may raise some concerns. the s. maltophilia strains in our study had a preserved susceptibility to ticarcillin-clavulanate and tmp-smx, 73 and 88% respectively as expected [44] . however, only 29% of s. maltophilia hap were treated with tmp-smx. these discrepancies may be related to icu physicians' habits, the fear of tmp-smx-related side effects, and the type of antibiotics administered prior to occurrence of s. maltophilia hap. the use of fluoroquinolones could have been considered easier. when prescribed, tmp-smx was combined with another antibiotic effective on s. maltophilia in 80% of cases. in addition, antimicrobial agent shortages change antimicrobial therapy armamentarium, with a cessation of manufacture of ticarcillin-clavulanate in 2015 [45] . although ceftazidime/avibactam has poor activity on s. maltophilia [46] , it may restore the susceptibility to aztreonam through the inhibition of the l2 β-lactamase in vitro [47] . the clinical efficacy of this combination has been reported in a case report of a transplant renal patient [48] . augmented renal clearance can alter the pharmacokinetics and pharmacodynamics (pk/pd) of several antimicrobial agents, mainly ß-lactams [49] . the detailed dosages of antimicrobial agents and the measured creatinine clearance were not collected in the present study. however, tmp-smx and fluoroquinolones were the most prescribed agents. their plasma concentrations are not dramatically influenced by augmented renal clearance and not easily monitored in daily practice. our study differs from previous studies, where patients with and without s. maltophilia infection were compared. we did not consider s. maltophilia colonizations but only hap, unlike previous studies [4] . in the case of a polymicrobial sample, it is uncertain which bacteria were responsible for the hap. one may argue that our study suffers from inaccurate diagnoses differentiating between vap and ventilator-associated tracheobronchitis due to its retrospective design using icd codes. we acknowledge that the diagnosis method (eta versus bal or psb) may influence the detection of s. maltophilia. this was a pragmatic study that describes different icu practices, and to date, there is no formal evidence of improved outcomes depending on the diagnosis method used [50] . despite strict inclusion criteria, and search for consensus in case of debatable case, it is possible that the physician's judgment and diagnosis reported in the medical record were inaccurate. however, 80% of hap were vap in our study and excluding nonventilated patients did not alter the observed results. s. maltophilia hap had a very low incidence in critically ill patients but was associated with high mortality rate in this large multicenter study. its onset is hard to predict because of lack of specific risk factors but occurs mainly in long-stay icu patients. the present study did not provide evidence of a significant effect of delay, duration, or combination of antimicrobial therapy on mortality. efforts in developing novel and effective approaches for prevention are warranted. in critically ill patients with stenotrophomonas maltophilia hospital-acquired pneumonia, delay to appropriate antimicrobial treatment, combination antimicrobial therapy, or prolonged antimicrobial therapy may not be associated with increased survival. authors' contributions pg, hb, and ab contributed to the study design, screening for eligibility and inclusion of patients, data analysis, writing of the first draft and of the final version, and review of the manuscript. nm contributed to the screening for eligibility and inclusion of patients, data analysis, writing of the first draft and of the final version, and review of the manuscript. dh contributed to the writing of the first draft and of the final version, data analysis, and review of the manuscript. sl and en contributed to the screening for eligibility and inclusion of patients, writing of the last draft, and review of the manuscript. mm, jg, cc, gl, pt, cd, ak, tg, jp, and j-ml contributed to the screening for eligibility and inclusion of patients and review of the manuscript. all authors read and approved the final manuscript. this study has been solely funded by the department of anaesthesiology and critical care medicine of the university hospital of nancy, france. the unit of methodology, data and statistics kindly provided free of charge redcap support. 4 service d'anesthésie-réanimation chirurgicale, hôpital hautepierre réanimation chirurgicale polyvalente, hôpital central 11 réanimation médicale, institut lorrain du coeur et des vaisseaux, chu nancy-brabois, vandoeuvre-lès-nancy, france. 12 réanimation adultes et soins continus, pôle de médecine péri-opératoire 14 service d'anesthésie-réanimation, réanimation polyvalente equipe pharmacoépidémiologie et évaluation des soins multistate point-prevalence survey of health care-associated infections healthcare-associated infections in intensive care units -annual epidemiological report for 2015 intensive 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intensive care unit mortality: a systematic review antibiotic stewardship in the intensive care unit antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilatorassociated pneumonia pseudomonas aeruginosa ventilator-associated pneumonia. predictive factors of treatment failure impact of multidrug resistance on pseudomonas aeruginosa ventilatorassociated pneumonia outcome: predictors of early and crude mortality comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial efficacy of combination therapy versus monotherapy in the treatment of stenotrophomonas maltophilia pneumonia antimicrobial susceptibility of gram-negative organisms isolated from patients hospitalised with pneumonia in us and european hospitals: results from the sentry antimicrobial surveillance program clinical implications of stenotrophomonas maltophilia resistant to trimethoprimsulfamethoxazole: a study of 69 patients at 2 university hospitals antimicrobial activities of ceftazidime-avibactam and comparator agents against clinical bacteria isolated from patients with cancer avibactam restores the susceptibility of clinical isolates of stenotrophomonas maltophilia to aztreonam successful treatment of bloodstream infection due to metallo-β-lactamaseproducing stenotrophomonas maltophilia in a renal transplant patient pharmacokinetics-pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilatorassociated pneumonia springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank geoffroy cagninacci and cédric baumann for their excellent implementation and support of redcap. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-019-2649-5.additional file 1. list of participating centers, collaborators and case-mix of icu patients.additional file 2: table s1 . invasive devices inserted at the diagnosis of stenotrophomonas maltophilia hospital-acquired pneumonia. description of invasive devices inserted at the diagnosis of stenotrophomonas maltophilia hospital-acquired pneumonia.additional file 3: table s2 . diagnosis methods for isolation of stenotrophomonas maltophilia. description of diagnosis methods for isolation of stenotrophomonas maltophilia.additional file 4: table s3 . treatment failure of stenotrophomonas maltophilia hospital-acquired pneumonia. description of treatment failures of stenotrophomonas maltophilia hospital-acquired pneumonia.additional file 5: table s4 . variables associated with the time to inhospital death in patients with s. maltophilia ventilator-associated pneumonia. variables associated with the time to in-hospital death in patients with s. maltophilia ventilator-associated pneumonia.additional file 6: table s5 . propensity score matching. time to inhospital death was compared between matched groups using a cox proportional hazard model. additional file 7: table s6 . variable associated with time-to-death in the propensity matched population. variable associated with timeto-death in the propensity matched population. the datasets analyzed in this study are not publicly available due to privacy issues, but are available from the corresponding author upon reasonable request.ethics approval and consent to participate this study was approved by the ethics committee of the société française d'anesthésie et de réanimation (irb 00010254-2015-010; february 19, 2016) . this study was the subject of a favorable decision from the comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé on april 20, 2017, and of a declaration to the comission nationale informatique et libertés on may 20, 2017 . this study complies with the principles of the 1964 declaration of helsinki in reviewing and publishing information from the patient's medical records. the requirement for informed consent from each patient was waived because the design of study was retrospective in nature and because of the use of anonymized patient and hospital data. all the authors have read the manuscript, approved this submission, and consented for publication. the authors declare that they have no competing interests. 1 key: cord-004096-obrq7q57 authors: benghanem, sarah; mazeraud, aurélien; azabou, eric; chhor, vibol; shinotsuka, cassia righy; claassen, jan; rohaut, benjamin; sharshar, tarek title: brainstem dysfunction in critically ill patients date: 2020-01-06 journal: crit care doi: 10.1186/s13054-019-2718-9 sha: doc_id: 4096 cord_uid: obrq7q57 the brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. it controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. the brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, mri, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. in the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting. the brainstem is the caudal portion of the brain that connects the diencephalon to the spinal cord and the cerebellum [1] . the brainstem mediates sensory and motor pathways between the spinal cord and the brain and contains nuclei of the cranial nerves, the ascending reticular activating system (aras), and the autonomic nuclei. it controls the brainstem reflexes and the sleepwake cycle and is responsible for the autonomic control of the cardiocirculatory, respiratory, digestive, and immune systems. brainstem dysfunction may result from various acute or chronic insults, including stroke, infectious, tumors, inflammatory, and neurodegenerative diseases. in the context of critical illness, the brainstem can be susceptible to various insults that can be categorized as structural and non-structural origin. brainstem dysfunction can then contribute to impairment of consciousness, cardiocirculatory and respiratory failure, and thus increased mortality [2] [3] [4] [5] . in the present review, we describe brainstem functional neuroanatomy, clinical syndromes, and assessment methods before addressing the concept of critical illnessassociated brainstem dysfunction. the brainstem can be categorized into three major parts: midbrain, pons, and medulla oblongata ( figs. 1 and 2) . the brainstem contains both gray and white matter, with the basilar artery representing the vascular supply. the gray matter includes the nuclei of the cranial nerves (anterior part), the aras (posterior part), the extrapyramidal and the central autonomic nervous system (ans). this gray matter controls brainstem reflexes, arousal, automatic movements, and homeostasis, respectively. the white matter is composed of ascending sensory pathways and descending pyramidal and extrapyramidal pathways (table 1) . brainstem pathology should be considered in cases of (a) sensory or motor deficits combined with cranial nerve palsy, (b) impairment of consciousness, (c) dysautonomia, or (d) neurological respiratory failure. the pyramidal and extrapyramidal tracts connect the upper motor neurons and the extrapyramidal nuclei with the lower motor neurons located in either the brainstem or the spinal cord [6] . while the former controls voluntary movement, the latter is involved in reflexes, motion, complex movements, and postural control (tables 1 and 2 ). upper motor neuron damage can lead to symptoms, ranging from hemiparesis to the locked-in syndrome, which is typically characterized by intact awareness, quadriplegia, anarthria, and absence of eye movements except for preserved vertical gaze. it usually results from bilateral pontine white matter lesions [7] . characteristic clinical features of brainstem lesions include ipsilateral cranial nerve palsies or cerebellar signs combined with contralateral motor deficits. brainstem lesions may present with abnormal movements, such as hemichorea, hemiballism, dystonia, tremor, asterixis, pseudo-athetosis, and non-epileptic myoclonus [8] ( table 2) . bilateral motor corticobulbar tract lesion may present with swallowing impairment, dysphagia, dysphonia, velo-pharyngo-laryngeal impairments, uncontrollable crying/laughing episodes, and emotional lability (i.e., pseudobulbar affect; table 2 ). a brainstem lesion of the posterior column-medial lemniscus pathway and the spinothalamic tract results in a contralateral proprioceptive/touch and temperature/pain deficit, respectively. the testing of the cranial nerves and brainstem reflexes is described in table 3 . abnormal spontaneous eye position and movements may be encountered in patients with brainstem lesions and can be seen in comatose patients. assessment of pupillary size allows the diagnosis of third nerve lesion (i.e., mydriasis) or horner's syndrome (i.e., myosis, ptosis, enophtalmia, and anhidrosis). pupillary light, corneal, oculocephalic, and gag reflexes are routinely assessed in the critical care setting. the oculovestibular responses and oculocardiac are less frequently tested, except to determine brain death. the absence of brainstem reflexes and spontaneous breathing is a prerequisite for the diagnosis of brain death [9] . automated pupillometry could improve the assessment of the pupil light reflex and thereby its prognostic value [10] . corneo-mandibular reflexes can be detected in acute brain injury, but its prognostic relevance remains controversial. finally, assessments of primitive reflexes are less relevant in the icu context but can (table 3) . when suspecting brainstem lesions, mri will have the highest yield to further localize and characterize brainstem lesions [6] (table 4 ). evoked potentials may be also useful for detecting a brainstem lesion. eeg [11] may be supportive in patients with abnormal movements and disorders of consciousness, and cerebrospinal fluid (csf) analysis for those with suspected inflammatory or infectious diseases. the aras controls the sleep-wake cycle and includes several nuclei mainly located in the pontine and midbrain tegmentum [12] (table 2 , figs. 1 and 2): the rostral raphe complex, the parabrachial nucleus, the laterodorsal tegmental nucleus, the locus coeruleus (lc), the nucleus pontis oralis, the basal forebrain, and the thalamus. monoaminergic neurons are directly linked to the cortex and are inhibited during deep sleep. cholinergic pedunculopontine and laterodorsal tegmental nuclei are indirectly connected to the cortex via the thalamus and remain active during rapid eye movement sleep. these pathways are modulated by hypothalamic neurons [13] . disorders of consciousness can be organized between acute and subacute or chronic [14] . acute impairments of consciousness include coma which is defined as a "state of unresponsiveness in which the patient lies with eyes closed and cannot be aroused to respond appropriately to stimuli even with vigorous stimulation" [14] . the association of a prolonged non-responsive coma with a complete cessation of brainstem reflexes and functions suggests the diagnosis of brain death which is defined as an irreversible loss of all functions of the entire brain. delirium is defined as an acute and fluctuating disturbance of consciousness, including attention and impairment of cognition, associated with motor hyperactivity or hypoactivity [15, 16] . delirium has been associated with long-term cognitive impairment, functional disability in icu survivors, and hospital mortality [15] . brainstem dysfunction could account for some features of delirium, such as fluctuations in arousal and attentional impairment that could be related to aras and to ponto-mesencephalic tegmentum dysfunction, respectively. other states of acute impairment of consciousness include clouding of consciousness and stupor, but they are less frequently used [14] . subacute or chronic disorders of consciousness include the vegetative state (vs, also called unresponsive wakefulness syndrome) defined as state of unresponsiveness in which the patient shows spontaneous eye opening without any behavioral evidence of self or environmental awareness [17] . the minimally conscious state (mcs) is defined as state of severely impaired consciousness with minimal behavioral evidence of self or environmental awareness, characterized by the presence of non-reflexive behavior (visual pursuit, appropriate motor response to painful stimulus) or even intermittent command following indicating a cortical integration [18, 19] . the vs and mcs are related to a preservation of brainstem arousal functions but with persistent impairment of supratentorial networks implicated in consciousness [20] . stimulation of the aras may improve consciousness in vegetative or mcs patients [21] . in addition to deep brain stimulation, vagal nerve stimulation, which probably modulates the activity of the nucleus of the tractus solitarius and the dorsal raphe, has shown promising results [22] . in addition to these classical syndromes, other consciousness impairments have been described. peduncular lesions can cause hallucinations [23] which may be encountered in icu patients. more generally speaking, it is likely that brainstem dysfunctions account for a portion of the sleep-wake cycle impairments experienced by icu patients. brainstem lesions can induce cognitive deficits including impaired attention, naming ability, executive functioning, and memory impairment [24] , ascribed to a disruption of interconnection between the frontalsubcortical system and the brainstem [1] . finally, deep sedation is a pharmacologically induced coma, and its mechanisms of action involve the brainstem gaba and n-methyl-d-aspartate (nmda) receptors [25] . assessments of consciousness are based on neurological examination to confirm the diagnosis, determine the underlying cause, and evaluate the prognosis. in clinical practice, this assessment most commonly relies on the glasgow coma scale (gcs) [20] . focusing on the brainstem in particular, the four (full outline of un-responsiveness) score is to be preferred as it includes the corneal, pupil light, and cough reflexes and respiratory patterns [26] . in comatose patients, pupil sizes and reactivity can be suggestive of particular etiologies, such as drug overdose (myosis for opioids or mydriasis for tricyclic anti-depressants). in comatose brain-injured patients, brainstem reflex assessment is crucial to detect a uncal or downward cerebellar (tonsillar) herniation [10] . while the absence of corneal and pupillary light reflexes is strongly associated with poor outcome in post-anoxia, their prognostic value is less validated in other causes [27] . patients with severe critical illness may be comatose due to sedation, which in clinical practice can be assessed using the rass (richmond agitation sedation scale) [28] . in deeply sedated patients (i.e., rass − 4 or − 5), the brainstem reflexes assessment sedation scale (brass) might be useful to assess the effect of sedatives on the brainstem and potentially detect a brainstem dysfunction [29] ( table 5 ). the cam-icu and icdsc are appropriate to monitor delirium [16, 30] . finally, in vs and mcs patients, the coma recovery scale-revised has also been validated [20] . coma due to structural brainstem lesions is predominantly related to pedunculo-pontine tegmental lesions, usually detected on mri [12] (table 4) . neurophysiological tests may be useful to assess the neurological prognosis in patients with impairment of consciousness. somatosensory evoked potentials (ssep) assess conduction from peripheral nerves (n9) to the somatosensory cortical (n20) regions passing through the brainstem (p14). brainstem auditory evoked potentials (baep) are described in table 6 [11] . interestingly, sedation increases latencies and decreases amplitudes of evoked potentials in a dose-dependent manner but does probably not change the amplitudes with low to moderate doses used in icu [31] . the intracranial conduction time and intrapontine conduction time are assessed by measures of the p14-n20 inter-peak latency on ssep and the iii-v interpeak latency on baep [11] . the prognostic value of baep has been explored in various causes of coma [32] [33] [34] . after cardiac arrest, the predictive value of baep for poor outcomes is limited [35] . however, in traumatic brain injury, preserved baep are associated with a good outcome [36] . wave i can disappear if the auditory nerve is injured (traumatic or hypoxic injuries) [37] . reactivity on eeg to auditory, visual, or nociceptive stimuli is important to assess after cardiac arrest because its absence is associated with poor outcome [38, 39] . absent reactivity can result from a thalamus-brainstem loops and aras dysfunction [40] [41] [42] [43] . the electrophysiological measurement of the blink reflex (table 6) is a way to study the trigemino-facial loop [44] , but its prognostic value in comatose patients remains insufficiently supported [45] . the ans plays a key role in homeostasis and allostasis by controlling vital functions and the immune system [46] and is composed of sympathetic (e.g., noradrenergic) and parasympathetic (e.g., cholinergic) systems. sympathetic effects originate from the spinal cord (d1 to l3), while parasympathetic neuronal cell bodies are present in the nuclei of cranial nerves iii (edinger westphal nuclei), vii, ix, and x and the sacral spinal cord (s2 to s4). activation of the parasympathetic nervous system results in a decrease in heart rate (hr) and blood pressure (bp), and an increase in gastrointestinal tonus, vesical detrusor contraction, and myosis. activation of the sympathetic system results in opposite effects. cortical input can modulate responses in the ans [46] as well as various receptors throughout the body, including the baroreceptors [47] . brainstem injury may cause dysautonomic symptoms, which can be life-threatening [48] (table 2) . cardiac arrhythmias frequently occur after brainstem stroke and are associated with increased mortality [48] . an intracranial hypertension-induced midbrain insult can impair parasympathetic control and thereby induce adrenergic storm. in brain death, there is a disappearance of the vasomotor tone and an impairment of myocardial contractility [49] . as exhaustive discussions of tests that allow testing of the ans are beyond the scope of this review, we will focus on cardiovascular tests degenerative/atrophic injury mri magnetic resonance imaging, tdm tomodensitometry, csf cerebrospinal fluid, ecg electrocardiogram mri results according to etiologies: vascular injury: diffusion and flair-weighted sequence hyperintensity restricted to a vascular territory hemorrhage: swi/t2* sequence hypointensity inflammatory: diffuse or multifocal white matter lesions on t2-and flairweighted sequences, with or without contrast enhancement inflammatory nmo (mri of optical nerve and medullary mri): extensive and confluent myelitis on more than three vertebrae and optical neuritis with possible contrast enhancement traumatic injury: hyperintensity on diffusion sequence, diffuse axonal injuries on dti (diffusion tensor imaging) sequence, hemorrhage lesions on t2*/swi metabolic: t2 hyperintensity specifically involves the central pons infectious: abscess/nodes with contrast enhancement paraneoplastic: limbic encephalitis with temporal diffusion and flair hyperintensity tumor: mass with possible necrosis, contrast enhancement and oedema revealed by a flair hyperintensity around tumor degenerative injury: brain and brainstem atrophy (colibri sign) absence of grimacing to pain and absence of ocr 1 absence of grimacing to pain and presence of ocr 3 ocr: oculocephalic reflex brass is a clinical score that has been developed for scoring brainstem dysfunction in deeply sedated, non-brain-injured, mechanically ventilated, critically ill patients and ranges from 0 to 7 the brass has prognostic value, as 28-day mortality proportionally increases with the brass score applicable to icu patients. standard monitoring allows for the detection of variations in hr and bp that can be suggestive of dysautonomia. however, the lack of apparent changes in cardiovascular signals does not rule out dysautonomia, which can be then assessed with the hr and bp spectral analysis. high frequency (hf) band (i.e., 0.15 to 0.4 hz) variability of the hr is thought to predominantly reflect parasympathetic tone, while low frequency (lf) variability (i.e., 0.04 to 0.15 hz) is primarily mediated by sympathetic activity. the lf/hf ratio reflects the sympathovagal balance. therefore, spectral analysis allows studying the sympathetic, parasympathetic, and baroreflex activities both at rest and during stimulation [50] . if the valsalva maneuver, the cold pressure test, and the pharmacological tests (with yohimbine or clonidine) allow testing the ans, their use in icu is very limited. conversely, pupillometry is much more applicable for assessing dysautonomia in icu. thus, patients with dysautonomia present a pupil dilatation at resting state and a slow redilatation time [51] . there are two types of muscles that play a major role in the respiratory system, dilatator muscles of the superior airway that are innervated by the brainstem via cranial nerves (motor neurons present in the v, vii, and xii nuclei) and contractor/pump muscles (diaphragm, intercostal, sternocleidomastoid, abdominal muscles) that are innervated by spinal motor neurons. they are controlled by bulbospinal (automatic command) and corticospinal (voluntary command) pathways. the respiratory drive originates from neurons of the latero-rostro-ventral medulla oblongata, which includes the pre-botzinger complex and the parafacial respiratory group that control inspiration and expiration, respectively [52] ( table 2) . this center receives various inputs to automatically adjust the respiratory drive to metabolic and mechanic changes [53] . metabolic inputs are mediated by both peripheral (aortic and carotid) and central (medulla oblongata and lc) chemoreceptors [54] . the mechanical inputs are mediated by mechanoreceptors localized in the pulmonary parenchyma, bronchial wall, and muscle. at the level of the pons, the pedunculopontine tegmentum, the lc, the lateral parabrachial and kölliker-fuse nuclei are involved in the automatic respiratory control [55] ( table 2) . automatic and voluntary control of respiratory motor neurons can be injured together or separately. for instance, automatic control is impaired in central congenital and acquired hypoventilation syndrome (i.e., ondine syndrome), while voluntary control is preserved [56] . acquired hypoventilation syndrome can result from brainstem tumoral, traumatic, ischemic, and inflammatory injuries [57] , which implies the need for long-term mechanical ventilation. ventilator management may be significantly affected by brainstem lesions, and importantly, clinical features of neurological respiratory dysfunction are related to the localization of brainstem injury. the more caudal the lesion is, the more it is associated with an impairment of the respiratory drive. midbrain injuries do not usually affect the respiratory rate (rr). injuries to the upper pons increase the tidal volume and decrease the rr, while injuries of the lower pons are associated with respiratory asynchrony (e.g., ponto-peduncular injury). ataxic breathing (irregular pauses and apnea periods) and central apnea are observed in rostro-ventral medulla oblongata injuries and associated with poor outcomes. central neurogenic hyperventilation results from activation of the medullary respiratory center. finally, yawning or refractory hiccups may be seen with lesions of the posterolateral medulla oblongata [58] . swallowing impairment contributes also to the difficulty of weaning mechanical ventilation and can be an indication for a tracheostomy. there are various structural and non-structural causes of neurological respiratory dysfunction, including infratentorial lesions, drug toxicity, heart failure, and sepsis [59] [60] [61] . diagnosis relies on standard assessments of brainstem lesions can result in absent or delayed peaks iii and v, prolonged iii-v and i-v inter-peak latency, or a reduced i/v amplitude ratio (< 0.5) delay or absence of r1 indicates a facial /trigeminal nerve injury. r2 can be delayed in comatose patient and is also bilaterally delayed or absent in wallenberg's syndrome (with a r1 preserved) respiratory function (e.g., ventilator curves, tidal volumes (vt), and rr in mechanically ventilated patients) but also on assessing the ventilatory response to hypercapnia (e.g., during a t-piece trial). an electromyogram of the respiratory muscles, notably the diaphragm, provides relevant information on the central drive. this technique may be helpful in patients that are impossible to wean from mechanical ventilation. as a caveat, it may be at times difficult to differentiate central respiratory dysfunction from critical illness neuropathy/myopathy. emg and nerve conduction studies may help with the distinction, but limited assessments of every respiratory muscle group and available at highly specialized units limit this approach [62] . in mechanically ventilated patients, spirography can be performed (with the vt/inspiration duration (ti) ratio reflects the ventilatory command intensity) as well as the occlusion pressure measurement (i.e., p0.1). the latter reflects the "unconscious"/central respiratory command, but variability of its measurements limits routine application. the leading causes of primary brainstem dysfunction are summarized in table 4 and major differential diagnosis of brainstem dysfunction in table 7 . in the following section, we will discuss evidence for brainstem dysfunction encountered in critically ill patients beyond primary brainstem dysfunction. the "brainstem dysfunction" hypothesis originates from our study on usefulness of neurological examination in non-brain-injured critically ill patients who required deep sedation. these patients have usually a severe critical illness and therefore a higher risk to develop severe secondary brain insult [3, 29] . furthermore, protracted deep sedation is still required in more than 30% of critically ill patients [63] and has been reported to be associated with increased mortality [63] . we found that assessment of brainstem reflexes was reproducible in this population [3, 29] . we also found that routinely used sedative and analgesic agents such as midazolam and fentanyl do not impair pupillary light, corneal, and cough reflexes in 90% of cases but depress oculocephalic response and grimacing to painful stimulation (absent in 50 and 70%, respectively) [3, 29, 63] . the cessation of brainstem reflexes results from the combining effects of critical illness (i.e., secondary brain insult), sedative, and analgesic agents. it is interesting to note that guedel observed more than 70 years ago that sedative drugs abolish brainstem reflexes according to a sequential pattern (the loss of consciousness, followed by the cessation of brainstem reflexes in a rostro-caudal way until apnea) [64] . in deeply sedated non-brain-injured critically ill patients, the cessation of brainstem responses follows two distinct patterns. the first is characterized by a depression of whole brainstem responses (similar to guedel's description), and the second is characterized by a preferential impairment of the corneal reflex, the pupillary light reflex, and to a lesser extent the cough reflex, with paradoxical preservation of the oculocephalic response. the latter profile is associated with the severity of critical illness and the depth of sedation. interestingly, this pattern cannot be ascribed to a unique focal brainstem lesion which most likely relies on a functional rather than a structural origin. this suggests that some neuroanatomical centers are more sensitive to deep sedation, critical illness, or both. opioids might also contribute to brainstem dysfunction, as they depress the aras, respiratory centers, and brainstem reflexes (notably pupillary light and cough reflexes). however, morphine infusion rates did not differ in our study between the two cessation patterns of brainstem reflexes [29] . to assess brainstem reactivity in deeply sedated critically ill patients, we developed the brass [29] ( table 5 ). the principle of the brass development is not in agreement with the traditional paradigm of jackson, which states that the brainstem reflexes are abolished in a rostro-caudal way. it thus differs from the four score [65] , which conditions the assessment of the cough reflex to the cessation of the pupillary light and corneal reflexes. besides improving the prediction of mortality in deeply sedated patients, the assessment of brainstem reflexes, with help of either the brass or the four score, might prompt the icu physician to perform a brainstem imaging. it is however likely that the processes involved in critical illness-related brainstem dysfunction are radiologically assessable. neurophysiological tests provide further arguments for brainstem dysfunction in critically ill patients without primary brainstem injury. for instance, eeg is not reactive in 25% of patients with sepsis [42, 43] , knowing that absence of reactivity can result from a dysfunction of the aras [40] [41] [42] [43] . middle latency baep responses and ssep latencies were increased in 24% and 45% of deeply sedated non-brain-injured critically ill patients, respectively [34] , indicating an impairment of the brainstem conduction. interestingly, mean values of these latencies did not differ from those recorded in deeply sedated brain-injured patients. critical illness is also associated with decreased variability in hr and bp, with an impaired sympathetic tone and baroreflex [2, 50] and also with a reduced tidal volume variability [66] that can correlate with weaning failure. since most of these findings concerned sedated patients, one may argue that sedative agents might be involved as a revealing or aggravating underlying insults. this hypothesis is further supported by the fact that increase in evoked potential latencies cannot be only ascribe to sedation since long-term swallowing disorders [67] and aspiration pneumonia are more frequent in sepsis survivors [68] . thus, a multimodal assessment of brainstem dysfunction in critical illness is warranted. the undergoing multicenter proretro study (clinicaltrials.gov: nct02395861) aims to evaluate a multimodal approach based on neurological examination and neurophysiological tests. neuroimaging and neuropathological studies show that the brainstem is prone to vascular, inflammatory, and excitotoxic insults [5] . for instance, sepsis can be associated with impaired autoregulation of cerebral blood flow and microcirculatory dysfunction, which may compromise the brainstem perfusion. second, a multifocal necrotizing leukoencephalopathy involving the brainstem can be secondary to an intense systemic inflammatory response [69] . finally, the neuro-inflammatory process can culminate in neuronal apoptosis, which is evidenced in brainstem autonomic nuclei in patients who died from septic shock or in experimental sepsis [5] . interestingly, it has been shown that apoptosis of autonomic nuclei can induce hypotension in septic rat [70] . both humoral and neural pathways can induce a neuroinflammatory process. the former involves the area postrema (fig. 1) , which allows the diffusion of circulating inflammatory mediators into the brainstem; the latter involves mainly the vagal nerve, which mediates the transmission of peripheral inflammatory signals to the brainstem [71, 72] . autonomic brainstem nuclei are regulated by these two pathways, which then play a major role in the control of systemic inflammatory response. finally, metabolic processes can be involved. it is well known that electrolyte disturbances but also renal and liver failure impair brainstem responses, as illustrated by centro-pontine myelinolysis or by usefulness of four score in hepatic encephalopathy [73] . the predictive value of the neurological examination findings and neurophysiological responses has been assessed in critically ill patients. there is a proportional relationship between the brass value and mortality. interestingly, absence of a grimacing response associated with preserved oculocephalic responses is the most predictive of mortality [29] , suggesting that prediction is better when first based on a combination of signs, and second, a decoupling process between the upper and lower part of the brainstem is involved [29] . the absence of eeg reactivity and of ssep p14 response and increased p14-n20 ssep latencies are associated with increased mortality [34, 42, 43] . impaired hr variability and decreased sympathetic control are associated with mortality and organ failure [74] . there are arguments for a relationship between delirium and brainstem dysfunction. the drugs currently used for treating delirium are involving brainstem receptors. thus, neuroleptics are antagonists of the dopamine d2 and serotoninergic 5ht2a receptors that are prevalent in the brainstem [75] . dexmedetomidine is a selective agonist of alpha-2 receptor, notably at the level of the lc [76] . the role of the brainstem in patients with delirium is supported by these pharmacological data and further supported by neuropathological findings that demonstrate hypoxic and ischemic insults of the pons in delirious patients [77] . absent oculocephalic responses and delayed middle-latency baep have been associated with delayed awakening or delirium after sedation discontinuation [34] . in neuroanatomical point of view, it is likely that cessation of the oculocephalic response reflects a dysfunction of the aras while cessation of the cough reflex reflects a dysfunction of the cardiovascular and respiratory autonomic nuclei. finally, if conceivable, we do not know to what extent brainstem dysfunction contributes to long-term post-icu mortality and functional disability. another contributing factor of the brainstem dysfunction in critical illness course might be the impaired sympatho-vagal control of the inflammatory response. the vagus nerve first senses and modulates peripheral inflammation, constituting the so-called cholinergic reflex [78] ; second, it senses the microbiota metabolites, being a major component of the gut-brain axis [79] ( table 2 ). the adrenergic system controls the immune system, with alpha and beta-1 receptors being proinflammatory and beta-2 receptors anti-inflammatory [80] . it is therefore conceivable that a brainstem-related neuro-immune impairment can contribute to infection, organ failure, or death by facilitating a maladapted immune response. the modulation of the cholinergic reflex by α7nachr agonists and by vagal nerve stimulation has been proposed in sepsis and critical illness to improve peripheral immune response and reduce organ dysfunction [81] . in addition to its peripheral immune effects, cholinergic modulation and vagal stimulation can promote anti-inflammatory microglial polarization [82] . however, we shall remind that rivastigmine, a cholinesterase inhibitor, is deleterious in critically ill patients. vagal nerve stimulation is also proposed in refractory status epilepticus [83] and consciousness disorders [22] , suggesting its potential but not yet demonstrated effect in critical illness-related encephalopathy. beta-blockers reduce the mortality in cardiac diseases by attenuating the deleterious effects of sympathetic hyperactivation and increasing the vagal tone [84] . in sepsis, betablockers improve hr control, reduce systemic inflammation, and decrease mortality, acknowledging that their routine use is not yet warranted [85, 86] . brainstem dysfunction can present with 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heart rate control with adrenergic blockade: clinical outcomes in cardiovascular medicine. vasc health risk manag systematic review of use of β-blockers in sepsis the effect of beta-adrenergic blockade on inflammatory and cardiovascular responses to acute mental stress publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank the reviewers for their comments and suggestions to improve our manuscript. authors' contributions sb, am, br, and ea drafted the manuscript. jc, crs, vb, and ts critically revised the manuscript for important intellectual content. all authors read and approved the final manuscript. availability of data and materials not applicable ethics approval and consent to participate key: cord-000492-ec5qzurk authors: devaney, james; contreras, maya; laffey, john g title: clinical review: gene-based therapies for ali/ards: where are we now? date: 2011-06-20 journal: crit care doi: 10.1186/cc10216 sha: doc_id: 492 cord_uid: ec5qzurk acute lung injury (ali) and acute respiratory distress syndrome (ards) confer substantial morbidity and mortality, and have no specific therapy. the accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ali/ards, suggest that the disease may be amenable to gene-based therapies. ongoing advances in our understanding of the pathophysiology of ali/ards have revealed multiple therapeutic targets for gene-based approaches. strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ali/ards have all demonstrated promise in preclinical models. despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ali/ards remains to be realized. multiple barriers to effective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection efficiency of nonviral delivery methods. deficits remain in our knowledge regarding the optimal molecular targets for gene-based approaches. encouragingly, recent progress in overcoming these barriers offers hope for the successful translation of gene-based approaches for ali/ards to the clinical setting. gene-based therapy involves the insertion of genes or smaller nucleic acid sequences into cells and tissues to replace the function of a defective gene, or to alter the production of a specifi c gene product, in order to treat a disease. gene therapy can be classifi ed into germline and somatic gene therapies. germline approaches modify the sperm or egg prior to fertilization and confer a stable heritable genetic modifi cation. somatic gene approaches use gene therapy to alter the function of mature cells. commonly used somatic gene therapy strategies include the overexpression of an existing gene and/or the insertion of smaller nucleic acid sequences into cells to alter the production of an existing gene. ali/ards may be suitable for gene-based therapies as it is an acute but relatively transient process [8] , requiring short-lived gene expression, obviating the need for repeated therapies and reducing the risk of an adverse immunological response. th e distal lung epithelium is selectively accessible via the tracheal route of administration, allowing targeting of the pulmonary epithelium [9] . th e pulmonary vasculature is also relatively accessible, as the entire cardiac output must transit this circulation. antibodies that bind antigens selectively expressed on the pulmonary endothelial surface can be complexed to gene vectors to facilitate selective targeting following intravenous administration [10] . it is also possible to use gene-based strategies to target other cells central to the pathogenesis of ali/ards, such as leuko cytes and abstract acute lung injury (ali) and acute respiratory distress syndrome (ards) confer substantial morbidity and mortality, and have no specifi c therapy. the accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ali/ ards, suggest that the disease may be amenable to gene-based therapies. ongoing advances in our understanding of the pathophysiology of ali/ards have revealed multiple therapeutic targets for genebased approaches. strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ali/ards have all demonstrated promise in preclinical models. despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ali/ ards remains to be realized. multiple barriers to eff ective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection effi ciency of nonviral delivery methods. defi cits remain in our knowledge regarding the optimal molecular targets for genebased approaches. encouragingly, recent progress in overcoming these barriers off ers hope for the successful translation of gene-based approaches for ali/ards to the clinical setting. fi bro blasts [11] . furthermore, gene-therapy-based approaches off er the potential to selectively target diff erent phases of the injury and repair process. th e potential to target specifi c aspects of the injury and repair processes such as epithelial-mesenchymal transition, fi brosis, fi brinolysis, coagulopathy and oxidative stress with these approaches is also clear. gene therapy requires the delivery of genes or smaller nucleic acid sequences into the cell nucleus using a carrier or vector. th e vector enables the gene to overcome barriers to entry into the cell, and to make its way to the nucleus to be transcribed and translated itself or to modulate transcription and/or translation of other genes. both viral and nonviral vector systems have been developed (table 1) . viral vectors are the most eff ective and effi cient way of getting larger nucleic acid sequences, particularly genes, into cells (table 1) . th e viral genome is modifi ed to remove the parts necessary for viral replication. th is segment is then replaced with the gene of interesttermed a transgene -coupled to a promoter that drives its expression. th e modifi ed genome is then encapsulated with viral proteins. following delivery to the target site, the virus binds to the host cell, enters the cytoplasm and releases its payload into the nucleus (figure 1 ). th e size of trans gene that can be used depends on the capsid size. a number of diff erent viral vectors have been used in preclinical lung injury studies to date. adenoviruses have double-stranded dna genomes, have demonstrated promise in preclinical models [12, 13] and are well tolerated at low to intermediate doses in humans [14, 15] . advantages include their ease of production, the high effi ciency at which they can infect the pulmonary epithelium [14, 16] and that they can deliver relatively large transgenes. a disadvantage of adenoviruses is their immunogenicity, particularly in repeated doses [14] . newer adenoviral vectors, in which much of the immuno genicity has been removed, hold promise [17] . while adenovirus-mediated gene transfer in the absence of epithelial damage is relatively ineffi cient [18] , this may be less of a problem in ali/ards that is characterized by widespread epithelial damage. adeno-associated viruses (aavs) are single-stranded dna parvoviruses that are replication defi cient [19] . a substantial proportion of the human population has been exposed to aavs but the clinical eff ects are unknown. aav vectors have a good safety profi le, and are less immunogenic compared with other viruses, although anti bodies do develop against aav capsid proteins that can compromise repeat administration. aav vectors can insert genes at a specifi c site on chromosome 19 . th e packaging capacity of the virus is limited to 4.7 kb, restricting the size of the transgene that can be used. aavs are less effi cient in transducing cells than adenoviral vectors. successful aav vector gene transfer has been demon strated in multiple lung cell types including lung progenitor cells, in both normal and naphthaleneinduced ali lungs [20] . aav serotypes have specifi c tissue tropisms, due to diff erent capsid proteins that bind to specifi c cell membrane receptors. aav-5 [21] and avv-6 [22] exhibit enhanced tropism for the pulmonary epi thelium [21, 22] . aavs can transduce nondividing cells and result in long-lived transgene expression. aav vectors have been used in clinical trials in cystic fi brosis patients, underlining their safety profi le [23, 24] . th ese rna viruses can transfect nondividing cells such as mature airway epithelial cells [25] . th e virus stably but randomly integrates into the genome and expression is likely to last for the lifetime of the cell (~100 days). th e transgene can be transmitted post mitosis, and there is also a risk of tumorigenesis if the transgene integrates near an oncogene. th e development of leukemias in children following gene therapy for severe combined immunodefi ciency highlights this risk [26, 27] . while lentiviral vectors may be useful to correct a gene defi ciency associated with increased risk of ali, the long-lived gene expression of lentiviral delivered genes may be more suitable for chronic diseases than for ali/ards. nonviral delivery systems, while generally less effi cient than viral vectors in transfecting the lung epithelium, are increasingly used to deliver smaller dna/rna molecules (table 1 ). strategies include the use of dna-lipid and dna-polymer complexes and naked dna/rna oligonucleotides, such as sirna [28] , decoy oligo nucleo tides [29] and plasmid dna [30] . nonviral delivery systems are less immunogenic than viral vector-based approaches, and can be generated in large amounts at relatively low cost. plasmid vectors are composed of closed circles of doublestranded dna. as naked and plasmid dna contain no proteins for attachment to cellular receptors, there is no specifi c targeting to diff erent cell types and thus it is essential that the dna is placed in close contact with the desired cell type. th ese limitations make this approach less relevant clinically. th e therapeutic dna is held within a sphere of lipids, termed a lipoplex, or within a sphere of polymers, such as polyethyleneimine, termed a polyplex. lipoplexes and polyplexes act to protect the dna, facilitate binding to the target cell membrane and also trigger endocytosis of the complex into the cell, thereby enhancing gene expression. th ese systems can be modifi ed to include a targeting peptide for a specifi c cell type, such as airway epithelial cells [31] . th ese complexes effi ciently and safely transfect airway epithelial cells [31] , and they have demonstrated promise in human studies [32] . sirnas are dsrna molecules of 20 to 25 nucleotides that can regulate the expression of specifi c genes. specifi c sirnas reduce infl ammation-associated lung injury in table 1 . viral vector-delivered gene therapy relatively easily produced immunogenic [14] adenoviral transfer of genes for a surfactant (dsdna genome) effi ciently transfect lung enzyme [49] , angiopoietin-1 [51] , hsp-70 [52] , epithelium [14, 16] apolipoprotein a-1 [53] , and na + ,k + -atpase pump can deliver larger genes [55] genes attenuate experimental ali well tolerated in lower doses [1, 3] adenoviral delivery of il-10 gene attenuates zymosan ali at low doses, but is harmful at high doses [58] adeno-associated virus good safety profi le; less limited transgene size aav vector gene transfer demonstrated in multiple vectors (ssdna genome) immunogenic diffi cult to produce in large lung cell types including progenitor cells in both inherently replication defi cient quantities normal lungs and following naphthalene-induced aav-5 and aav-6 lung epithelial ali [20] tropism [10, 11] transduce nondividing cells long-lived gene expression used in clinical trials for cf [12, 13] lentivirus vectors transduce nondividing cells [25] oncogenesis risk due to lentiviral transfer of shrna to silence cd36 gene (rna genome) integrate stably but randomly integration into genome expression suppresses silica-induced lung fi brosis into the genome [26, 27] in the rat [35] nonviral gene-based strategies plasmid transfer (closed easily produced at low cost no specifi c cell targeting electroporation-mediated gene transfer of the dsdna circles) very ineffi cient na + ,k + -atpase rescues endotoxin-induced lung injury [60] nonviral dna complexes complexes protect dna less effi cient than viral vectors cationic lipid-mediated transfer of the na + ,k + -(lipoplexes or polyplexes) complexes facilitate cellular atpase gene ameliorated high-permeability targeting [31] pulmonary edema [59] lipoplex-delivered il-10 gene decreased clp-induced ali [61] systemic cationic polyethylenimine polyplexes incorporating indoleamine-2,3-dioxygenase decreased ischemia-reperfusion ali [62] dna and rna easily produced at low cost no specifi c cell targeting specifi c sirnas reduce infl ammation-associated oligonucleotides (sirna, smaller molecules that can lung injury in humans [33] and in animal models shrna, decoy easily enter cells [28, 34] oligonucleotides) target regulation of specifi c genes shrna-based approaches have reduced lung injury in animal models [35, 36] cell-delivered gene therapy humans [33] and in animal models [28, 34] . shrna is a single strand of rna that, when introduced into the cell, is reverse transcribed and integrated into the genome, becoming heritable. during subsequent transcription, the sequence generates an oligonucleotide with a tight hairpin turn that is processed into sirna. shrnas have reduced lung injury in animal models [35, 36] . decoy oligonucleotides are double-stranded dna molecules of 20 to 28 nucleo tides, which bind to specifi c transcription factors to reduce expression of targeted genes, and have been successfully used in animal models [37, 38] . an alternative approach is to use systemically delivered cells to deliver genes to the lung. th is approach has been used to enhance the therapeutic potential of stem cellssuch as mesenchymal stem/stromal cells, which demon strate promise in preclinical ali/ards models [39] . fibroblasts have also been used to successfully deliver genes to the lung to attenuate ali [40] . preliminary data from a clinical trial in pulmonary hypertension show that endothelial progenitor cells overexpressing endothelial nitric oxide synthase (nos3) decrease pulmonary vascular resistance [41] , highlighting the potential of cell-delivered gene therapy for ali/ards. nebulization of genetic material into the lung is eff ective [42] , safe and well tolerated [32, 43, 44] . th e integrity of aav vectors [9, 43] and adenoviral virus vectors [44] are maintained post nebulization, as are cationic lipid vectors [32] and dna and rna oligonucleotides [45] . a number of gene therapy clinical trials have utilized nebulization to deliver the transgene to the lung [23, 43] , but without clear clinical benefi t to date [43, 44] . intravascular delivery approaches target the lung endothelium. th ese approaches have been successfully used in preclinical studies of cell-based gene therapies [39, 40] , and also with vectors that incorporate components such as antibodies to target antigens on the lung endothelium [10] . successful gene-based therapies require the delivery of high quantities of the gene or oligonucleotide to the pulmonary epithelial or endothelial surface, require effi cient entry into the cytoplasm of these large and insoluble nucleic acids, which then have to move from the cytoplasm into the nucleus, and activate transcription of its product. multiple barriers exist that hinder this process, not least the natural defense mechanisms of the lung, and additional diffi culties that exist in transducing the acutely injured lung (table 2 ). limitations regarding delivery technologies and defi ciencies in our knowledge regarding the optimal molecular targets also reduce the effi cacy of these approaches. th e lung has evolved eff ective barriers to prevent the uptake of any inhaled foreign particles [46] . while advantageous in minimizing the potential for uptake of external genetic material (for example, viral dna), these barriers make it more diffi cult to use gene-based therapies in the lung. barriers to entry of foreign genetic material into the lung include airway mucus and the epithelial lining fl uid, which traps and clears inhaled material. th e glycocalyceal barrier hinders contact with the cell membrane, while the tight intercellular epithelial junctions and limited luminal endocytosis further restrict entry of foreign material into the epithelial cells. transducing the acutely injured lung may be diffi cult, due to the presence of pulmonary edema, consolidated or collapsed alveoli, and additional extracellular barriers such as mucus. gene-based therapies targeted at the pulmonary epithelium may be less eff ective where there is extensive denudation of the pulmonary epithelium, as may occur in primary ards. encouragingly, there is some evidence to suggest that ali may not substantially impair viral gene transfer to the alveolar epithelium [47] . th e key limitation of nonviral vector approaches has been their lack of effi ciency in mediating gene transfer and transgene expression in the airway epithelium. viral vectors are immunogenic, due to the protein coat of the viral vector, and the immune response is related to both vector dose and number of administrations. th e potential to limit administration to a single dose in ali/ards may reduce this risk. however, the development of an infl amma tory response resulting in death following administration of a fi rst-generation adenoviral vector highlights the risks involved [48] . additional limitations of viral vectors include transgene size, which is limited by the size of the capsid that encloses the viral genes. th e therapeutic potential of gene therapy for ali/ards is underlined by a growing body of literature demon strating effi cacy in relevant preclinical models. in considering the clinical implications of these studies, it is important to acknowledge that animal models of ards do not fully replicate the complex pathophysiological changes seen in the clinical setting. th is is highlighted by the fact that many pharmacologic strategies demonstrating considerable promise in preclinical studies were later proven ineff ective in clinical trials. nevertheless, these studies provide insights into the clinical potential of these strategies. adenovirus-mediated transfer of a gene that enhances surfactant production improves lung function and confers resistance to pseudomonas aeruginosa infection ( figure 2 ) [49] . adenovirus-delivered superoxide dismutase and catalase genes protected against hyperoxic-induced, but not ischemia-reperfusion-induced, lung injury [50] . more recent studies have demonstrated the therapeutic potential of overexpression of a number of genes, including angio poietin-1 [51] , hsp-70 [52] , apolipo protein a-1 [53] , defensin î²2 [54] and the na + ,k + -atpase pump [55] . in contrast, overexpression of il-1î² can directly cause ali [56] , while overexpression of suppressor of cytokine signal ing-3 worsens immune-complex-induced ali [57] . intriguingly, intra tracheal administration of adenoviral vector incor porating il-10, prior to zymosan-induced lung injury, improved survival at a lower dose but was ineff ective and even harmful at higher doses [58] . an early murine study demonstrated that cationic lipidmediated transfer of the na + ,k + -atpase gene ameliorated high-permeability pulmonary edema [59] . electroporationassisted gene transfer of plasmids encoding for na + ,k + -atpase reverses endotoxin-induced lung injury [60] . th e lipoplex-delivered il-10 gene decreased lung and systemic organ injury induced by cecal ligation and puncture in mice [61] . systemically administered cationic polyethyleni mine polyplexes incorporating indoleamine-2,3-dioxyge nase transduced pulmonary endo thelial cells and decreased lung ischemia-reper fusion injury [62] . nf-îºb decoy oligonucleotides, incorporated into viral vectors, attenuate systemic sepsis-induced lung injury when administered intravenously (figure 3 ) [37] . in animal models, both intratracheal [34, 63] and intra venously [29, 64] administered sirna successfully silence their target genes. shrna-based approaches have been used to suppress silica-induced lung fi brosis [35] and to ameliorate lung ischemia-reperfusion-induced lung injury [36] . more recently, aerosolization of sirna that targets respiratory syncytial virus viral replication was safe and potentially eff ective in patients post lung transplant with respiratory syncytial virus infection [33] , clearly illustrating the therapeutic potential of these approaches for ali/ards. mei and colleagues enhanced the effi cacy of mesen chymal stem/stromal cells in endotoxin-induced ali by transducing them to overexpress angiopoeitin-1 (figure 4 ) [39] . mesenchymal stem/stromal cells overexpressing il-10 decreased alveolar infi ltration of cd4 and cd8 t cells following lung ischemia-reperfusion injury [65] . bone marrow stem cells expressing keratinocyte growth factor attenuate bleomycin-induced lung injury [66] . non stem cells can also be used to deliver genes to the injured lung [67] . fibroblasts overexpressing angiopoeitin-1 attenuate endotoxin-induced lung injury [40] , while fi broblasts overexpressing vascular endothelial growth factor and endothelial nitric oxide synthase can attenuate or even reverse endotoxin-induced ali [68] . advances in the identifi cation of therapeutic targets, improvements in viral and nonviral vector technologies, and regulation of gene-based therapies by temporal and spatial targeting off er the potential to translate the therapeutic promise of gene-based therapies for ali/ ards to the clinical setting (table 3) . viral vectors remain the focus of intensive research to optimize their effi ciency, to minimize their immuno genicity and to enhance their tissue specifi city [19, 31, 69, 70] . strategies to develop less immunogenic vectors have focused on modifying the naturally occurring proteins in the viral coat [71] . much research has been devoted to searching and characterizing both naturally occurring [71] and engineered capsid variants from mammalian species [72] . capsid protein modification has also been used to enhance tissue specifi city [70] . envelope protein pseudotyping involves encapsulating the modifi ed genome from one virus, such as simian immuno defi ci ency virus, with envelope proteins from another virus, such as vesicular stomatitic virus. th is encapsu lation can enhance the therapeutic potential of viral vectors, by combining the advantages of one viral genome (for example, bigger payload or site-specifi c integration) with the tissue tropism of another virus. strategies to enhance the eff ectiveness of the lipoplexes used to deliver plasmids and other dna/rna oligonucleotides involve manipulation of the lipoplex lipid content and the use of targeting peptides. th e choice of lipid infl uences expression effi ciency by enhancing release of the genetic material within the target cell [73, 74] . targeting peptides increases transfection effi ciency by directing the lipid to a particular cell membrane or cell type [31] . physical methods of plasmid delivery such as electroporation [60] and ultrasound can enhance gene transfer by bringing the plasmid dna into closer proximity with the cell membrane and/or causing temporary disruption of the cell membrane. other physical methods can also be used to increase in vivo gene transfer, including pressurized vascular delivery, laser, magnetic fi elds and gene gun delivery. th ese systems enable plasmid-based gene delivery to reach effi ciencies close to that achieved with viral vectors. successful gene therapy relies upon being able to target the injury site, and to control the duration and levels of gene expression. modifying the transgene dna to exclude nonmethylated cpg motifs, typical of bacterial dna, decreases the immune response and may increase transgene expression [75, 76] . high-effi ciency tissue-specifi c promoters may improve the effi ciency and specifi city of transgene expression. lung-specifi c promoters include surfactant promoters [77] such as the surfactant protein c promoter [78] , a ciliated cell-specifi c promoter foxj1 [79] , the cytokeratin 18 promoter [80] , and the clara cell 10-kda protein [78] . promoters can also be used to target a specifi c phase of illness, switching on when required to produce an eff ect at the optimal time point. a related approach is the development of promoters that allow for transfected genes to be turned on and off . currently, the tetracycline-dependent gene expression vector [81] is the most widely used regulated system as it has a good safety profi le. tetracycline is rapidly metabolized and cleared from the body, making it an ideal drug to control gene expression. however, the potential for an activator such as tetracycline to modulate the lung injury should be borne in mind. new-generation transactivators, with no basal activity and increased sensitivity, have now been developed [82] . in an ards context, conditional regulation of gene expression by the combined use of a lung-specifi c promoter and the tetracycline-dependent gene expression system may be a useful approach [83] . capsid protein modifi cation to reduce immunogenicity [71] capsid protein modifi cation to enhance tissue specifi city [70] envelope protein pseudotyping manipulation of lipoplex lipid content to enhance cellular uptake [73, 74] use of targeting peptides on lipoplexes and polyplexes [31] strategies to enhance gene transfer; for example, electroporation, ultrasound, gene gun delivery modifying transgene dna to eliminate bacterial motifs [75, 76] development of high-effi ciency tissue-specifi c promoters [77] [78] [79] [80] development of promoters that regulate gene expression [83] enhanced therapeutic targeting nebulization technologies [9] strategies to target the pulmonary endothelium [10] improved cellular uptake of vector surface active agents to enhance vector spread [84] reduce ubiquitination of viral capsid proteins [85] better therapeutic targets enhancement or restoration of lung epithelial and/or endothelial cell function [86] strengthening lung defense mechanisms against injury [87] speeding clearance of infl ammation and infection enhancement of the repair process following ali/ards [88] . an advantage of gene-based strategies is the ability to target specifi c cells within an organ; for example, the epithelial cells of the lung. novel nebulization technologies, which facilitate the delivery of large quantities of undamaged vector to the distal lung, demonstrate considerable promise in this regard [9] . alternative approaches to spatial targeting include targeting specifi c receptors that are plentiful on the target cell to increase transfection effi ciency. an interesting development in this regard is the targeting of systemically administered therapies to the pulmonary endothelium using antibodies to proteins expressed preferentially on these cells ( figure 5 ) [10] . in these studies, the antioxidant enzyme catalase was conjugated with antibodies to the adhesion molecule pecam, which is widely expressed on pulmonary endothelial cells, and to a nonspecifi c igg antibody. th e anti-pecam/catalase conjugate, but not the igg/catalase conjugate, bound specifi cally to the pulmonary endothelium and attenuated hydrogen peroxide injury. specifi c strategies have been developed to maximize uptake of vector into alveolar epithelial cells. it is possible to enhance lung transgene expression with the use of surface-active agents such as perfl urocarbon, which enhances the spread of vector and mixing within the epithelial lining fl uid [84] . agents that reduce ubiquitination of aav capsid proteins following endocytosis, such as tripeptide proteasome inhibitors, dramatically augment (>2,000-fold) aav vector transduction in airway epithelia [85] . ultimately, the success or failure of gene-based therapies for ali/ards is likely to rest on the identifi cation of better gene targets. ongoing advances in our understanding of the pathophysiology of ali/ards continue to reveal novel therapeutic targets for gene-based approaches. promising potential approaches include strate gies to enhance or restore lung epithelial and/or endothelial cell function [86] , to strengthen lung defense mechanisms against injury [87] , to speed clear ance of infl ammation and infection, and to enhance the repair process following ali/ards [88] . ali/ards may be a particularly suitable disease process for gene-based therapies (table 4 ). th is is supported by increasing evidence from relevant preclinical ards models for the effi cacy of gene-based therapies that enhance or restore lung epithelial and/or endothelial cell function, strengthen lung defense mecha nisms against injury, speed resolution of infl ammation and infection, and enhance the repair process following ali/ards. despite this promising preclinical evidence, the potential for gene based approaches to ali/ards in the clinical setting remains to be realized. multiple barriers exist to the successful use of gene-based therapies in the lung, which limit the effi cacy of these approaches. future research approaches should focus on overcoming these barriers, by developing more eff ective and less immunogenic vector delivery systems, developing strategies to focus gene expression on specifi c injury zones of the lung for defi ned time periods, and identifying better molecular targets that can take advantage of these potentially very powerful therapeutic approaches. abbreviations aav, adeno-associated virus; ali, acute lung injury; ards, acute respiratory distress syndrome; il, interleukin; nf, nuclear factor; shrna, small hairpin rna; sirna, small interfering rna. the authors declare that they have no competing interests. epidemiology of acute lung injury incidence and outcomes of acute lung injury one-year outcomes in survivors of the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network pulmonary-artery versus central venous catheter to guide treatment of acute lung injury prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis elbourne d: effi cacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial the acute respiratory distress syndrome optimized aerosol delivery to a mechanically ventilated rodent pecamdirected delivery of catalase to endothelium protects against pulmonary vascular oxidative stress adenoviral augmentation of elafi n protects the lung against acute injury mediated by activated neutrophils and bacterial infection aerosol delivery of a î²-galactosidase adenoviral vector to the lungs of rodents adenovirusmediated persistent cystic fi brosis transmembrane conductance regulator expression in mouse airway epithelium airway epithelial cftr mrna expression in cystic fi brosis patients after repetitive administration of a recombinant adenovirus analysis of risk factors for local delivery of low-and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions modifi cation of nasal epithelial potential diff erences of individuals with cystic fi brosis consequent to local administration of a normal cftr cdna adenovirus gene transfer vector a phase i study of adenovirus-mediated transfer of the human cystic fi brosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fi brosis aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fi brosis. i. methods, safety, and clinical implications recent developments in adeno-associated virus vector technology analysis of adeno-associated virus progenitor cell transduction in mouse lung adeno-associated virus type 5 (aav5) but not aav2 binds to the apical surfaces of airway epithelia and facilitates gene transfer adeno-associated virus type 6 (aav6) vectors mediate effi cient transduction of airway epithelial cells in mouse lungs compared to that of aav2 vectors repeated adeno-associated virus serotype 2 aerosol-mediated cystic fi brosis transmembrane regulator gene transfer to the lungs of patients with cystic fi brosis: a multicenter, double-blind, placebo-controlled trial safety and biological effi cacy of an adeno-associated virus vector-cystic fi brosis transmembrane regulator (aav-cftr) in the cystic fi brosis maxillary sinus lentivirus vectors pseudotyped with fi loviral envelope glycoproteins transduce airway epithelia from the apical surface independently of folate receptor alpha gene therapy of human severe combined immunodefi ciency (scid)-x1 disease cavazzana-calvo m: insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of scid-x1 rna interference for î±-enac inhibits rat lung fl uid absorption in vivo eff ect of antisense oligonucleotides to nuclear factor-îºb on the survival of lps-induced ards in mouse electroporation-mediated transfer of plasmids to the lung results in reduced tlr9 signaling and infl ammation a receptor-targeted nanocomplex vector system optimized for respiratory gene transfer cationic lipid-mediated cftr gene transfer to the lungs and nose of patients with cystic fi brosis: a double-blind placebo-controlled trial rna interference therapy in lung transplant patients infected with respiratory syncytial virus in vivo gene silencing (with sirna) of pulmonary expression of mip-2 versus kc results in divergent eff ects on hemorrhage-induced, neutrophil-mediated septic acute lung injury silencing cd36 gene expression results in the inhibition of latent-tgf-î²1 activation and suppression of silica-induced lung fi brosis in the rat prevention of lung ischemia-reperfusion injury by short hairpin rna-mediated caspase-3 gene silencing nuclear factor-îºb decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis eff ects of intratracheal administration of nuclear factor-îºb decoy oligodeoxynucleotides on long-term cigarette smokeinduced lung infl ammation and pathology in mice prevention of lpsinduced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1 cell-based angiopoietin-1 gene therapy for acute lung injury stem cells and cell therapies in lung biology and lung diseases calculating expected lung deposition of aerosolized administration of aav vector in human clinical studies repeated aerosolized aav-cftr for treatment of cystic fi brosis: a randomized placebo-controlled phase 2b trial aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fi brosis. ii. transfection effi ciency in airway epithelium inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance gene transfer to the lung: lessons learned from more than 2 decades of cf gene therapy acute lung injury does not impair adenoviral-mediated gene transfer to the alveolar epithelium fatal systemic infl ammatory response syndrome in a ornithine transcarbamylase defi cient patient following adenoviral gene transfer adenoviral gene transfer of a mutant surfactant enzyme ameliorates pseudomonas-induced lung injury gene therapy for oxidant injury-related diseases: adenovirus-mediated transfer of superoxide dismutase and catalase cdnas protects against hyperoxia but not against ischemiareperfusion lung injury angiopoietin-1 increases survival and reduces the development of lung edema induced by endotoxin administration in a murine model of acute lung injury enhanced expression of 70-kilodalton heat shock protein limits cell division in a sepsis-induced model of acute respiratory distress syndrome human apoa-i overexpression diminishes lps-induced systemic infl ammation and multiple organ damage in mice protection against pseudomonas aeruginosa pneumonia and sepsisinduced lung injury by overexpression of î²-defensin-2 in rats overexpression of the na-k-atpase î±2-subunit improves lung liquid clearance during ventilation-induced lung injury interleukin-1î² causes acute lung injury via î±vî²5 and î±vî²6 integrin-dependent mechanisms adenoviral-mediated overexpression of socs3 enhances igg immune complex-induced acute lung injury dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure pretreatment with cationic lipid-mediated transfer of the na + k + -atpase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema electroporation-mediated gene transfer of the na + ,k + -atpase rescues endotoxin-induced lung injury interleukin-10 gene transfer: prevention of multiple organ injury in a murine cecal ligation and puncture model of sepsis nonviral gene delivery with indoleamine 2,3-dioxygenase targeting pulmonary endothelium protects against ischemia-reperfusion injury silencing of fas, but not caspase-8, in lung epithelial cells ameliorates pulmonary apoptosis, infl ammation, and neutrophil infl ux after hemorrhagic shock and sepsis caveolin-1 sirna increases the pulmonary microvascular and alveolar epithelial permeability in rats interleukin-10 delivery via mesenchymal stem cells: a novel gene therapy approach to prevent lung ischemia-reperfusion injury bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fi brosis cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer tetracycline-inducible transgene expression mediated by a single aav vector effi cient transfection of non-proliferating human airway epithelial cells with a synthetic vector system tailoring the aav vector capsid for gene therapy artifi cial evolution with adeno-associated viral libraries analysis and optimization of the cationic lipid component of a lipid/ peptide vector formulation for enhanced transfection in vitro and in vivo stabilized integrin-targeting ternary lpd (lipopolyplex) vectors for gene delivery designed to disassemble within the target cell cpg-free plasmids confer reduced infl ammation and sustained pulmonary gene expression toll-like receptor expression reveals cpg dna as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with cd40 ligand to induce high amounts of il-12 targeting type ii and clara cells for adenovirus-mediated gene transfer using the surfactant protein b promoter development of lentiviral vectors with regulated respiratory epithelial expression in vivo expression of cftr from a ciliated cell-specifi c promoter is ineff ective at correcting nasal potential diff erence in cf mice a human epithelium-specifi c vector optimized in rat pneumocytes for lung gene therapy tight control of gene expression in mammalian cells by tetracycline-responsive promoters use of a new generation reverse tetracycline transactivator system for quantitative control of conditional gene expression in the murine lung construction of an rtta2(s)-m2/ tts(kid)-based transcription regulatory switch that displays no basal activity, good inducibility, and high responsiveness to doxycycline in mice and non-human primates adenoviral vector transfection into the pulmonary epithelium after cecal ligation and puncture in rats ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins aff ects the transduction effi ciency of recombinant vectors gp130-stat3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium spatial and temporal expression of surfactant proteins in hyperoxia-induced neonatal rat lung injury intrapulmonary tnf gene therapy reverses sepsis-induced suppression of lung antibacterial host defense clinical review: gene-based therapies for ali/ards: where are we now? the present work was supported by funding from the health research board key: cord-253006-r2a2ozrc authors: yan, xiquan; han, xiaotong; fan, yong; fang, zhixiong; long, da; zhu, yimin title: duration of sars-cov-2 viral rna in asymptomatic carriers date: 2020-05-24 journal: crit care doi: 10.1186/s13054-020-02952-0 sha: doc_id: 253006 cord_uid: r2a2ozrc nan course of the 24 patients with respiratory samples that were positive for sars-cov-2 rna is shown in fig. 1 . notably, patient 2 carried sars-cov-2 viral for 32 days continuously after exposure to covid-19 and tested positive for viral rna in the respiratory sample for 13 days after first positive test onset. the results indicate that asymptomatic human can carry sars-cov-2 viral rna after exposure to covid-19, and the carriage seems long-lived. yet, the viability of sars-cov-2 detected on qrt-pcr in carriers remains to be proved by means of viral culture. due to limited resources, we did not perform these tests. further study is needed to determine the potential for and mode of contagion of asymptomatic carriers to develop more scientific control strategies. the long duration of asymptomatic infection with sars-cov-2 may warrant a reassessment of quarantine as the current outbreak. and it is of great public health significance to strictly monitor close contacts via multiple nucleic acid screenings to contain potential outbreaks. zhang and colleagues provided evidence of asymptomatic transmission [2] , and the relatively high proportion of asymptomatic infections could have public health implications [3] . to prevent and control this highly infectious disease in early phases, people with close contact with sars-cov-2 infection should be closely monitored and examined to rule out infection, even if they do not have any symptoms. the us centers for disease control and prevention recommends that contacts of asymptomatic carriers self-isolate for 14 days [4] . social distancing is one of the most important ways to cut off transmission routes-people cannot pass on infection if they do not come into contact with other people. quarantine of asymptomatic carriers and identification of contacts are a crucial part of these control efforts. this study is limited by the small sample size. largescale multicenter studies are needed to verify our findings. there is a great need for further studies on the mechanism by which asymptomatic carriers could acquire and carry sars-cov-2 that causes covid-19. these results highlighted the importance of quarantine. hence, with extensive efforts on close contact tracing and longitudinally surveillance via sars-cov-2 viral rna tests, the prevention of sars-cov-2 infection would prove challenging. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. a novel coronavirus from patients with pneumonia in china familial cluster of covid-19 infection from an asymptomatic covert coronavirus infections could be seeding new outbreaks public health recommendations for community-related exposure we thank all patients involved in the study. all authors were the major contributors in writing the manuscript and approved the final manuscript. the authors declare that they have no competing interests. key: cord-001293-dfaxj3bv authors: cavaillon, jean-marc; eisen, damon; annane, djilalli title: is boosting the immune system in sepsis appropriate? date: 2014-03-24 journal: crit care doi: 10.1186/cc13787 sha: doc_id: 1293 cord_uid: dfaxj3bv a relative immunosuppression is observed in patients after sepsis, trauma, burns, or any severe insults. it is currently proposed that selected patients will benefit from treatment aimed at boosting their immune systems. however, the host immune response needs to be considered in context with pathogen-type, timing, and mainly tissue specificity. indeed, the immune status of leukocytes is not universally decreased and their activated status in tissues contributes to organ failure. accordingly, any new immune-stimulatory therapeutic intervention should take into consideration potentially deleterious effects in some situations. refinements of supportive care of patients with severe sepsis have decreased their overall mortality, but no adjuvant drug therapy has emerged despite strenuous efforts in the field. twenty years have passed since the first patients with sepsis were included in clinical trials based on the understanding that tnf orchestrates the inflammatory response and should be the target for therapeutic intervention. in response to the failure of therapies aiming to target either the up-stream microbial activators or the effector molecules of the inflammatory cascade, a new concept has emerged of boosting the immune system to counter immunosuppression that develops in patients who survive the initial, hyperinflammatory period of sepsis [1] . inflammation is a highly sophisticated and complex response that fundamentally 'aims' to protect the host. in this review, we argue against the promulgation of what we believe is a misleading perception of sepsis inducing secondary immunosuppression. the possible negative consequences of immune system-boosting therapy are paradoxical properties have also been reported for il-10, the prototypic anti-inflammatory cytokine. its proinflammatory activity been established in human volunteers receiving endotoxin injection [6] . our own in vitro studies showed that adherence of human monocytes modulated the effect of il-10 on expression of 16 genes, including 'suppressor of cytokine stimulation' (socs) molecules, in the opposite direction as compared with non-adherent cells [7] . these observations illustrate the statement by moore and colleagues that 'il-10 can effect very different outcomes depending on timing, dose, and location of expression. in some scenarios, the expected immuno-suppressive activities are observed, while in others, il-10 enhances immune or inflammatory responses' [8] . among other cytokines classified as antiinflammatory, transforming growth factor-beta (tgfβ) may behave as pro-inflammatory mediator as tgfβtransgenic mice are more sensitive to lps-induced shock [9] and some of its inflammatory activities reflect its capacity to favor the differentiation of t helper (th) 17 and production of the pro-inflammatory il-17. the classification of non-cytokine inflammatory mediators also relies on an overly simplistic division between proand anti-inflammatory properties. this is well illustrated by prostaglandin e 2 (pge 2 ), a key mediator of infectious immunopathology. on one hand, pge 2 induces fever, increases vascular permeability, increases vasodilatation, and causes pain while also inhibiting production of tnf, increasing production of il-6, inhibiting 5-lipoxygenase and leukotriene a4 generation, and inducing 15lipoxygenase and the generation of the lipoxins involved in inflammation resolution. on the other hand, pge 2 has inhibitory properties on macrophages, neutrophils, th1 lymphocytes, natural killer (nk) cells, and cytotoxic lymphocytes but activates mast cells, th2, th17, and regulatory t lymphocytes (t reg ) [10] . this panoply of pge 2 -stimulated events amply demonstrates the inability to simply characterize the activities of this and the other molecules mentioned as pro-or anti-inflammatory. in an early anti-tnf monoclonal antibody intervention study, a significant improvement in day 3 survival was observed between the antibody-treated group and the placebo group [11] . although this was not a prespecified primary outcome, it is interesting to see that the treatment targeting tnf consisting of a single early injection was beneficial within a short period of time after sepsis onset, reinforcing the idea that tnf plays a key deleterious role in the early events of sepsis. once anti-tnf treatments were better targeted to the sickest patients by adding biological inclusion parameters (plasma il-6 level), survival was significantly improved on day 28 [12] . synergistic effects between immune modulators are a key characteristic of their effect. this explains how a non-lethal dose of one cytokine can lead to mortality when injected with a non-lethal dose of another cytokine. similarly, it may explain how the removal of some inflammatory mediators by coupled plasma filtrationadsorption was protective in an endotoxin-shock model while levels of circulating bio-active tnf were unaffected [13] . clear demonstrations of cytokine-mediated tissue damage exist. nevertheless, because of their ambiguous role mentioned above, identification of their precise role during sepsis has led to controversy. in animal models of sepsis, the role of tnf may vary depending upon the type of infection [14] . many model parameters influence conclusions of the relative role of the different mediators studied. identical cytokines have been found to be protective or deleterious depending upon the model. this has been the case for ifnγ [15] and granulocytemacrophage colony-stimulating factor (gm-csf) [16] among others (for example, il-17, il-33, 'tnf-related apoptosis-inducing ligand' (trail), and tgfβ). host-protective innate immune responses and consequent inflammation are inextricably linked and overlapping. consequently, the same cellular actors are key elements defending the host against infection while simultaneously contributing to deleterious events. for example, neutrophil extracellular traps that catch and kill bacteria and fungi are associated with the release of elements such as histones and mitochondria that behave like damage-associated molecular patterns perpetuating the inflammatory process. beneficial or deleterious roles of the same leukocyte subset have been reported depending upon the experimental model. for example, a peritonitis model using nude mice (lacking t cells) suggested that t lymphocytes contribute to protective immune responses [17] . by contrast, in an escherichia coli sepsis murine model, t lymphocytes markedly contributed to severity [18] . similarly, t reg improved survival in polymicrobial sepsis [19] whereas, in another report, reduced t reg activity led to improved survival [20] . the 'half angel/half devil' role of nk cells during severe infection is also described. nk cells contribute to systemic inflammation during polymicrobial sepsis but play a critical protective role in host defense against staphylococcus aureus lung infection (as reviewed in [21] ). although apoptosis of dendritic cells (dcs) is particularly increased during sepsis, they are protective in murine polymicrobial sepsis [22] . transcriptomic analysis of dcs in trauma patients shows a large number of upregulated inflammatory genes, suggesting their contribution to systemic inflammation and organ failure [23] . apoptosis of lymphocytes, dcs, and nk cells is a hallmark of sepsis. hotchkiss and colleagues [24] provided key experiments demonstrating that lymphocyte apoptosis was deleterious and its prevention highly protective. in addition to the depletion of apoptotic lymphocytes that contribute to the alteration of the immune status, apoptotic t cells themselves can further produce an immunosuppressive milieu following their release of tgfβ [25] . in contrast, the apoptosis of neutrophils is reduced. interestingly, injection of apoptotic neutrophils in lps-challenged mice with or undergoing cecal ligature puncture improved outcomes [26] . this may be due to the capacity of apoptotic neutrophils to limit the production of il-1 and tnf by lps-activated monocytes and to favor the production of il-10 and tgfβ [27] . favoring neutrophil apoptosis while differentially preventing that of lymphocytes and dcs would represent a considerable interventional challenge! in sepsis, apoptosis does not only affect immune cells. apoptosis of epithelial cells, endothelial cells, neurons, and cardiac myocytes is reported with crucial effects of loss of altered barrier function ( figure 1 ): in the lungs -acute lung injury and adult respiratory response syndrome [28] ; in the kidneys -acute kidney injury [29] . enhanced translocation of bacteria and bacterial products occurs consequent on intestinal epithelial cell apoptosis [30] , contributing to the concept of the gut as the motor of multiple organ failure (mof). sepsis-induced cardiac myocyte apoptosis produces altered contractility and cardiac dysfunction [31] . apoptosis of endothelial cells [32] induces vascular leakage. finally, microglial and neuronal apoptosis may follow autonomic failure that precedes shock and mof [33] . in addition to epithelial apoptosis, tight junction alterations enhance organ dysfunction. it has been demonstrated that nitric oxide favors disruption of epithelial cell tight junctions in numerous organs, including liver, gut, and lung. leukotrienes favor protein extravasation as shown in the kidney of septic mice [34] . still, cytokines remain the main orchestrators of these tissue injuries. in a model of acute kidney injury, it was nicely demonstrated that inflammatory cytokines, including tnf and il-17, cause small intestine and liver injury [35] . among others, il-17a is critical for generation of intestinal ischemia/reperfusion injury and subsequent liver and kidney injury [36] . all together, the altered functions of epithelial cells, endothelial cells, neurons, and cardiac myocytes contribute to mof that may influence outcomes in sepsis more than altered immune status. the concomitant occurrence of inflammation, anti-infectious response, and altered immune status in sepsis when roger bone coined the concepts of systemic inflammatory response syndrome (sirs) and compensatory anti-inflammatory response syndrome (cars), he conceived that one or the other would be predominating figure 1 during sepsis, many types of cells (but not neutrophils) display enhanced apoptosis, leading to various deleterious consequences. aki, acute kidney injury; ali/ards, acute lung injury/acute respiratory distress syndrome; nk, natural killer. [37] . however, we contend that cars should be considered an adapted compartmentalized response with the aim of silencing some acute pro-inflammatory genes and maintaining the expression of certain genes involved in the anti-infectious process. despite our views [38] , authors still propose a two-wave concept with sirs appearing before cars, although they admit that 'rigorous examination of previous studies provides evidence that both proinflammatory and opposing anti-inflammatory response(s) occur concomitantly in sepsis' [1] . tamayo and colleagues [39] studied a large panel of circulating cytokines in patients with sirs or sepsis, concluding that both pro-and anti-inflammatory mediators play roles from the very beginning of this life-threatening condition. similarly, meta-analysis of 12 transcriptomic studies including 784 individuals led to the conclusion that 'the arbitrary distinction of separating sepsis into proinflammatory and anti-inflammatory phases is not supported by gene-expression data' [40] . immune status has been studied frequently by measuring tnf or other inflammatory cytokine production by circulating monocytes in response to lps [41] . we studied patients undergoing abdominal aortic surgery, showing that reduced expression of human leukocyte antigen (hla)-dr on cd14 high monocytes occurs during surgery [42] . similarly, hla-dr expression was already reduced on monocytes taken very soon after severe trauma at accident scenes [43] . altered tnf production capacity of circulating cells in response to tlr2 or tlr4 agonists is also observed very soon after injurious insults, such as on admission of patients after cardiac arrest [44] . even if soon after the initial insult the intensity of the inflammatory response reaches its peak, there is a persistent inflammation associated with altered immune status in surviving patients [45] . the more severe the insult, the more profound is the alteration and the more chance the patients have to develop adverse clinical outcome. the immune status of leukocytes during sepsis and sirs varies depending on the compartment in which they reside terms such as 'immunoparalysis, immunosuppression, and anergy' are far too extreme to describe the immune status of circulating leukocytes in patients with sepsis or sirs. altered immune status of circulating leukocytes is not globally present. indeed, some functions like phagocytosis remain unaltered [46] , and ex vivo cytokine production in response to heat-killed s. aureus (hksa) remains unchanged in patients with sepsis [47] compared with healthy controls. this is in full agreement with the observation that lps primes hksa-induced tnf production in macrophage cell lines instead of leading to cross-tolerance [48] . while the concept of endotoxin tolerance is considered to partially mimic the alteration of immune status in sepsis, it is worth mentioning that cross-tolerance between microbial agonists is not invariant. for example, candida albicans and fungal cell wall β-glucan also prime lps-induced proinflammatory cytokine production [49] . these observations led us to propose the concept of leukocyte reprogramming [50] to explain the fact that tolerised macrophages retain anti-infectious properties. in addition, in tissues, there are numerous examples to illustrate the hyper-activity of these cells. for example, in mice with polymicrobial sepsis alone or as a 'second hit' after traumatic hemorrhage, it was nicely demonstrated by chaudry's group [51] that the ex vivo production of tnf or il-6 after lps activation was significantly reduced among peripheral blood mononuclear cells and splenic macrophages but that it was enhanced in alveolar and kupffer cells. similarly, in a murine model of trauma, the cytokine productive capacity of kupffer cells and alveolar macrophages was enhanced [52] . indeed, macrophage functions differ depending on the compartment from which they derive. we established [53] that the specific cytokine and cellular microenvironment within the lung was responsible for this particular resistance of alveolar macrophages to endotoxin tolerance, which can also be observed in human alveolar macrophages [54] . similarly, in kidneys, in response to a second challenge with lps, the expression of tnf and inducible nitric oxide synthase was further enhanced [55] . this may explain why unilateral nephrectomy could be protective in a murine peritonitis model and after lps injection [56] . most importantly, despite the fashionable concept of m1/m2 macrophages, the response of macrophages to il-4 and ifnγ is in fact completely different depending upon their origin [57] . as a consequence of this great heterogeneity of immune cells within different compartments, each tissue behaves independently, contributing to the global inflammatory response with a specific pattern, as illustrated by differential cytokine expression in liver, lungs, heart, brain, muscle, kidney, intestine, and spleen [58] . another example of the different behavior of leukocytes in various compartments is the frequent occurrence of hemophagocytosis (>60%) directly observed in the bone marrow of the critically ill [59] . this phenomenon is associated with extreme production of inflammatory cytokines. accordingly, it has been proposed that when hemophagocytosis is diagnosed in critical care patients, aggressive immunosuppressive therapy be undertaken without delay [59] . differences between cells harvested from different compartments after sepsis have also been reported for spleen and peritoneal myeloid dcs [60] . the major differences between compartments are further illustrated by the fact that gene deficiency may differentially affect outcomes of infection. for example, il-10 deficiency protects against francisella tularensis pulmonary infection but aggravates cutaneous infection [61] . similarly, we showed that scavenger receptor-a (sr-a), 'macrophage associated receptor with a collagenous base' (marco), cd36, or tlr2 deficiency protect mice against peritoneal s. aureus infection while these deficiencies aggravated pneumonia [62] . interestingly, when streptococcus pneumoniae was the pathogen used to colonize the murine nasopharynx, marco ko mice (but not sr-a ko mice) had significantly impaired clearance of pneumococcal colonization [63] . furthermore, inflammatory foci cells may not behave similarly to cells from other healthy compartments. for example, it was shown that neutrophils derived from sputum of patients with chronic bronchitis or cystic fibrosis are insensitive to inhibitory effects of il-10 in contrast to circulating neutrophils [64] . the concomitant presence of inflammation within tissues and altered immune status within the hematopoietic compartment is short-lived in murine models rendering them inappropriate to study patients with concomitant sepsis and cars [65] . in addition, mice are highly resistant to bacteria like s. aureus and their serum contains factors that limit inflammatory response intensity as compared with human serum [66] . a most provocative report comparing transcriptomic patterns of circulating cells from trauma patients, human endotoxemia-model participants, and murine-model equivalents revealed total absence of correlation [67] . when most therapeutic approaches have been validated in preclinical studies performed with murine models, one understands why those were not the most appropriate ones. the scientific community needs to reconsider models used to validate therapeutic approaches. if murine responses do not resemble human processes, maybe other species, like the pig, should be preferred. porcine monocytes and lps-activated macrophages are closer to their human counterparts than murine cells [68] . of course, murine models remain valuable to further decipher the mechanisms of sepsis. the best example is the two-hit model, which demonstrated that the nature of the first hit and its severity, the nature of the infection, and the route of infection may influence the outcome in a completely opposite direction [69] . are patients with sepsis dying of immune failure -dissecting the arguments used to describe compensatory immunosuppression occurring after sepsis? the clinical observations used to argue that immunosuppression occurs in sepsis patients surviving the initial inflammatory cascade [1] are in essence that patients develop nosocomial infections due to opportunistic pathogens, including reactivated chronic viral infections, and that patients who die after sepsis have unresolved foci of infection. these underpinning observations require further consideration. representing bacteria such as enterococcus faecium, stentrophomonas maltophilia, and pseudomonas aeruginosa along with candida as 'opportunistic pathogens' overstates the role of sepsis-induced immune dysregulation as the primary cause of nosocomial infection in these patients. these multiply-instrumented, high-intensity care, bed-bound, vulnerable patients often have breaches in their integument and mucous membranes (airways, surgical sites, indwelling catheters) and perturbed microbiomes from antibiotic treatments. overgrowth of antibioticresistant microorganisms and barrier defects predispose them to secondary infections, even without overt defects in their immune defenses [70] . these are all organisms of normal virulence that cause nosocomial infections in sepsis patients because of the selection pressure of potent antibiotics and the presence of biofilm affected/colonized intravascular and urinary catheters. additionally, reactivation of herpes simplex virus (hsv) and cytomegalovirus (cmv) may have some clinical relevance in critically ill patients. cmv-emia is quite common in patients with sepsis (30% in some studies) and is at least associated with worse outcome in icu patients in recent meta-analyses. whether cmv could cause immune compromise itself, be a reflection of immune compromise, or simply be an indicator of poor outcome in patients with sepsis remains unclear [71] . reactivation of oro-labial hsv is extremely common in sepsis, and hsv can frequently be detected in respiratory secretions. however, only one study has reliably investigated lower respiratory tract infection in critically ill, immunocompetent patients, showing that 21% of patients with ventilator-associated pneumonia (vap) had bronchopneumonitis due to hsv [72] . in 55% of these patients, the vap appeared to be due to hsv alone. however, acyclovir treatment had no impact on the outcome in patients with hsv bronchopneumonitis [72] . of greater relevance to predisposition to nosocomial infection in sepsis patients remaining in icus for prolonged periods are physical breaches in innate immune system barriers. intravascular catheters, endotracheal tubes with consequently increased dead space, and increased gastric ph due to peptic ulcer prophylaxis regimens are all, along with broad-spectrum antibiotics, potent promoters of nosocomial infection. post-mortems (pms) identifying unresolved infection foci are not reliable proof that patients are dying of sepsis. pneumonia is frequently present in patients in whom supportive care is withdrawn due to failure to thrive. where pneumonia has been found more frequently at pm than was appreciated ante-mortem, the extent of pulmonary involvement was not quantified [73] . in this series, there was clear agreement by clinical and pm assessment that mof was the commonest cause of death [73] . these data call into question the relevance of unresolved, pm infection in patients dying in the icu as a direct indicator of immunosuppression following as a direct consequence of previous sepsis. if the patients die with infectious foci and altered immune status, it does not mean they die because of them. because of the monocyte deactivation in sepsis, it was proposed to restore it with the use of either ifnγ or gm-csf, two cytokines that counteract endotoxin tolerance. the first attempt was successfully performed in nine septic patients who received subcutaneous ifnγ that restored ex vivo cytokine production and hla-dr expression by monocytes [74] . the authors claimed that overall mortality was lower in the treated group compared with historical controls. in mechanically ventilated trauma patients, ifnγ was aerosolized. however, in a previous phase iii study in burn patients, ifnγ had failed to protect patients from infection or decrease mortality [75] . we must recall that ifnγ injection increases mortality in animal models of polymicrobial infection [15] . all together, these data have limited the routine use of ifnγ in icu patients, although a dutch clinical trial is ongoing. gm-csf has been demonstrated to be able to restore some immune status parameters. however, a metaanalysis concluded that gm-csf did not significantly reduce in-hospital mortality, although it significantly increased infection recovery [76] . although no adverse effects were reported, it is worth recalling a case report of a patient who developed a fatal adult respiratory distress syndrome after gm-csf treatment [77] . in animal models, gm-csf favors lps-induced lung inflammation, amplifying lps-induced bronchoconstriction [78] . gm-csf favors production of tnf and il-1. in a recent study, it was confirmed that gm-csf synergizes with lps, promoting il-1β secretion [79] . lethal injection of lps in gm-csf receptor ko mice led to far lower mortality among these mice as compared to wild type mice. given all the efforts made by some authors to convince the scientific community of the use of gm-csf, it is challenging to read the conclusion of this present paper given that gm-csf has been previously underestimated as a target for therapeutic intervention in many bacterial infections and inflammatory disorders associated with the production of il-1β. il-7 is another cytokine that is promoted for the treatment of sepsis and that is supported by murine and human ex vivo tissue data [1, 80] . one can conjecture that systemic treatment with il-7 may act in undesired places, as illustrated by the following: il-7 worsens graft-versus-host-induced tissue inflammation [81] ; favors inflammation in colitis [82] , contributes to arthritis severity [83] ; upregulates chemokines, ifnγ, macrophage recruitment, and lung inflammation [84] ; and, finally, increases production of inflammatory cytokines by monocytes and t cells [85] . many other cytokines (for example, il-2, il-12, il-15, and tnf) can boost the immune system and are reported to be beneficial in murine sepsis models. however, one wonders whether systemic treatment with any immunostimulating cytokine may act on tissue leukocytes boosting the inflammatory process while boosting immune status as well. in this perspective, the attempt to treat peripheral mononuclear cells of sepsis patients ex vivo with il-2 before re-injecting them is an interesting approach that prevents the delivery of this cytokine to the bloodstream, allowing it to act strictly on the desired cells [86] . in this study, the mortality was 8% in the extracorporeally treated group of patients (n = 121) but was 21% in the patients receiving standard treatment (n = 52). rather than repeating the mistakes of past experimental treatments for sepsis in which therapies were developed after successful preclinical models that may be far from mimicking human disease, it would be ideal to proceed in the future with new treatments in which extensive human data are available prior to embarking on expensive licensure studies. furthermore, identifying currently licensed drugs with tolerable safety profiles as potential sepsis agents leap-frogs costly drug development and early-phase human studies. in animal models, extant licensed drugs, such as chloroquine [87] and androstenenediol [51] , have successfully restored immune status. most interestingly, in the latter case, the treatment protected mice against polymicrobial sepsis and boosted altered ex vivo cytokine production observed with peripheral blood cells and spleen macrophages, dampening production observed with alveolar macrophages and kupffer cells. a similar compartmentalized adapted specificity was reported with estradiol [88] . other approaches involve pro-resolving lipid mediators [89] , although it is uncertain whether they may also adversely boost immune status. the recently recognized aspirin-triggered lipoxins, anti-inflammatory mediators of inflammation resolution, make aspirin a possible inexpensive agent for both prevention and treatment of sepsis. considerable observational cohort data show improvements in mortality in patients with sepsis pretreated with aspirin [90] . this approach is being prospectively studied as part of an aspirin primary prevention trial. could other immunomodulatory approaches be considered with less putative dangerous consequences on inflamed tissues. this may be the case of thymosin-α1. indeed, a very promising study demonstrated its efficiency to improve clinical outcome in patients with severe sepsis [91] , after a preliminary investigation had demonstrated a better performance with respect to organ failure scores in thymosin-α1-treated patients with sepsis arising from intra-abdominal infection due to carbapenem-resistant bacteria [92] . however, one must call for caution since thymosin-α1 can also favor the production of inflammatory cytokines and nitric oxide and further increases the percentage of t reg cells [93, 94] . still, very little is known of its effect on leukocytes present in different compartments. the cell surface molecules containing in their intracytoplasmic domain an immunoreceptor tyrosine-based inhibition motif -such as programmed death-1 (pd-1), b and t lymphocyte attenuator (btla), and cytotoxic t-lymphocyte antigen 4 (ctla-4) -could also be interesting targets for new therapeutic approaches. the expression of pd-1 on t cells and its ligand (pd-l1) on monocytes is upregulated in critically ill [95] or septic shock [96] patients. increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock [97] . not only are pd-1-deficient mice markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response [98] , but also blockade of pd-1 or pd-l1 improves survival in a murine model of sepsis, reverses immune dysfunction, inhibits lymphocyte apoptosis, and attenuates organ dysfunction [99] [100] [101] . the relevance of these observations in human settings is still needed. ctla-4 is a high-avidity receptor for cd80 and cd86. enhanced ctla-4 expression was demonstrated more frequently in patients with sepsis than in non-infected critically ill patients or control subjects [102] , and blocking ctla-4 improved survival in bacterial and fungal experimental sepsis [103, 104] . however, the use of such an approach seems tricky since, in animal models at high dose, anti-ctla-4 could worsen survival [103] , and the use of abatacept (a soluble ctla-4 dimerized with an fc fragment of immunoglobulin) led to increased survival in invasive pneumococcal infection [105] . similarly, btla expression is enhanced in patients with sirs or sepsis [106] and, in a murine model of sepsis, btla-deficient mice displayed an enhanced resistance [107] . in contrast, these mice displayed enhanced susceptibility to endotoxin-induced shock [108] . accordingly, the exact role of btla needs to be further deciphered before strategies targeting btla could be proposed to treat patients with sepsis. new therapeutic approaches to treat sepsis should take into consideration that the immune status of leukocytes in the peripheral blood might be quite different from those present in inflamed tissues. we believe that a systemic approach to immune stimulation is not appropriate if immune cells are boosted generally, independent of their location. an ideal drug would limit the overzealous inflammatory process that leads to organ failure and favor homeostatic responsiveness of leukocytes ( figure 2 ). this is the challenge we have to address if we wish to avoid further decades of disillusionment. figure 2 new therapeutic interventions should address both the events in the tissues that lead to organ failure and the altered immune status of leukocytes restricted to some specific compartments. cars: compensatory anti-inflammatory response syndrome; cmv: cytomegalovirus; ctla-4: cytotoxic t-lymphocyte antigen 4; dc: dendritic cell; gm-csf: granulocyte-macrophage colony-stimulating factor; hksa: heat-killed staphylococcus aureus hsv: herpes simplex virus; ifnγ: interferon-gamma lps: lipopolysaccharide; marco: macrophage-associated receptor with a collagenous base; mof: multiple organ failure; nk: natural killer pd-1: programmed death-1; pd-l1: programmed death-1 ligand prostaglandin e 2 ; pm: post-mortem; sirs: systemic inflammatory response syndrome; sr-a: scavenger receptor-a; tgfβ: transforming growth factor-beta th: t helper; tlr: toll-like receptor; tnf: tumor necrosis factor; t reg : regulatory t lymphocyte; vap: ventilator-associated pneumonia immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach paradoxical anti-inflammatory actions of tnf-alpha: inhibition of il-12 and il-23 via tnf receptor 1 in macrophages and dendritic cells tnf suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis interleukin 1 receptor signaling regulates duba expression and facilitates toll-like receptor 9-driven antiinflammatory cytokine production systemic interferon-gamma suppresses the development of endotoxin-induced uveitis in mice proinflammatory effects of il-10 during human endotoxemia adib-conquy m: adherence modifies the regulation of gene expression induced by interleukin-10 a: interleukin-10 and the interleukin-10 receptor hepatic 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is boosting the immune system in sepsis appropriate? critical care key: cord-000072-2ygb80sc authors: van meurs, matijs; kümpers, philipp; ligtenberg, jack jm; meertens, john hjm; molema, grietje; zijlstra, jan g title: bench-to-bedside review: angiopoietin signalling in critical illness – a future target? date: 2009-03-09 journal: crit care doi: 10.1186/cc7153 sha: doc_id: 72 cord_uid: 2ygb80sc multiple organ dysfunction syndrome (mods) occurs in response to major insults such as sepsis, severe haemorrhage, trauma, major surgery and pancreatitis. the mortality rate is high despite intensive supportive care. the pathophysiological mechanism underlying mods are not entirely clear, although several have been proposed. overwhelming inflammation, immunoparesis, occult oxygen debt and other mechanisms have been investigated, and – despite many unanswered questions – therapies targeting these mechanisms have been developed. unfortunately, only a few interventions, usually those targeting multiple mechanisms at the same time, have appeared to be beneficial. we clearly need to understand better the mechanisms that underlie mods. the endothelium certainly plays an active role in mods. it functions at the intersection of several systems, including inflammation, coagulation, haemodynamics, fluid and electrolyte balance, and cell migration. an important regulator of these systems is the angiopoietin/tie2 signalling system. in this review we describe this signalling system, giving special attention to what is known about it in critically ill patients and its potential as a target for therapy. critical illness is a life-threatening disease by definition. patients treated for critical illness in the intensive care unit have underlying causes such as infection, trauma, major surgery, hemorrhagic shock, pancreatitis and other major insults. despite maximal supportive care, severely ill patients treated in intensive care units are still likely to die, usually after an episode of increasing failure of multiple organs [1] . the mechanisms that underlie multiple organ dysfunction syndrome (mods) are not known [2] , although several have been proposed, including overwhelming infection or immune response, immune paralysis, occult oxygen debt and mitochondrial dysfunction [3] [4] [5] . although these potential mechanisms have features in common, it is not clear whether mods is a final common pathway or when it is engaged. the innate and adaptive immune systems, coagulation, and hormonal and neuronal signalling are undoubtedly involved and are all connected. for example, the hypoxic response is linked to innate immunity and inflammation by the transcription factor nuclear factor-κb (nf-κb) [6] . it is no coincidence that the few interventions that appear to be of benefit, although this is still under debate, have pleiotropic mechanisms of action [7] [8] [9] . thus, it seems reasonable to study the intersections between and within cellular and molecular systems to elucidate the interactions and to develop therapeutic options. one of the central cellular players in this system is the endothelial cell (ec). once thought to serve as an inert vascular lining, ecs are highly heterogeneous and constitute an active disseminated organ throughout the circulatory system. ecs form the border between every organ and the bloodstream and thus with the rest of the body. the ec receives and gives signals, stores active substances of multiple systems, and regulates the passage of fluids, electrolytes, proteins and cells. the ec has a time and place dependent phenotype that is dynamically controlled, and its reactions to stimuli are specific to organ and vascular bed [10] [11] [12] [13] . the ec merits robust investigation in critical illness, as in vascular medicine [14] . genesis and organogenesis in normal physiology and in wound repair, but it is considered pathologic in tumour growth and diabetes [15] . second, in the adult organism, ecs help to maintain homeostasis, including fluid, electrolyte and protein transport, and cell migration into and out of the vessel, and to regulate blood flow. third, ecs react and respond to disturbances of homeostasis (for example, in inflammation, coagulation and hypoxia/reperfusion). all three functions are involved in mods, in which ecs are shed, blood flow regulation is hampered, vessels become leaky, cells migrate out of the vessel and into the surrounding tissue, and coagulation and inflammation pathways are activated [16] . the machinery involved -receptors, signalling pathways and effectors -is largely the same in each function, but the net effect is determined by the balance between the parts of the machinery and the context [15] . the angiopoietin/tie2 signalling system (ang/tie system) appears to be crucial in all three functions [17, 18] . the ang/tie system, which was discovered after vascular endothelial growth factor (vegf) and its receptors, is mainly restricted to ec regulation and is the focus of this review. accumulating evidence suggests that this system is nonredundant and is involved in multiple mods-related pathways. all components of potential pathophysiological mechanisms in mods should be viewed within their own context, because all systems are mutually dependent. thus, examination of the ang/tie system might offer insight into the mechanisms underlying mods and provide opportunities for therapeutic intervention. the notion that the ang/tie system contributes to disease pathogenesis is supported by clinical studies and studies in animal models, and by the relation between symptoms of critical illness and disturbances in this system. in mice, ang-2 over-expression in glomeruli causes proteinuria and apoptosis of glomerular ecs [19] . in a rat model of glomerulonephritis, tie2 is over-expressed by ecs, and ang-1 and ang-2 are over-expressed by podocytes in a time-dependent manner during the repair phase [20] . therefore, ang/tie might be involved in renal failure and repair. lung dysfunction is common in critical illness, and evidence of ang/tie involvement has been found in animal models. in a rat model of acute respiratory distress syndrome, ang-1 reduces permeability and inflammation, whereas tie2 deficiency increases damage [21] . in an experimental model of asthma, ang-1 mrna was decreased, and ang-1 supplementation decreased alveolar leakage and nf-κb-dependent inflammation [22] . in hypoxia-induced pulmonary hypertension in rats, decreased activity of the tie2 pathway contributed to right ventricular load, and this effect was antagonized by ang-1 [23]. on the other hand, a causative role for ang-1 in pulmonary hypertension has also been suggested [24] . in hyperoxic lung injury, ang-2 is involved in lung permeability and inflammation [25] . ang/tie also may contribute to critical illness in patients with pulmonary conditions. ang-1 and ang-2 concentrations in sputum from asthma patients correlated with airway microvascular permeability [26] . in patients with exudative pleural effusion, the ang-2 level was increased whereas ang-1 was unchanged [27] . ang-2 levels are associated with pulmonary vascular leakage and the severity of acute lung injury. plasma from patients with acute lung injury and high ang-2 concentrations disrupts junctional architecture in vitro in human microvascular ecs [28, 29] . patients with cardiovascular disorders also exhibit changes in the ang/tie system. circulating ang-1 concentrations are stable in patients with atrial fibrillation, but ang-2 concentrations are increased, along with markers of platelet activation, angiogenesis and inflammation [30] . patients with hypertension resulting in end-organ damage have increased levels of circulating ang-1, ang-2, tie2 and vegf [31] . congestive heart failure is associated with elevated plasma levels of ang-2, tie2 and vegf, but normal levels of ang-1 [32]. a similar pattern is seen in acute coronary syndrome [33] . circulating levels of components of the ang/tie system have been measured in patients admitted to the critical care unit. in trauma patients plasma ang-2, but not plasma ang-1 or vegf, was increased early after trauma, and the level correlated with disease severity and outcome [34] . in children with sepsis and septic shock, ang-2 levels in plasma were increased and once again correlated with disease severity, whereas ang-1 levels were decreased [35] . the same ang-1/ ang-2 pattern is seen in adults with sepsis [28, 29, [36] [37] [38] [39] . the results of studies of the ang/tie system in humans are summarized in table 1 . in sepsis, vegf and its soluble receptor sflt-1 (soluble vegfr-1) are also increased in a disease severity-dependent manner [40] [41] [42] .the picture that emerges from these studies is that the ang/tie signalling system appears to play a crucial role in the symptoms of mods. findings in animal models and in patients suggest that ang-1 stabilizes ecs and ang-2 prepares them for action. the close relation with vegf is also apparent. four (ang-1) and two (ang-2) subunits [48, 49] . the dissimilarity between ang-1 and ang-2 signalling lies in subtle differences in the receptor binding domain that lead to distinct intracellular actions of the receptor; differential cellular handling of both receptor and ligands after binding and signalling initiation may also play a role [49, 50] . the receptors are tie1 and tie2 [51] . tie2 is a 140-kda tyrosine kinase receptor with homology to immunoglobulin and epidermal growth factor [47, 52] . tie receptors have an amino-terminal ligand binding domain, a single transmembrane domain and an intracellular tyrosine kinase domain [51] . ligand binding to the extracellular domain of tie2 results in receptor dimerization, autophosphorylation and docking of adaptors, and coupling to intracellular signalling pathways [47, [53] [54] [55] . tie2 is shed from the ec and can be detected in soluble form in normal human serum and plasma; soluble tie2 may be involved in ligand scavenging without signalling [56] . tie2 shedding is both constitutive and induced; the latter can be controlled by vegf via a pathway that is dependent on phosphoinositide-3 kinase (pi3k) and akt [57] . shed soluble tie2 can scavenge ang-1 and ang-2 [56] . tie1 does not act as a transmembrane kinase; rather, it regulates the binding of ligands to tie2 and modulates its signalling [58] [59] [60] . ang-1 is produced by pericytes and smooth muscle cells ( figure 1 ). in the glomerulus, which lacks pericytes, ang-1 is produced by podocytes [61] . ang-1 has a high affinity for the extracellular matrix, and so circulating levels do not reflect tissue levels, which in part is probably responsible for the constitutive phosphorylation of tie2 in quiescent endothelium [62] [63] [64] [65] . ang-2 is produced in ecs and stored in weibel-palade bodies (wpbs) [66, 67] . the release of ang-2 from wpbs by exocytosis can be regulated independently of the release of other stored proteins [68] . tie2 is expressed predominantly by ecs, although some subsets of macrophages and multiple other cell types express tie2 at low levels [69, 70] . in ecs, tie2 is most abundant in the endothelial caveolae [71] . the ang-1 and ang-2 genes are located on chromosome 8. functional polymorphisms have not been identified in the ang-1 gene, but three have been identified in the coding region of ang-2 [72] . in ecs under stress, ang-2 mrna expression is induced by vegf, fibroblast growth factor 2 and hypoxia [44, 73] . upregulation of ang-2 induced by vegf and hypoxia can be abolished by inhibiting tyrosine kinase or mitogen-activated protein kinase [73] . ang-2 mrna expression can be downregulated by ang-1, ang-2, or transforming growth factor [74] . after inhibition of pi3k by wortmannin, ang-2 mrna production is induced by the transcription factor foxo1 (forkhead box o1) [75] . ec-specific ang-2 promoter activity is regulated by ets-1 and the ets family member elf-1 [76, 77] . because tie2 signalling is required under circumstances that usually hamper cell metabolism, its promoter contains repeats that ensure transcription under difficult circumstances, including hypoxia [78] . tie2 is present in phosphorylated form in quiescent and activated ecs throughout the body [62] . signalling is initiated by autophosphorylation of tie2 after ang-1 binding and is conducted by several distinct pathways [54, 71, 79, 80] . tie2 can also be activated at cell-cell contacts when ang-1 induces tie2/tie2 homotypic intercellular bridges [65] . in human umbilical vein endothelial cells (huvecs), ang/tie signalling resulted in 86 upregulated genes and 49 downregulated genes [81, 82] . akt phosphorylation by pi3k with interaction of nitric oxide is the most important intracellular pathway [51, [83] [84] [85] [86] ; however, erk1/2, p38mapk, and sapk/jnk can also participate in ang/tie downstream signalling [71, 81, 84, [87] [88] [89] [90] . endothelial barrier control by ang-1 requires p190rhogap, a gtpase regulator that can modify the cytoskeleton [80] . the transcription factors foxo1, activator protein-1, and nf-κ b are involved in ang/tie-regulated gene transcription [75, [91] [92] [93] . ang-1induced signalling is has also been implicated in cell migration induced by reactive oxygen species [94] . abin-2 (a20-binding inhibitor of nf-κb 2), an inhibitor of nf-κb, is involved in ang-1-regulated inhibition of endothelial apoptosis and inflammation in huvecs [93] . however, the downstream signalling of tie2 varies depending on cell type and localization and whether a cell-cell or cell-matrix interaction in involved, which results in spatiotemporally different patterns of gene expression. for example, ang-1/tie2 signalling leads to akt activation within the context of cell-cell interaction, but it leads to erk activation in the context of cell-matrix interaction. the microenvironment of the receptor in the cell membrane plays a central role in this signal differentiation. adaptor molecules such as dok and shp2 and the availability of substrate determine which protein is phosphorylated [95] . after binding of ang-1, and to a lesser extent ang-2, tie2 is internalized and degraded, and ang-1 is shed in a reusable form [50] . vegf is an important co-factor that can exert different effects on ang-1 and ang-2 signalling [88] . ang-2 is antiapoptotic in the presence of vegf but induces ec apoptosis in its absence [96] . autophosphorylation and subsequent signalling are inhibited by heteropolymerization of tie1 and tie2 [59] . although the ang/tie system appears to play its role mainly in paracrine and autocrine processes, its circulating components have been found in plasma. the significance of this finding in health and disease has yet to be determined. the ang/tie system is an integrated, highly complex system of checks and balances ( figure 1) [45,54]. the response of ecs to ang-1 and ang-2 depends on the location of the cells and the biological and biomechanical context [97, 98] . it is believed that pi3k/akt is among the most important downstream signalling pathways and that vegf is one of the most important modulators of effects. below we describe in more detail how this system responds to changes in homeostatic balances under various conditions of damage and repair. angiogenesis, inflammation and homeostasis are highly related, and the ang/tie system lies at the intersection of all three processes [99, 100] . the ang/tie system is critically important for angiogenesis during embryogenesis, but in healthy adults its function shifts toward maintenance of homeostasis and reaction to insults. except for follicle formation, menstruation and pregnancy, angiogenesis in adults is disease related. neoplasia-associated neoangiogenesis and neovascularization in diabetes and rheumatoid arthritis are unfavourable events, and improper angiogenesis is the subject of research in ischaemic disorders and atherosclerosis. finally, failure to maintain homeostasis and an inappropriate reaction to injury are detrimental features in critical illness. a schematic model of the angiopoietin-tie2 ligand-receptor system. quiescent endothelial cells are attached to pericytes that constitutively produce ang-1. as a vascular maintenance factor, ang-1 reacts with the endothelial tyrosine kinase receptor tie2. ligand binding to the extracellular domain of tie2 results in receptor dimerization, autophosphorylation, docking of adaptors and coupling to intracellular signalling pathways. signal transduction by tie2 activates the pi3k/akt cell survival signalling pathway, thereby leading to vascular stabilization. tie2 activation also inhibits the nf-κb-dependent expression of inflammatory genes, such as those encoding luminal adhesion molecules (for example, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and e-selectin). ang-2 is stored and rapidly released from wpbs in an autocrine and paracrine fashion upon stimulation by various inflammatory agents. ang-2 acts as an antagonist of ang-1, stops tie2 signalling, and sensitizes endothelium to inflammatory mediators (for example, tumour necrosis factor-α) or facilitates vascular endothelial growth factor-induced angiogenesis. ang-2-mediated disruption of protective ang-1/tie2 signalling causes disassembly of cell-cell junctions via the rho kinase pathway. in inflammation, this process causes capillary leakage and facilitates transmigration of leucocytes. in angiogenesis, loss of cell-cell contacts is a prerequisite for endothelial cell migration and new vessel formation. ang, angiopoietin; nf-κb, nuclear factor-κb; pi3k, phosphoinositide-3 kinase; wpb, weibel-palade body. angiogenesis is dependent on multiple growth factors and receptors and their signalling systems and transcriptional regulators [101] . the process is complex and encompasses the recruitment of mobile ecs and endothelial progenitor cells, the proliferation and apoptosis of these cells, and reorganization of the surroundings [102] . to form stable new blood vessels, the response must be coordinated in time and space, and the ang/tie system is involved from beginning to end. to prepare for angiogenesis, ang-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism [44, 103] . before vascular sprouting starts, focal adhesion kinase and proteinases such as plasmin and metalloproteinases are excreted [85] . often, this stage is preceded by activation of innate immunity and inflammation [104] . apparently, the machinery to clean up after the work has been finished is installed before the work is commenced, again illustrating the close relations among the different processes [104] . ang-1 maintains and, when required, restores the higher order architecture of growing blood vessels [43,44, 105, 106] . this is achieved by inhibiting apoptosis of ecs by tie2mediated activation of pi3k/akt signalling [107] [108] [109] . ang-1/ tie2 signalling is involved in angiogenesis induced by cyclic strain and hypoxia [110, 111] . although its role is less clear, tie1 might be involved in ec reactions to shear stress [112] . ang-1 is a chemoattractant for ecs [83] [84] [85] , and both ang-1 and ang-2 have proliferative effects on those cells [98, 113] . at the end of a vascular remodelling phase, ang-2 induces apoptosis of ecs for vessel regression in competition with the survival signal of ang-1 [106] . this apoptotic process requires macrophages, which are recruited by ang-2 [70, 114] . ecs require support from surrounding cells such as pericytes, podocytes, and smooth muscle cells [63] . these cells actively control vascular behaviour by producing signalling compounds (for instance, ang-1 and vegf) that govern the activity and response of ecs [61] . to attract ecs, ang-1 secreted by support cells binds to the extracellular matrix. in quiescent ecs, this binding results in tie2 movement to the site of cell-cell interaction. in mobile ecs, ang-1 polarizes the cell with tie2 movement abluminal site [65] . in tumour angiogenesis and in inflammation, ang-2 recruits tie2positive monocytes and causes them to release cytokines and adopt a pro-angiogenic phenotype [111] . the ang/tie system provides vascular wall stability by inducing ec survival and vascular integrity. however, this stability can be disrupted by ang-2 injection, which in healthy mice causes oedema [28, 79, 115, 116] that can be blocked by systemic administration of soluble tie2 [115] . ang-2 can impair homeostatic capacity by disrupting cell-cell adhesion through e-cadherin discharge and ec contraction [28, 117] . in contrast, through effects on intracellular signalling, the cytoskeleton and junction-related molecules, ang-1 reduces leakage from inflamed venules by restricting the number and size of gaps that form at endothelial cell junctions [80, 118, 119] . ang-1 also suppresses expression of tissue factor induced by vegf and tumour necrosis factor (tnf)-α, as well as expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and e-selectin. as a result, endothelial inflammation is suppressed [120] [121] [122] [123] . in primary human glomerular ecs in vitro, ang-1 stabilizes the endothelium by inhibiting angiogenesis, and vegf increases water permeability [124] . similar observations were made in bovine lung ecs and immortalized huvecs, in which ang-1 decreased permeability, adherence of polymorphonuclear leucocytes and interleukin-8 production [123] . reaction to injury can be seen as an attempt to maintain homeostasis under exceptional conditions. ecs can be affected by several noxious mechanisms. the ang/tie system is considered crucial in fine-tuning their reaction to injury and in containing that reaction. ang-2-deficient mice cannot mount an inflammatory response to peritonitis induced chemically or with staphylococcus aureus [125] , but they can mount a response to pneumonia, suggesting the existence of inflammatory reactions for which ang-2 is not mandatory. ang-2 sensitizes ecs to activation by inflammatory cytokines. in ang-2-deficient mice, leucocytes do roll on activated endothelium but they are not firmly attached, owing to the lack of ang-2-dependent upregulation of adhesion molecules and the dominance of ang-1-regulated suppression of adhesion molecules [120] [121] [122] [123] 125] . in bovine retinal pericytes, hypoxia and vegf induce ang-1 and tie2 gene expression acutely without altering ang-2 mrna levels. the opposite occurs in bovine aortic ecs and microvascular ecs, underscoring the heterogeneity of ecs from different microvascular beds [73, 126, 127] . lipopolysaccharide (lps) and pro-inflammatory cytokines can shift the ang/tie balance, rouse ecs from quiescence and provoke an inflammatory response. in rodents lps injection induces expression of ang-2 mrna and protein and reduces the levels of ang-1, tie2 and tie2 phosphorylation in lung, liver and diaphragm within 24 hours, which may promote or maintain vascular leakage. the initial increase in permeability is probably due to release of ang-2 stored in wpbs [39, 128] . in a mouse model of lps-induced lung injury, pulmonary oedema was found to be related to the balance between vegf, ang-1 and ang-4 [129] . in a comparable model, ang-1-producing transfected cells reduced alveolar inflammation and leakage [130] . in choroidal ecs, tnf induces ang-2 mrna and protein before affecting ang-1 and vegf levels [131] . in huvecs, tnf-induced upregulation of ang-2 is mediated by the nf-κb pathway [132] , and tnf-induced tie2 expression can be attenuated by both ang-1 and ang-2. without tnf stimulation, only ang-1 can reduce tie2 expression [133] . ang-2 sensitizes ecs to tnf, resulting in enhanced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and e-selectin [74, 125, 134] . by inhibiting those endothelial adhesion molecules, ang-1 decreases leucocyte adhesion [122] . angiopoietins can mediate the synthesis of platelet-activating factor by ecs to stimulate inflammation [90] . moreover, both ang-1 and ang-2 can translocate p-selectin from wpbs to the surface of the ec [135] , and both can also increase neutrophil adhesion and chemotaxis and enhance those processes when they are induced by interleukin-8 [86, 136, 137] . in a rat model of haemorrhagic shock, ang-1 reduced vascular leakage, and it inhibited microvascular endothelial cell apoptosis in vitro and in vivo [107, 138] . in this model, ang-1promoted cell survival was partly controlled through integrin adhesion [139] . it has been suggested that ec apoptosis in haemorrhagic shock contributes to endothelial hyperpermeability [140] [141] [142] . apoptosis is one of the reactions to modsrelated injury as demonstrated in hypoxia/reperfusion [143] . ang-1 and ang-2 are involved in cell-cell and cell-matrix binding [139, [144] [145] [146] . endothelial permeability is greatly dependent on cell-cell adhesion. the major adherens junction is largely composed of vascular-endothelial cadherin. this complex can be disrupted by vegf, leading to increased vascular permeability [147, 148] , which can be antagonized by ang-1 [149, 150] . ecs can also bind to the matrix through the binding of ang-1 to integrins, which can mediate some of the effects of ang-1 without tie2 phosphorylation [146, 151] . at low ang-1 concentrations, integrin and tie2 can cooperate to stabilize ecs [151] . ang-2 might play a role in inflammatory diseases such as vasculitis by disrupting the cell-cell junction and inducing denudation of the basal membrane [152] . ang-1 can mediate the translocation of tie2 to endothelial cell-cell contacts and induce tie2-tie2 bridges with signal pathway activation, leading to diminished paracellular permeability [65] . in the mature vessel, ang-1 acts as a paracrine signal to maintain a quiescent status quo, whereas ang-2 induces or facilitates an autocrine ec response [74, 153] . in general, ang-1 can be viewed as a stabilizing messenger, causing continuous tie2 phosphorylation, and ang-2 as a destabilizing messenger preparing for action [17] . attempts to unravel the exact molecular mechanisms that control the system are complicated by microenvironment-dependent endothelial phenotypes and reactivity and by flow typedependent reactions to dynamic changes [13, 154, 155] . hence, the ec must be viewed in the context of its surroundings -the pericyte at the abluminal site, and the blood and its constituents on the luminal site [64] . the ang/tie system certainly functions as one of the junctions in signal transduction and plays a key role in multiple cellular processes, many of which have been linked to mods. a therapy should intervene in the right place and at the right time, with the proper duration of action and without collateral damage [156, 157] . the ang/tie system is involved in many processes and lies at the intersection of molecular mechanisms of disease. thus, interventions targeting this system might have benefits. as in other pleiotropic systems, however, unexpected and unwanted side effects are a serious risk. the absence of redundant systems to take over the function of ang/tie2 has the advantage that the effect of therapeutic intervention cannot easily be bypassed by the cell. on the other hand, because the cell has no escape, the effect may become uncontrolled and irreversible. moreover, the exact function of the ang/tie system in the pathological cascade is not fully established. what we see in animal models and in patients is most probably the systemic reflection of a local process. we do not know whether this systemic reflection is just a marker of organ injury or even a mediator of distant organ involvement. of the three main functions of the ang/tie system, it is mainly angiogenesis that has been evaluated as a therapeutic target. so far, the focus of ang/tie modulation has been on inhibiting angiogenesis related to malignant and ophthalmological diseases and to complications of diabetes [158, 159] . in peripheral arterial occlusive disease, stimulation of angiogenesis seems a logical strategy to attenuate the consequences of ongoing tissue ischaemia. in a rat model of hind limb ischaemia, combined delivery of ang-1 and vegf genes stimulated collateral vessel development to the greatest extent [160, 161] . thus far, therapy directed at vegf has reached the clinic, but not therapy directed at ang/tie [162] . targeting homeostasis and repair/inflammation in critically ill patients is an attractive option and has already led to the development of new drugs [45, 158, 163] . from current knowledge, one can speculate about the best options for therapy aimed at the ang/tie system. in critical illness, ang-1 is considered to be the 'good guy' because it can create vascular stability and thus its activity should be supported. in contrast, ang-2 appears to be a 'bad guy' that induces vascular leakage, so its activity should be inhibited [164] . production of recombinant ang-1 is technically challenging as ang-1 is 'sticky' because of its high affinity for the extracellular matrix [165] . however, stable ang-1 variants with improved receptor affinity have been engineered. a stable soluble ang-1 variant has anti-permeability activity [165] . when injected intraperitoneally in mice, human recombinant ang-1 can prevent lps-induced lung hyperpermeability [80] . in diabetic mice, a stable ang-1 derivative attenuated proteinuria and delayed renal failure [166] , and manipulating the ang-1/ang-2 ratio changed infarct size [167] . a more profound ang-1 effect can be achieved by locally stimulating ang-1 production. in experimental acute respiratory distress syndrome, transfected cells expressing ang-1 reduced alveolar inflammation and leakage [130] . an adenovirus construct encoding ang-1 protected mice from death in an lps model, and ang-1 gene therapy reduced acute lung injury in a rat model [21, 168, 169] . in hypertensive rats, a plasmid expressing a stable ang-1 protein reduced blood pressure and end-organ damage [170] . if used in a disease with a limited duration, as critical illness should be, virus/plasmid-driven production of ang-1 could easily be shut down when it is no longer needed. manipulating ang-2 activity is also difficult. ang-2 stored in wpbs is rapidly released and must be captured immediately to prevent autocrine/paracrine disruption of protective ang-1/ tie signalling. soluble tie2 or ang-2 inhibitors should be effective [26, 171] . neutralizing antibodies against ang-2 might also be an option. replenishment of ang-2 stores could be abolished by small interfering rna techniques or spiegelmer/aptamer approaches [25, 172, 173] . however, no bad guy is all bad, and no good guy is all good. for example, ang-1 has been linked to the development of pulmonary hypertension [174] . also, under certain circumstances ang-2 can act as a tie2 agonist and exert effects similar to those of ang-1 -an unexplained finding that illustrates our limited understanding of the ang/tie system [75] . complete blockade of ang-2 might also hamper innate immunity and revascularization. finding the right balance and timing will be the major challenge when developing therapies to target the ang/tie system. in the meantime, we might have already used ang/tie-directed therapy with the most pleiotropic of all drugs -corticosteroids. in the airways, steroids suppressed ang-2 and increased ang-1 expression [26, 171, 175] . interventions further downstream targeting specific adaptor molecules, signalling pathways, or transcription factors have yet to be explored. in patients with malignant disease, the ang/tie system might serve as a tumour or response marker. in patients with multiple myeloma, normalization of the ang-1/ang-2 ratio reflects a response to treatment with anti-angiogenesis medication [176] . in patients with non-small-cell lung cancer, ang-2 is increased in serum and indicates tumour progression [177] . after allogeneic stem cell transplantation in patients with high-risk myeloid malignancies, the serum ang-2 concentration predicts disease-free survival [178] , possibly reflecting a relation between cancer-driven angiogenesis and ang-2 serum level. in nonmalignant disease, the levels of ang/tie system components correlate with disease severity [28, 29, [34] [35] [36] [37] 39 ]. however, current data are insufficient to justify the use of serum soluble tie2/ang levels for diagnostic and prognostic purposes. in critical illness, assessment of the ang/tie system in patients with different severities of disease and with involvement of different organ systems might help to define our patient population and allow us to rethink our concepts of mods. in this way, such work may lead to enhanced diagnosis and prognostication in the future [2] . accumulating evidence from animal and human studies points to the involvement of the ang/tie system in vascular barrier dysfunction during critical illness. many processes in injury and in repair act through this nonredundant system. thus far, only preliminary studies in critically ill patients have been reported. methods to manipulate this system are available but have not been tested in such patients. the response to treatment is difficult to predict because of the pleiotropic functions of the ang/tie system, because the balance among its components appears to be more important than the absolute levels, and because the sensitivity of the endothelium to disease-related stimuli varies, depending on the environment and the organ involved. to avoid disappointment, further experimental and translational research must be carried out, and ang/tie modulation must not be introduced into the clinic prematurely. implementing the results of this research in critical care represents an opportunity to show what we have learned [2] . ang/tie signalling is a very promising target and must not be allowed to become lost in translation [179] . treating sepsis sepsis: rethinking the approach to clinical research multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation sir isaac newton, sepsis, sirs, and cars apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction nf-kappab links innate immunity to the hypoxic response through transcriptional regulation of hif-1alpha efficacy and safety of recombinant human activated protein c for severe sepsis effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering activation of tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization functional significance of tie2 signaling in the adult vasculature structure of the extracellular domain of tie receptor tyrosine kinases and localization of the angiopoietinbinding epitope protein tyrosine kinase structure and function tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling identification of tek/tie2 binding partners. binding to a multifunctional docking site mediates cell survival and migration identification of a soluble form of the angiopoietin receptor tie-2 released from endothelial cells and present in human blood vegf induces tie2 shedding via a phosphoinositide 3-kinase/akt dependent pathway to modulate tie2 signaling regulated proteolytic processing of tie1 modulates ligand responsiveness of the receptor-tyrosine kinase tie2 activation of the orphan endothelial receptor tie1 modifies tie2-mediated intracellular signaling and cell survival interaction between tie receptors modulates angiogenic activity of angiopoietin2 in endothelial progenitor cells. cardiovasc res functional symbiosis between endothelium and epithelial cells in glomeruli tie2 expression and phosphorylation in angiogenic and quiescent adult tissues endothelial/pericyte interactions the role of pericytes in blood-vessel formation and maintenance angiopoietins assemble distinct tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts formation and function of weibel-palade bodies the tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell weibel-palade bodies dynamics and plasticity of weibel-palade bodies in endothelial cells tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2 tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications localization of tie2 and phospholipase d in endothelial caveolae is involved in angiopoietin-1-induced mek/erk phosphorylation and migration in endothelial cells genomic structures of the human angiopoietins show polymorphism in angiopoietin-2 hypoxia and vascular endothelial growth factor selectively upregulate angiopoietin-2 in bovine microvascular endothelial cells regulation of angiopoietin-2 mrna levels in bovine microvascular endothelial cells by cytokines and hypoxia angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements transcriptional regulation of human angiopoietin-2 by transcription factor ets-1 internal translation initiation mediated by the angiogenic factor tie2 signaling mechanisms regulating endothelial permeability angiopoietin-1 requires p190 rhogap to protect against vascular leakage in vivo transcriptome of angiopoietin 1-activated human umbilical vein endothelial cells gene expression analysis of tek/tie2 signaling angiogenic actions of angiopoietin-1 require endothelium-derived nitric oxide mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion angiopoietin chemotactic activities on neutrophils are regulated by pi-3k activation angiopoietin-1 activates both anti-and proapoptotic mitogen-activated protein kinases signaling and regulation of endothelial cell survival by angiopoietin-2 angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3'-kinase/akt signal transduction pathway angiopoietins-1 and -2 are both capable of mediating endothelial paf synthesis: intracellular signalling pathways angiopoietin-1 promotes endothelial cell proliferation and migration through ap-1-dependent autocrine production of interleukin-8 angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor fkhr (foxo1) abin-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1 roles of reactive oxygen species in angiopoietin-1/tie-2 receptor signaling differential function of tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1 angiopoietin-2 displays vegfdependent modulation of capillary structure and endothelial cell survival in vivo differential response of lymphatic, venous and arterial endothelial cells to angiopoietin-1 and angiopoietin-2 biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of tie2 angiogenesis and inflammation face off innate immunity and angiogenesis transcriptional regulators of angiogenesis extracellular matrix mediates a molecular balance between vascular morphogenesis and regression the tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells contextual role for angiopoietins and tgfbeta1 in blood vessel stabilization angiopoietin-1 is an apoptosis survival factor for endothelial cells direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors angiopoietin-1 inhibits endothelial cell apoptosis via the akt/survivin pathway cyclic strain regulates the notch/cbf-1 signaling pathway in endothelial cells: role in angiogenic activity expression of tie-2 by human monocytes and their responses to angiopoietin-2 transcriptional and post-translation regulation of the tie1 receptor by fluid shear stress changes in vascular endothelial cells chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase tie2 obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch angiopoietin-2 causes inflammation in vivo by promoting vascular leakage expressional regulation of the angiopoietin-1 and -2 and the endothelial-specific receptor tyrosine kinase tie2 in adrenal atrophy: a study of adrenocorticotropin-induced repair angiopoietins: a link between angiogenesis and inflammation angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules angiopoietin-1 protects the adult vasculature against plasma leakage angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions angiopoietin-1 reduces vegf-stimulated leukocyte adhesion to endothelial cells by reducing icam-1, vcam-1, and e-selectin expression angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and il-8 production angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties angiopoietin-2 sensitizes endothelial cells to tnf-alpha and has a crucial role in the induction of inflammation hypoxia and vascular endothelial growth factor acutely up-regulate angiopoietin-1 and tie2 mrna in bovine retinal pericytes hypoxic regulation of angiopoietin-2 expression in endothelial cells regulation of angiopoietin expression by bacterial lipopolysaccharide angiogenic growth factors in the pathophysiology of a murine model of acute lung injury prevention of lps-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1 sequential induction of angiogenic growth factors by tnfalpha in choroidal endothelial cells tumor necrosis factoralpha upregulates angiopoietin-2 in human umbilical vein endothelial cells regulation of tie2 expression by angiopoietin-potential feedback system osteoprotegerin upregulates endothelial cell adhesion molecule response to tumor necrosis factor-alpha associated with induction of angiopoietin-2 angiopoietin-mediated endothelial p-selectin translocation: cell signaling mechanisms ang-2 and pdgf-bb cooperatively stimulate human peripheral blood monocyte fibrinolysis angiopoietins can directly activate endothelial cells and neutrophils to promote proinflammatory responses angiopoietin-1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins apoptotic signaling induces hyperpermeability following hemorrhagic shock alpha lipoic acid attenuates microvascular endothelial cell hyperpermeability by inhibiting the intrinsic apoptotic signaling trauma-hemorrhagic shock mesenteric lymph induces endothelial apoptosis that involves both caspase-dependent and caspase-independent mechanisms rho-kinase-dependent factin rearrangement is involved in the inhibition of pi3-kinase/akt during ischemia-reperfusion-induced endothelial cell apoptosis besides adhesion: new perspectives of integrin functions in angiogenesis. cardiovasc res direct cell adhesion to the angiopoietins mediated by integrins effects of protein and gene transfer of the angiopoietin-1 fibrinogen-like receptor-binding domain on endothelial and vessel organization the role of adherens junctions and ve-cadherin in the control of vascular permeability vegf receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells opposing effect of angiopoietin-1 on vegf-mediated disruption of endothelial cell-cell interactions requires activation of pkc beta angiopoietin-1 prevents vegfinduced endothelial permeability by sequestering src through mdia stable interaction between alpha5beta1 integrin and tie2 tyrosine kinase receptor regulates endothelial cell response to ang-1 elevated serum angiopoietin-2 correlates with degree of arteriosclerosis in ckd v patients emerging roles of the angiopoietin-tie and the ephrin-eph systems as regulators of cell trafficking endothelial immunogenicity: a matter of matrix microarchitecture vascular bed origin dictates flow pattern regulation of endothelial adhesion molecule expression angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation angiogenesis treatment, new concepts on the horizon inhibition of tie-2 signaling induces endothelial cell apoptosis, decreases akt signaling, and induces endothelial cell expression of the endogenous anti-angiogenic molecule, thrombospondin-1 kerbel rs: tumor angiogenesis coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization combined angiopoietin-1 and vascular endothelial growth factor gene transfer restores cavernous angiogenesis and erectile function in a rat model of hypercholesterolemia inhibitors of growth factor receptors, signaling pathways and angiogenesis as therapeutic molecular agents biomedical significance of endothelial cell specific growth factor, angiopoietin angiopoietin-2: modulator of vascular permeability in acute lung injury comp-ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity renoprotective effect of comp-angiopoietin-1 in db/db mice with type 2 diabetes critical role of angiopoietins/tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization protective role of angiopoietin-1 in endotoxic shock angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial tie2 receptor angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific rna aptamer therapeutic application of rnai: is mrna targeting finally ready for prime time? angiopoietin/tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension relationship between vascular endothelial growth factor and angiopoietin-2 in asthmatics before and after inhaled beclomethasone therapy normalization of the serum angiopoietin-1 to angiopoietin-2 ratio reflects response in refractory/resistant multiple myeloma patients treated with bortezomib serum angiopoietin-2 as a clinical marker for lung cancer angiopoietin-2 predicts disease-free survival after allogeneic stem cell transplantation in patients with high-risk myeloid malignancies the full cycle angiopoietin 2 is a potential mediator of high-dose interleukin 2-induced vascular leak angiopoietin-2 serum levels are elevated in patients with liver cirrhosis and hepatocellular carcinoma the author(s) declare that they have no competing interests. key: cord-030131-klhg7x8z authors: tan, dingyu; walline, joseph harold; ling, bingyu; xu, yan; sun, jiayan; wang, bingxia; shan, xueqin; wang, yunyun; cao, peng; zhu, qingcheng; geng, ping; xu, jun title: high-flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease patients after extubation: a multicenter, randomized controlled trial date: 2020-08-06 journal: crit care doi: 10.1186/s13054-020-03214-9 sha: doc_id: 30131 cord_uid: klhg7x8z background: high-flow nasal cannula (hfnc) oxygen therapy is being increasingly used to prevent post-extubation hypoxemic respiratory failure and reintubation. however, evidence to support the use of hfnc in chronic obstructive pulmonary disease (copd) patients with hypercapnic respiratory failure after extubation is limited. this study was conducted to test if hfnc is non-inferior to non-invasive ventilation (niv) in preventing post-extubation treatment failure in copd patients previously intubated for hypercapnic respiratory failure. methods: copd patients with hypercapnic respiratory failure who were already receiving invasive ventilation were randomized to hfnc or niv at extubation at two large tertiary academic teaching hospitals. the primary endpoint was treatment failure, defined as either resumption of invasive ventilation or switching to the other study treatment modality (niv for patients in the nfnc group or vice versa). results: ninety-six patients were randomly assigned to the hfnc group or niv group. after secondary exclusion, 44 patients in the hfnc group and 42 patients in the niv group were included in the analysis. the treatment failure rate in the hfnc group was 22.7% and 28.6% in the niv group—risk difference of − 5.8% (95% ci, − 23.8–12.4%, p = 0.535), which was significantly lower than the non-inferior margin of 9%. analysis of the causes of treatment failure showed that treatment intolerance in the hfnc group was significantly lower than that in the niv group, with a risk difference of − 50.0% (95% ci, − 74.6 to − 12.9%, p = 0.015). one hour after extubation, the mean respiratory rates of both groups were faster than their baseline levels before extubation (p < 0.050). twenty-four hours after extubation, the respiratory rate of the hfnc group had returned to baseline, but the niv group was still higher than the baseline. forty-eight hours after extubation, the respiratory rates of both groups were not significantly different from the baseline. the average number of daily airway care interventions in the niv group was 7 (5–9.3), which was significantly higher than 6 (4–7) times in the hfnc group (p = 0.006). the comfort score and incidence of nasal and facial skin breakdown of the hfnc group was also significantly better than that of the niv group [7 (6–8) vs 5 (4–7), p < 0.001] and [0 vs 9.6%, p = 0.027], respectively. conclusion: among copd patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of hfnc after extubation did not result in increased rates of treatment failure compared with niv. hfnc also had better tolerance and comfort than niv. trial registration: chictr.org (chictr1800018530). registered on 22 september 2018, http://www.chictr.org.cn/usercenter.aspx chronic obstructive pulmonary disease (copd) is one of the leading causes of death worldwide. acute hypercapnic respiratory failure is a common serious complication of copd, and invasive mechanical ventilation is often required for severe cases. longer durations of invasive mechanical ventilation will increase the incidence of ventilator-associated pneumonia and difficulty weaning off ventilation [1, 2] . multiple studies have shown that a sequential strategy with non-invasive ventilation (niv) using a pulmonary infection control (pic) window as the switching point can reduce the duration of invasive ventilation in copd patients and significantly improve prognosis [3, 4] . the success of niv is closely related to the experience and abilities of the treating medical staff, the level of education and compliance of patients, and the performance of the niv device [5, 6] . due primarily to poor patient tolerance, niv fails in approximately 15 to 25% of patients, potentially leading to endotracheal intubation [7] [8] [9] . for post-extubation patients with copd who cannot tolerate niv or have contraindications to niv, alternative respiratory support methods are urgently needed. high-flow nasal cannula (hfnc) oxygen therapy is a new type of respiratory support system which can supply high flow mixed gases through special nasal prongs at a sufficient temperature and humidity for patient comfort. many studies have confirmed that the comfort and tolerance of hfnc is significantly higher than that of niv [10] [11] [12] . as an alternative to niv, hfnc has been shown to be as efficacious as niv in preventing post-extubation respiratory failure or re-intubation in patients with hypoxemic respiratory failure [13, 14] . however, the postextubation application of hfnc in copd patients with hypercapnic respiratory failure has not been widely studied. in a pilot study, hfnc was reported to maintain similar patient vital signs and arterial blood gases as niv in post-extubated hypercapnic copd patients [15] . this trial was conducted to test the hypothesis that hfnc immediately after extubation is non-inferior to niv in reducing treatment failure in copd patients previously intubated for hypercapnic respiratory failure. this was a multicenter, unblinded, non-inferiority, randomized controlled trial, registered at chictr.org (chictr1800018530). from january 2019 to february 2020, the study was performed in the intensive care units (icus) of two large tertiary-care hospitals. this study was approved by the human subjects ethics committees of the two hospitals involved (2018ky-081 and 20180012), and informed consent was obtained from all enrolled patients or their relatives. copd patients with hypercapnic respiratory failure who received invasive ventilation were screened for enrollment. the diagnosis of copd was established according to the gold criteria [16] . other inclusion criteria included patients who were ≤ 85 years of age, able to care for themselves within the past year, respiratory failure induced by broncho-pulmonary infection, and meeting criteria of the pic window. exclusion criteria were age less than 18 years; lacking informed consent; contraindications to niv (oral or facial trauma, poor sputum excretion ability, hemodynamic instability); poor shortterm prognosis (high risk of death within7 days or receiving palliative treatment); heart, brain, liver, or kidney failure; tracheotomy; or a weak cough ability during the pic window. the following types of patients were secondarily excluded: withdrawn informed consent, loss to followup, uncertain 28-day survival, discharge from hospital within 48 h after enrollment, and patients who refused to use their assigned device. the settings of the enrolled patients' invasive mechanical ventilation were adjusted by the attending physician according to the patient's ventilation status and blood gas analysis. the patients were randomly divided into the hfnc group and the niv group when the pic window appeared. randomization was performed using a computer-generated random number generator, and allocation was concealed through an opaque envelope. these envelopes were kept in permuted blocks of ten, five each for niv and hfnc, to ensure an even distribution of subject numbers in both groups at both centers. all subjects receiving niv (philips v60 or bipap vision) were set in s/t mode with a standard oral-nasal (full-face) mask (rt040). niv settings were adjusted with an adaptive method: the initial expiratory pressure airway pressure was set to 4 cmh 2 o, and the pressure level was gradually increased to ensure that the patient could trigger the niv device with each inhalation. the inspiratory airway pressure was initially set to 8 cmh 2 o and gradually increased to achieve a satisfactory tidal volume with acceptable tolerance. the pressure level and the fraction of inspiration oxygen (fio 2 ) were adjusted to maintain a respiratory rate ≤ 28/min, a pulse oxygen saturation (spo 2 ) of 88-92%, and a partial pressure of arterial carbon dioxide (paco 2 ) of either 45-60 mmhg or the last paco 2 level recorded prior to extubation. subjects randomized to the hfnc group (airvo™ 2, fisher & paykel healthcare, auckland, new zealand) were given suitable large-bore nasal prongs selected according to the size of the patients' nostrils. the initial airflow was set at 50 l/min and adjusted according to patient tolerance. the hfnc was set to an absolute humidity of 44 mg h 2 o/l, temperature was set to 37°c, and fio 2 was adjusted to maintain an spo 2 of 88-92%. the patient's initial respiratory support was targeted to last at least 2 h and then continued as needed. nasal cannula oxygen was administered during any interruptions to niv. niv or hfnc were discontinued when the total daily treatment duration was less than 4 h and could be reused if needed. treatment success was defined as no need for respiratory support within 72 h after stopping niv or hfnc. the primary outcome was treatment failure, defined as a return to invasive mechanical ventilation, or a switch in respiratory support modality (i.e., changing from hfnc to niv or from niv to hfnc). secondary outcomes included arterial blood gas analysis [ph, pao 2 (partial pressure of oxygen in arterial blood), paco 2 , and fio 2 ] and vital signs such as respiratory rate, heart rate, and blood pressure at 1, 24, and 48 h after extubation, as well as the total duration of respiratory support after extubation, the daily number of nursing airway care interventions, the patients' comfort score, the patients' dyspnea score, the incidence of nasofacial skin breakdown, 28-day mortality, and total icu and hospital lengths of stay. airway care interventions were defined as the need for nursing staff to correct unplanned device displacement due to intolerance, discomfort, or another reason, or the need for nursing staff to assist in the removal or fixation of the device due to sputum, eating, or drinking. the patient's comfort score was assessed using a modified 10-cm visual analog scale, in which 1 meant very uncomfortable and 10 meant very comfortable [11] . the patients' dyspnea was evaluated with a borg rating scale [17] . the criteria for reintubation in this study were [18, 19] cardiac arrest or obvious hemodynamic instability, refractory hypoxemia (pao 2 < 50 mmhg with sufficient oxygen therapy), significant hypercapnia with ph ≤ 7.20, severe disturbances of consciousness such as coma, respiratory depression (respiratory frequency < 8/min), or severe dyspnea (respiratory frequency > 40/min). based on previous studies [20, 21] , we estimated that niv would fail in 22% patients (either intubation or intolerance) of included copd patients, and the absolute difference of treatment failure rates between hfnc and niv was likely to fall between 4 and 12% [14] . after discussions with three senior pulmonologists, we set the non-inferiority cutoff at 9%. to assess non-inferiority using an α = 0.50, β = 0.20, and 1-sided testing, 44 subjects were needed in each group (88 total). for the primary outcome, analysis was performed both on an intention-to-treat and on a per-protocol basis. the kaplan-meier method was used to draw the cumulative survival and failure curves. the kolmogorov-smirnov test was used to test the normal distribution for measurement data. normally distributed data were expressed as means ± standard deviation, and the skewed distributed data was reported as medians with interquartile (25th-75th) percentiles. the two groups were compared using t tests or mann-whitney u tests. numeric data were expressed as a percentage (%), using χ 2 or fisher's exact probability tests. the comparison of vital signs and blood gas analyses at multiple time points was performed by repeated measures analysis of variance, or non-parametric test of multiple correlated samples (friedman test for heterogeneity of variance or the skewed distributed data), in which the significance level was adjusted using the bonferroni correction method. all data analysis was conducted using spss 26.0 (ibm corporation, armonk, ny, usa). among 149 copd patients who received invasive ventilation in our enrolling centers during the study period, 96 (64.4%) patients were randomized to the niv or hfnc groups after 53 patients were excluded for various reasons (see fig. 1 ). six patients in the niv group and four patients in the hfnc group were secondarily excluded. finally, 42 patients in the niv group and 44 patients in the hfnc group were included in the analysis. demographic, relevant comorbidities, smoking history, copd medications, respiratory therapy at home, available pulmonary function tests, the simplified acute physiology score ii (saps ii), and the acute physiological and chronic health status score ii (apache ii) at admission in the two groups were similar (see table 1 ). seventeen (38.6%) patients in the hfnc group and 18 (42.9%) in the niv group initially received niv or hfnc after admission before invasive ventilation, and the remaining patients received invasive ventilation directly. there were also no significant differences in respiratory parameters, blood gas analyses, and vital signs between the two groups at the time of enrollment (pic window before extubation). the stable fio 2 after extubation in the hfnc group was 0.32 (0.28-0.38), which was not significantly different from 0.35 (0.30-0.40) in the niv group. treatment failure occurred in 10 patients (22.7%) in the hfnc group and 12 patients (28.6%) in the niv group (risk difference, − 5.8%; 95% ci, − 23.8 to 12.4%; see table 2 ). additionally, kaplan-meier curves showed no statistical difference in cumulative failure rates between the two groups (log-rank test 0.521, p = 0.470, see fig. 2 ). among the patients with treatment failure, the intubation rate in the hfnc group was similar to that of the niv group (− 0.65%; 95% ci, − 16.01 to 14.46%), and the treatment switch rate was lower than that in the niv group (− 5.2%; 95% ci, − 19.82 to 9.05%). however, there were no significant differences between the two groups in intubation or treatment switch rate. analysis of the causes of treatment failure showed that treatment intolerance was significantly lower in the hfnc group than in the niv group, with a risk difference of − 50.0% (95% ci, − 74.6 to − 12.9%, p = 0.015, see table 2 ). there was no significant difference between the two groups in exacerbated respiratory distress, hypoxemia, or carbon dioxide retention. the causes for six intolerances in the niv group were feelings of data are shown as means ± standard deviation, number (%) patients, or median (interquartile range) hfnc high-flow nasal cannula oxygen therapy, niv non-invasive ventilation, copd chronic obstructive pulmonary disease, nco nasal cannula oxygen, icu intensive care unit, apache ii acute physiology and chronic health evaluation ii, saps ii simplified acute physiology score ii, imv invasive mechanical ventilation, pic pulmonary infection control, peep positive end expiratory pressure, paco 2 partial pressure of arterial carbon dioxide, pao 2 partial pressure of arterial oxygen, fio 2 fraction of inspiration oxygen *twenty-five cases in the hfnc group and 27 cases in the niv group claustrophobia (n = 2), excessive air flow or pressure (n = 2), breathlessness (n = 1), and headache (n = 1). heart rate and mean arterial pressure within 48 h after extubation in the two groups were not significantly different from baseline levels before extubation. respiratory rate in both groups was faster than before extubation at 1 h after extubation (p < 0.050, see table 3 ). the respiratory rate 24 h after extubation in the hfnc group had decreased to its baseline and was lower than the respiratory rate in the niv group [20 (17.3-24.5)/min vs 24.5 (18-27)/min, p < 0.050]. the niv group's respiratory rate was also higher than its baseline level. there was no significant difference in respiratory rate between the two groups at 48 h after extubation. arterial blood gas analyses showed that the pao 2 /fio 2 and ph values in the hfnc group were lower than their baseline levels, while paco 2 was higher than the baseline level 1 h after extubation (all p < 0.050, see table 3 ). the pao 2 /fio 2 , ph, and paco 2 in the hfnc and niv groups 24 h and 48 h after extubation were not statistically different from the baseline levels. there were no significant differences in the duration of post-extubation respiratory support, dyspnea scores, icu, or hospital total lengths of stay between the two groups (all p < 0.050, see table 4 ). the 28-day mortality in the hfnc group was 15.9%, which was not significantly different from the 11.9% in the niv group (logrank test 0.288, p = 0.591, see fig. 3 ). the number of daily airway care interventions was significantly lower in the hfnc group than in the niv group [6 (4-7) vs 7 (5-9.3), p = 0.006]. the comfort score in the hfnc group was also significantly higher than that in the niv group [7 (6-8) vs 5 (4-7), p < 0.001], whereas the incidence of nasofacial skin breakdown was significantly lower in the hfnc group than in the niv group (0 vs 9.6%, p = 0.027). this multicenter, randomized controlled trial showed that hfnc was not inferior to niv at preventing postextubation treatment failure and re-intubation for copd patients recently extubated after hypercapnic respiratory failure. compared with niv, hfnc was more comfortable and better tolerated. the number of airway care interventions and the incidence of nasofacial skin breakdown associated with hfnc were significantly lower than in niv. hfnc appears to be an effective means of respiratory support for copd patients extubated after severe hypercapnic respiratory failure. invasive ventilation is sometimes necessary to rescue copd patients with severe hypercapnic respiratory failure. weaning strategies which include niv are recommended as the standard treatment to reduce rates of ventilator-associated pneumonia and mortality without increasing the risk of re-intubation or weaning failure [22] . however, niv intolerance appears in more than 15% patients due to various reasons, which increases the risk of treatment failure and re-intubation [23, 24] . like in this study, many others have found that hfnc is often better tolerated than niv, but data on copd patients so far has been limited. hfnc has been increasingly suggested for use in patients with copd with acute hypercapnic respiratory failure. bräunlich et al. reported that in 38 patients with an acute exacerbation of copd and a ph of less than 7.38, hfnc increased the ph by 0.052 and reduced carbon dioxide by 9.1 mmhg [25] . in a prospective observational study involving 30 patients with moderate hypercapnic respiratory failure who were intolerant to niv, patients' ph improved and respiratory rate decreased with hfnc treatment, and the non-response rate to hfnc was only 13.3% [26] . subsequently, two cohort studies with larger samples showed that for copd patients with acute moderate hypercapnic respiratory failure, similar tracheal intubation and mortality rates were observed between hfnc and niv, while hfnc was better tolerated [27, 28] . other efforts to observe the efficacy of hfnc in copd patients after invasive ventilation have been limited. in a cross-over study comparing hfnc to conventional low-flow oxygen therapy, hfnc was found to significantly decrease post-extubation work of breathing and neuroventilatory drive in copd patients recovering from acute hypercapnic respiratory failure [29] . in a small randomized controlled trial, hypercapnic copd patients received either hfnc or niv immediately after extubation [15] . at 3 and 24 h after extubation, the ph in the hfnc group was higher than niv group. no significant differences of vital signs and arterial blood gases were found at 48 h after extubation. unlike in the above study, the respiratory rate in both groups of our study increased at 1 h after extubation, which may be related to the relatively lower intensity of respiratory support after extubation. the respiratory rate in the hfnc group decreased to its baseline level 24 h after extubation, while the respiratory rate in the niv group was still high at 24 h. this can be explained by the relatively poor tolerance of niv and the increase in effective alveolar ventilation caused by the washout effect of dead space in hfnc. one hour after extubation, the ph in the hfnc group of this study decreased and the paco 2 increased, while the niv group had no significant change from its baseline level. the difference between the two groups may be because hfnc does not have the added pressure support of niv, resulting in decreased ventilation and oxygenation. however, the excellent tolerance and increased effective alveolar ventilation gradually made up for the above deficiencies, so that there was no significant difference in blood gas values between the two groups at 24 and 48 h after extubation. to the best of our knowledge, this is the first randomized controlled trial to compare the failure rate of hfnc and niv in patients with copd after invasive ventilation. treatment failure in this study was defined as reintubation or switch to the other treatment modality. although the latter criterion added an element of patient subjectivity to the definition, this composite end-point reflects the pragmatic application of hfnc or niv in everyday clinical practice [30] . analysis of the causes of treatment failure in this study showed that treatment intolerance was significantly higher in the niv group than in the hfnc group, suggesting that poor tolerance is an important reason for the failure of niv treatment. doshi et al. also found that 29% of niv failures were attributed to treatment intolerance, which was significantly higher than the 4% rate of hfnc [31] . hfnc's design does not lead to a sense of claustrophobia, which significantly improves compliance. at the same time, the heating and humidifying function of hfnc enables the gas delivered to reach an absolute humidity of 44 mg h 2 o/l and a temperature of 37°c, which effectively promotes the discharge of secretions while avoiding side effects such as dry mucous membranes [32] . because of these characteristics, patients can easily tolerate a gas flow rate of up to 50-60 l/min. the better tolerance of hfnc over niv is clearly seen in comparing the comfort scores between the two groups. the number of airway care interventions and cases of nasofacial skin breakdown in the hfnc group were also significantly lower than those in the niv group, which was related to the hfnc nasal plug design and better comfort. due to intolerance, drinking and eating, sputum clearance, communication, discomfort, or displacement of the niv mask, niv patients frequently remove their masks and significantly increase the nursing workload [28] . patients in the hfnc group were not restricted by respiratory support in eating, drinking, and communicating. the incidence of skin breakdown and displacement of nasal prongs was extremely low. there were some limitations to this study. first, the primary endpoint of this study was a composite of reintubation rate and switching to the other treatment modality, which has potential limitations described above. as for the re-intubation rate, the possibility of obtaining a positive result by increasing the sample size cannot be ruled out. second, the settings for the hfnc gas flow in this study were based on each patient's tolerance level, which is subjective. in subsequent studies, the hfnc gas flow could be titrated through diaphragmatic potential or ultrasound assessment of diaphragmatic muscle movement for better standardization. finally, attending physicians could not be blinded to the study group since the devices were clearly different. however, investigators were excluded from clinical decisions and randomization was employed to help reduce bias. among copd patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of hfnc as compared with niv after extubation did not result in increased rates of treatment failure, while hfnc had better tolerance and comfort. these findings support the use of hfnc in such patients, especially for those who cannot tolerate niv. abbreviations copd: chronic obstructive pulmonary disease; niv: non-invasive ventilation; hfnc: high-flow nasal cannula oxygen therapy; pic: pulmonary infection control; icu: intensive care unit; apache ii: acute physiological and chronic health status score ii; saps ii: simplified acute physiology score ii; paco 2 : partial pressure of arterial carbon dioxide; pao 2 : partial pressure of arterial oxygen; fio 2 : fraction of inspired oxygen weaning from mechanical ventilation the attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. the canadian critical trials group efficacy of two noninvasive weaning strategies in intubated patients with chronic obstructive pulmonary disease: a meta-analysis and indirect treatment comparison pulmonary infection control window as a switching point for sequential ventilation in the treatment of copd patients: a metaanalysis practical insight to monitor home niv in copd patients causes of failure of noninvasive mechanical ventilation evolution of mechanical ventilation in response to clinical research complications of noninvasive ventilation in acute care a multicenter randomized trial assessing the efficacy of helium/oxygen in severe exacerbations of chronic obstructive pulmonary disease high-flow oxygen through nasal cannula in 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with copd? global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. gold executive summary non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: cochrane systematic review and meta-analysis collaborating research group for noninvasive mechanical ventilation of chinese respiratory, s. pulmonary infection control window in treatment of severe respiratory failure of chronic obstructive pulmonary diseases: a prospective, randomized controlled, multi-centred study non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease noninvasive ventilation intolerance: characteristics, predictors, and outcomes treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial nasal high-flow in acute hypercapnic exacerbation of copd efficacy and safety of high-flow nasal cannula oxygen therapy in moderate acute hypercapnic respiratory failure. rev bras ter intensiva high flow nasal cannulae oxygen therapy in acute-moderate hypercapnic respiratory failure high flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease with acute-moderate hypercapnic respiratory failure: an observational cohort study high-flow nasal cannula oxygen therapy decreases postextubation neuroventilatory drive and work of breathing in patients with chronic obstructive pulmonary disease high-flow nasal oxygen vs noninvasive positive airway pressure in hypoxemic patients after cardiothoracic surgery: a randomized clinical trial high-velocity nasal insufflation in the treatment of respiratory failure: a randomized clinical trial high-flow nasal cannula oxygen therapy in adults: physiological benefits, indication, clinical benefits, and adverse effects publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. the datasets used and analyzed during the current study are available from the corresponding author in response to reasonable requests. this study was approved by the human subjects ethics committees of the two hospitals involved (2018ky-081 and 20180012), and informed consent was obtained from all enrolled patients or their relatives. not applicable. the authors declare that they have no competing interests. key: cord-028835-jby1btv7 authors: rilinger, jonathan; zotzmann, viviane; bemtgen, xavier; schumacher, carin; biever, paul m.; duerschmied, daniel; kaier, klaus; stachon, peter; von zur mühlen, constantin; zehender, manfred; bode, christoph; staudacher, dawid l.; wengenmayer, tobias title: prone positioning in severe ards requiring extracorporeal membrane oxygenation date: 2020-07-08 journal: crit care doi: 10.1186/s13054-020-03110-2 sha: doc_id: 28835 cord_uid: jby1btv7 background: prone positioning (pp) has shown to improve survival in patients with severe acute respiratory distress syndrome (ards). to this point, it is unclear if pp is also beneficial for ards patients treated with veno-venous extracorporeal membrane oxygenation (vv ecmo) support. methods: we report retrospective data of a single-centre registry of patients with severe ards requiring vv ecmo support between october 2010 and may 2018. patients were allocated to the pp group if pp was performed during vv ecmo treatment or the supine positioning group. vv ecmo weaning success and hospital survival were analysed before and after propensity score matching. results: a total of 158 patients could be analysed, and 38 patients (24.1%) received pp. there were no significant differences in vv ecmo weaning rate (47.4% vs. 46.7%, p = 0.94) and hospital survival (36.8% vs. 36.7%, p = 0.98) between the prone and supine groups, respectively. the analysis of 38 propensity score matched pairs also showed no difference in hospital survival (36.8% vs. 36.8%, p = 1.0) or vv ecmo weaning rate (47.4% vs. 44.7%, p = 0.82). hospital survival was superior in the subgroup of patients treated with early pp (cutoff < 17 h via youden’s index) as compared to late or no pp (81.8% vs. 33.3%, p = 0.02). conclusion: in this propensity score matched cohort of severe ards patients requiring vv ecmo support, prone positioning at any time was not associated with improved weaning or survival. however, early initiation of prone positioning was linked to a significant reduction of hospital mortality. in case of severe acute respiratory distress syndrome (ards), veno-venous extracorporeal membrane oxygenation (vv ecmo) support may be considered when lung-protective mechanical ventilation is not able to prevent hypoxia or hypercapnia [1] [2] [3] . nevertheless, mortality of severe ards remains high-even with ecmo support. the eolia trial for instance showed a mortality rate of 35% in patients treated with ecmo compared to 46% in patients without ecmo support in very severe ards [2] . moreover, several studies showed that prone positioning (pp) is able to improve survival in these critically ill patients [4, 5] . pp provides various positive effects on oxygenation and lung compliance [6, 7] . furthermore, pp can reduce ventilator-induced lung injury [8] and is associated with less days on mechanical ventilation (mv) and shorter length of intensive care unit (icu) stay [5] . hence, pp might be beneficial for patients receiving ecmo support. it has been demonstrated that pp can be performed safely [9] [10] [11] [12] [13] during ecmo support and improves oxygenation and lung compliance [14] . so far, there is little evidence about the outcome of these patients. we performed a retrospective analysis of ards patients treated with pp during ecmo support at our centre. we report retrospective data of a single-centre registry of patients with severe ards treated with vv ecmo. all patients treated at the interdisciplinary medical intensive care unit at the medical centre, university of freiburg, germany, between october 2010 and may 2018 were registered. patient identity data derived from the registry were blinded, and the study plan was approved by the local ethics committee (ek-freiburg 151/14). all patients suffered from severe ards. vv ecmo support was initiated in cases of severe hypoxic respiratory failure or co 2 retention despite of mechanical ventilation as suggested by the elso guidelines. patients receiving pp during ecmo support were allocated to the prone group, whereas the remaining patients formed the supine group. pp before initiation of ecmo support did not influence the allocation of patients in one or the other group. primary endpoints were successful ecmo weaning, and icu and hospital survival. successful ecmo weaning was defined as being free from ecmo and alive for at least 48 h after decannulation. unsuccessful weaning was defined as the inability to explant the ecmo device because of persistent respiratory failure or death during ecmo support and the need for recannulation within 48 h. moreover, ventilator settings of the first 10 days after ecmo initiation were analysed. to compare the patients' disease severity, the resp [15] , sofa [16] , and apache ii scores [17] as well as the horowitz index (pao 2 /fio 2 ) were analysed. our institution features a 24/7 ecmo centre localised within a tertiary hospital with a 30-bed medical intensive care unit. cannulations in our ecmo centre are performed by two experienced intensivists and a perfusionist in seldinger's technique without primary surgical cut down. all member of the ecmo team can be gathered within 30 min. typical numbers for veno-arterial and veno-venous cannulations are 65 and 35 per year, respectively. there is a 24 h/7 days outreach team. for this research, only in-house cases were considered. as ecmo system, either scpc (sorin centrifugal pump console, livanova, london, uk) or cardiohelp (maquet getlinge group, rastatt, germany) was used. cannulation was predominantly performed with dual-lumen cannula (avalon, maquet, rastatt, germany). for patients without life-threatening bleeding, anticoagulation was provided by intravenous unfractionated heparin aiming at a partial thromboplastin time 1.5 times upper normal limit. the management of vasopressors and fluid therapy was driven by clinical judgement of the ecmo experienced intensivist in charge and has been reported earlier [18] . treatment algorithms and standard operating procedures were subject to optimizations during the observational period, reflecting current state-of-the-art recommendations and scientific knowledge. controlled mv mode used at our institution mostly was biphasic positive airway pressure (bipap). in few patients, airway pressure release ventilation (aprv) was used, when considered beneficial. vv ecmo support was implemented in case of severe but potentially reversible respiratory failure, when lung-protective mv resulted in hypoxemia or hypercapnia. lung-protective mv was defined as positive end expiratory pressure (peep) ≤ 15 cmh 2 o, plateau pressure ≤ 30 cmh 2 o, driving pressure ≤ 15 cmh 2 o, and fio 2 ≤ 50%. cannulation was performed predominately jugulary using a duallumen cannula. after initiation of the vv ecmo support, invasivity of mv was reduced and ecmo flow was adjusted aiming for a peripheral oxygen saturation of 85-90% and partial pressure arterial oxygen of approximately 50 mmhg, respectively. typical ventilator settings were as follows: peep 15 cmh 2 o, plateau pressure 25 cmh 2 o, fio 2 50%, and respiratory rate 10/min. indications and performance of prone positioning during ecmo support ards treatment was carried out according to the currently valid guidelines [19] . the decision on whether to perform pp in the individual case lays with the treating medical team's judgement. prone positioning was done face down. sedation for pp patients at our institution was titrated to preserve spontaneous breathing if possible. neuromuscular blockade was not given on a routine basis for executing pp. however, in individual cases, especially in cases of strong respiratory drive and concerns about a self-inflicted lung injury [20] , neuromuscular blocking agents were used. summary results for categorical variables are presented as frequency and percentage. results for numeric variables are presented as median with interquartile range (iqr). fisher's exact test and pearson's chisquared test were used for analysing nominal variables. in dependence of normal distribution, student's t test or mann-whitney u test was performed for continuous variables. multivariate regression analysis was performed for univariate (dependent) predictors of hospital survival. results are given as odds ratio [(or), 95% confidence interval (ci)], and a p value of ≤ 0.05 was considered statistically significant. roc analysis and youden's index (youden's index = sensitivity + specificity − 1) were used for reaching the optimal cutoff of survival-associated factors with highest discrimination of sensitivity and specificity. propensity score matching was performed using spss with a nearest neighbour matching algorithm using a calliper of 0.01. matching was performed for age, sex, sofa score, the duration of mv before ecmo, and performance of prior pp before ecmo. cumulative incidences of 60-day mortality were calculated using competing risk regression (fine and gray method) with discharge alive considered a competing event [21] . statistical calculations were performed using ibm spss statistics 25.0 (armonk, ny: ibm corp, 2017). a total of 158 patients with complete medical data could be analysed (age 54.5 (41.8-64.0) years, 67% male). the collective showed a relatively high rate of comorbidities, and this was especially true for immunosuppression (36%, table 1) . thirty-eight patients (24.1%) received pp during ecmo therapy. no relevant complications (e.g. decannulation) occurred during the positioning procedures. patients with pp during ecmo support had a higher rate of pre-existing chronic renal failure and pneumoniainduced ards. patients in the prone group displayed a different pulmonary pathogen spectrum (more viral and fungal infections, especially pneumocystis jirovecii, table 1 ). survival prediction scores (sofa, apache ii, and resp) did not differ between both groups. pp before ecmo initiation was performed in 16.5% of the patients in both groups. on average, the first pp during ecmo support was performed after 1.7 (0.5-5.0) days on ecmo support, with 2.0 (1.0-3.0) pp manoeuvres performed per patient. average pp duration was 19.5 (16.8-20.8 ) h (additional file 1, table e1). patients with pp during ecmo support showed higher peep levels from day 4 and higher plateau pressures from day 4 to 8 (additional file 1, figure e1 ). there was no difference in driving pressures as well as in tidal volumes. however, patients with pp during ecmo support showed less spontaneous breathing on day 5 and day 8 to 10. there were no differences in ecmo weaning rate (47.4% vs. 46.7%, p = 0.940), and icu or hospital survival (36.8% vs. 36.7%, respectively, p = 0.984) between the prone and the supine groups (table 2) . cumulative incidences of 60-day in-hospital death were 55% and 64% for the prone and supine groups, respectively (p = 0.207, fig. 1 ). thirty-eight propensity score matched pairs (76 patients) with similar baseline characteristics could be analysed (fig. 2 , see also additional file 1, table e2). successful ecmo weaning rate was 47.4% vs. 44.7% (p = 0.818) in patients with and without pp during ecmo support, respectively. furthermore, there was no difference in survival between both groups (36.8% vs. 36.8%, p = 1.0). cumulative incidences of 60-day in-hospital death were 58% and 65% for the prone and supine groups, respectively (p = 0.482, additional file 1, figure e1 ). underlying lung fibrosis, status of immunosuppression, and aspiration were associated with death, whereas proof of bacterial infections was associated with survival (table 3) . moreover, a high proportion of spontaneous breathing in the first 10 days was strongly associated with survival. in multivariate analysis, only underlying lung fibrosis (odds ratio 0.15 [95% ci 0.0-0.7]) and a high proportion of spontaneous breathing in the first 10 days (odds ratio 20.0 [95% ci 5.4-73.5]) were independent predictors for death and survival, respectively. in patients with pp, higher age, acute renal failure, and underlying pulmonary disease were associated with death. proof of pulmonary bacterial infection and timing of the first pp after ecmo initiation were associated with survival in a univariate analysis (additional file 1, table e4). in a multivariate analysis, only early initiation of pp (< 17 h) was associated with survival (odds ratio 20.6 [95% ci 1.4-312.9], fig. 3 ). optimal cutoff value for duration from ecmo initiation to first pp was calculated using roc analysis (auc = 0.789) and youden's index. highest sensitivity and specificity for beneficial survival were achieved for initiation of pp in < 17 h. next to this optimal cutoff, a clinical cutoff of 1 day (24 h) also was associated with improved survival (p = 0.005). patients treated with early pp during ecmo (n = 11) showed a superior survival to patients treated with late pp or without pp during ecmo support (81.8% vs. 33.3%). cumulative incidences of 60-day in-hospital death were 18% for the early pp group and 65% for the late and no pp group, respectively (p = 0.027, fig. 4) . also, in a separate comparison of patients with late pp as well as patients without pp, early pp showed superior survival rates (81.8% vs. 18.5% and 36.7%, p < 0.001 and p = 0.003, respectively). patients in the early pp group were younger than patients with late or without pp during ecmo support (40.0 vs. 56.0 years, p = 0.004). the groups did not differ concerning vasoactive support or in sofa and apac he ii scores at the time of ecmo implantation. moreover, there was no difference in the sofa score between both groups in the first 3 days (additional file 1, table e8). the resp score of the patients with early pp was higher (2.0 (1.0-6.0) vs. 0 (− 2.0-2.0), p = 0.025, additional file 1, table e5). the resp score without including age was 3 (2.0-6.0) vs. 2 (0-4.0), p = 0.096). prone positioning has shown to improve survival in non-ecmo ards patients [5] . there is sparse data on pp in ards patients with vv ecmo support. we therefore retrospectively analysed a large cohort of ecmo patients suffering from severe ards treated with or without pp at our centre. our results do not indicate an overall survival benefit for pp during ecmo support per se. however, timing of pp may be crucial when designing future studies. in comparison to previous pp studies, technical execution of pp in this analysis showed favourable characteristics. beginning of pp after ecmo initiation was earlier than in other studies (1.7 vs. 6 or 9 days, respectively) [6, 10] . moreover, the average duration of each performed pp was longer (19.5 h) and more pp manoeuvres were performed per patient (2.0) than described before [10, 11, 22] . this is especially important, as the survival benefit for pp in ards without ecmo support shown by guerin et al. was achieved with long pp periods (17 h) [5] . patients treated with pp in our patient collective showed increased peep and plateau pressure levels but still remained in the recommended limits of the elso guideline [3] . as intended by the treating medical team, driving pressure was kept below 15 cmh 2 o, as high driving pressures are strongly associated with increased mortality [23] . furthermore, no differences in driving pressure were found between both groups. patients with pp during ecmo showed a reduced rate of spontaneous breathing compared to patients without pp, despite the fact that neuromuscular blocking agents were not used on a routine basis during pp periods. however, it seems reasonable that pp patients might have been on deeper sedation levels than patients in the supine group. in contrast to this, the elso guidelines recommend an early reduction of sedation levels and a switch to spontaneous breathing after 24 to 48 h after ecmo initiation [3] . furthermore, low proportions of spontaneous breathing episodes were associated with a higher mortality. however, this only allows hypothesis generating, since causality between a reduced rate of spontaneous breathing and increased mortality cannot be proven in this analysis and could also be an expression of higher disease severity. nevertheless, the reduced rate of spontaneous breathing in patients with pp should be considered in the discussion of benefits and disadvantages of this additional treatment. our results are in contrast to the study of guervilly et al. their retrospective study of additional pp showed an encouraging survival benefit [24] . survival rate in the pp group was markedly higher than in the supine group (30-day survival 71% vs. 43%). in terms of age, sex, and pp manoeuvres performed per patient, the cohort of guervilly et al. and our patients did not differ. however, our patients were sicker than those of guervilly and coworkers (predicted mortality by sofa score approx. 55% vs. 35% [16] ) and showed a much lower rate of fig. 1 in-hospital death of ecmo patients with vs. without prone positioning during ecmo. the fine-gray model for in-hospital death (shr 0.77, p = 0.21, cumulative incidence of 60-day death 55% vs. 64%). ecmo, extracorporeal membrane oxygenation fig. 2 propensity score matched pair patient assignment. *matching was performed for age, sex, sofa score, the duration of mv before ecmo, and performance of prior pp before ecmo. ecmo, extracorporeal membrane oxygenation; mv, mechanical ventilation; pp, prone positioning; sofa, sequential organ failure assessment prior pp before ecmo (17% vs. 64%). furthermore, guervilly et al. reported deep sedation and routine use of neuromuscular blocking agents during pp which is in contrast to our approach. to compare our findings with those from guervilly et al., we used the same matching parameters for propensity score matching, which did not alter our findings. timing of pp was an independent predictor of survival in our cohort. early initiation of pp after ecmo cannulation was strongly associated with improved survival. a beginning of pp in less than 1 day (cutoff < 17 h via youden's index) in comparison to late or no pp showed a strong survival benefit (82% vs. 33%). this finding is in line with the study protocol of the proseva trial [5] , where the survival benefit for pp in non-ecmo ards patients was achieved with an early beginning of pp (initiated in average 36 h after beginning of mechanical ventilation). this association suggests that an early beginning of pp after initiation of ecmo support could be an important factor for survival, which requires further investigation. because of the retrospective design of this study, the reasons why patients were treated with pp or not, or received early or late pp, cannot be pinned down. patients receiving early pp were younger, but they did not differ in terms of haemodynamic stability and showed no difference regarding the sofa and apache ii scores. patients of the early pp group showed a higher resp score (2.0 vs. 0), indicating a certain difference in predicted mortality rate (35% vs. 50%). nevertheless, the factor age could have influenced the team's decisionmaking for or against early pp. interestingly, in the early pp group, in contrast to the whole pp group, a higher rate of spontaneous breathing within the first 10 days was observed (not significant), which could be one factor that may improve survival rate for early pp. from a theoretical standpoint, there are many positive effects of additional pp in patients receiving ecmo support, like improving oxygenation and lung compliance as well as reducing ventilator-induced lung injury [6] [7] [8] . in clinical practice, patient-safety concerns often prevent prone positioning during ecmo therapy, even though feasibility and safety have been demonstrated in several studies. in this retrospective analysis, pp at any time was not associated with improved survival per se. however, our results indicate that a very early initiation of pp therapy (within 1 day after cannulation) could be beneficial. no complications related to pp were detected. in consideration of the retrospective design of this study, we think that a randomised controlled trial is imperatively needed for further evaluation of pp in ecmo patients. considering the pros and cons of a pp therapy, pp should not be withheld from ards patients requiring ecmo support. our data suggest that pp should be initiated very early in the clinical course. this is a retrospective observational study and therefore contains the risk of selection and reporting bias. another limitation is the small sample size of only 38 patients with pp and 76 patients in the matched pair analysis, respectively. moreover, this is a single-centre report and specific processes may influence the presented results. the same internal standard operating procedures applied to the entire treating physician team. however, the indication for performing pp during ecmo support was on basis of the treating ecmo physician and therefore was not standardised. despite using propensity score matching for outcome analysis, this among other factors might be remaining confounders that we did not control for. together, due to these limitations, our findings should be considered as hypothesis generating and should not prompt clinical decision-making. this retrospective analysis did not reveal an overall survival benefit associated with pp in patients with ards requiring ecmo support. however, a subgroup analysis suggested that early initiation of pp may improve survival and should be considered in the design of a randomised controlled trial for further evaluation. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03110-2. efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal membrane oxygenation for severe acute respiratory distress syndrome guidelines for adult respiratory failure effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis prone positioning in severe acute respiratory distress syndrome prolonged prone positioning under vv-ecmo is safe and improves oxygenation and respiratory compliance the effect of prone positioning in acute respiratory distress syndrome or acute lung injury: a meta-analysis. areas of uncertainty and recommendations for research prone position augments recruitment and prevents alveolar overinflation in acute lung injury complications of prone positioning during extracorporeal membrane oxygenation for respiratory failure: a systematic review prone positioning during veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in adults application of prone position in hypoxaemic patients supported by veno-venous ecmo prone positioning use to hasten veno-venous ecmo weaning in ards prone position during ecmo is safe and improves oxygenation combination of positioning therapy and venovenous extracorporeal membrane oxygenation in ards patients predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score prognostic accuracy of the sofa score, sirs criteria, and qsofa score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit apache ii: a severity of disease classification system early fluid resuscitation and volume therapy in venoarterial extracorporeal membrane oxygenation deutsche gesellschaft für anästhesiologie und intensivmedizin (dgai). s3-leitlinie -invasive beatmung und einsatz extrakorporaler verfahren bei akuter respiratorischer insuffizienz. 1. auflage mechanical ventilation to minimize progression of lung injury in acute respiratory failure a proportional hazards model for the subdistribution of a competing risk effect of prone positioning on cannula function and impaired oxygenation during extracorporeal circulation driving pressure and survival in the acute respiratory distress syndrome prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. authors' contributions jr and tw contributed to the conception of the study; jr, cs, and tw contributed to the data collection; jr, vz, xb, pmb, dd, kk, ps, cm, mz, cb, dls, and tw contributed to the data analysis and interpretation; jr and tw drafted the manuscript; vz, xb, pmb, dd, kk, ps, cm, mz, cb, and dls revised the manuscript for important intellectual content. all authors approved the final version of the manuscript. none. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. not applicable. the authors declare that they have no competing interests.author details 1 key: cord-263568-ea3k2i69 authors: price, elizabeth title: could the severity of covid-19 be increased by low gastric acidity? date: 2020-07-22 journal: crit care doi: 10.1186/s13054-020-03182-0 sha: doc_id: 263568 cord_uid: ea3k2i69 nan could the severity of covid-19 be increased by low gastric acidity? could low gastric acidity increase the risk of a severe covid-19 illness? although it is primarily a respiratory infection, gastrointestinal involvement from swallowed coronaviruses is reported for sars-cov-2 (the virus of covid-19 [1, 2] ), as well as sars-cov-1 [3] and mers-cov viruses [4] . the gastrointestinal tract may be a secondary route for spread to the lungs and other parts of the body. a possible hypothesis might be that the upper respiratory tract is attacked by viruses which are breathed in and coughed up in sputum while the lower respiratory tract is similarly infected, but is also attacked at the same time by bloodborne viruses (following translocation from a significant viral load in the gastrointestinal tract). the former might result in mild or moderate illnesses only. the latter may cause a more severe illness, as the lungs are being attacked by viruses coming from two routes simultaneously. although it can be transiently higher, the ph of normal gastric acid is generally between 1.5 and 3.5. the sars-cov-1 virus is inactivated at a ph < 3.0 and > 12.0 [5] . assuming these inactivation levels are similar for sars-cov-2, gastric acid will not inhibit all the viruses in the stomach (and some viruses will be hidden in food boluses). however, the inhibition that does occur may be enough to decrease the viral load entering the small intestine. in many older adults, the gastric acid ph is higher than normal, either because of atrophic gastritis or because of antacid and acid-reducing medications. one oral dose of a proton pump inhibitor raises the gastric acid ph from 2.0 to over 6.0, which will not inhibit the virus [6] . (for mers-cov, treatment with a proton pump inhibitor in an animal model resulted in exaggerated infection in the small intestine [4] .) in a study of 204 covid-19 patients, fever or respiratory symptoms were generally present but 50% also reported digestive symptoms, particularly appetite loss and diarrhoea [1] . in a literature search, abdominal pain was associated with a near fourfold increased odds of severe disease, possibly because of a high viral load, viral replication in the gut and viremia [2] . children rarely suffer from severe illnesses with covid-19. as well as protection related to immunological factors and possible differences in the ace2 receptor concentrations in their lungs, children (other than infants) generally have good levels of gastric acid. this may provide some protection from swallowed viruses, even though young children usually swallow their sputum rather than spit it out. to determine whether gastric acid gives some protection from covid-19, the amount of antacids and acid-reducing drugs used by patients with severe infections could be compared with the amount used by patients with mild or no disease. it should not be overlooked that many of these medications may be purchased over-the-counter and be taken only occasionally for gastrointestinal symptoms, rather than being prescribed by a medical practitioner. therefore, they may not appear on a list of a patient's usual medications. whether there is any relation between taking these drugs and the clinical course could be considered. drugs taken during hospital admissions should also be recorded, as hospitals may continue medications taken at home. in addition, many intubated patients are given acidreducing drugs and gastrointestinal feeding may be continuous rather than intermittent. such factors could result in a gastric ph of around 4.0 or 5.0. this would not inactivate these viruses, which might then pass into the small intestine where the relevant ace2 receptors are abundant. if there is evidence for some protection by gastric acidity, stopping antacids and acid-reducing medications could be considered, particularly at times when patients are at increased risk. implications of gastrointestinal manifestations of covid-19 gastrointestinal symptoms associated with severity of coronavirus disease 2019 (covid-19): a pooled analysis severe acute respiratory syndrome associated coronavirus is detected in intestinal tissues of fatal cases human intestinal tract serves as an alternative infection route for middle east respiratory syndrome coronavirus inactivation of the coronavirus that induces severe acute respiratory syndrome, sars-co-1 the impact of proton pump inhibitors on the human gastrointestinal microbiome publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations there was no conflict of interest.received: 1 july 2020 accepted: 15 july 2020 key: cord-010055-exi8t6jt authors: zhu, guang-wen; gao, zhou; rachid, abdoul; liu, hui title: whether the gfr measured by renal scintigraphy under non-steady state conditions for critically ill patients with aki can be used as a predictive parameter for clinical events date: 2020-04-19 journal: crit care doi: 10.1186/s13054-020-02850-5 sha: doc_id: 10055 cord_uid: exi8t6jt nan whether the gfr measured by renal scintigraphy under non-steady state conditions for critically ill patients with aki can be used as a predictive parameter for clinical events guang-wen zhu 1* , zhou gao 2 , abdoul rachid 3 whether the gfr measured by renal scintigraphy under non-steady state conditions for critically ill patients with aki can be used as a predictive parameter for clinical events dear editor: we read with great attention and interest the paper by katulka et al. about the current evidence for clinical and biochemical parameters for predicting successful discontinuation of rrt [1] . we would like to add some comments in regard to their conclusion that multiple studies reported on the same parameter (urine output, diuretic test, crcl, cystatin c, ngal, egfr, kegfr), but an optimal threshold value was not determined due also to heterogeneity. for gfr measurement, we believe that based on the principle of radionuclide-based techniques and its advantages of repeatability of results, the heterogeneity of those above results may be avoided. 99mtc-dtpa has become a standard gfr tracer, the hierarchy of 99mtc-dtpa renal imaging is considered to be the silver standard among all used approaches for detecting gfr [2] , including gates method, modified gates method, and plasma sample clearance method. especially for gfr measurement in aki patients, the result of renal scintigraphy may be more reliable than other existing technologies and is not affected by plasma creatinine changing rapidly, fluid loading in icu, and receiving crrt. to analyze kidney function in the acute setting, recently, our team completed a special renal scintigraphy for a critically ill patient with the only venous access site-picc. a renal scintigraphy of 99mtc-dtpa was performed for this critical patient with aki and artificially assisted ventilation. the normalized gfr was 36.5 ml/min (fig. 1) . in the absence of broad guidelines [3] , our team proposed the following procedure/practice for renal scintigraphy by picc/cvc. after intravenous hydration with 300-500 ml of fluid (dextrose; 5% glucose or 0.9% sodium chloride) 30 min, the patency of the catheter in the picc/cvc system is checked by 10 ml saline solution in a 10-ml syringe. then, a bolus injection of radiopharmaceutical via picc or cvc is done, immediately following and flushing with 10-20 ml normal saline or heparin (100 u) sodium solution using the "push-pause" technique for the lock of the system depositing with positive pressure [4] , while a standard 20/30-min dynamic renal scintigraphy is performed. although renal scintigraphy is rarely used clinically for critically ill patients with aki, partly because of a lack of understanding of the technology, it can actually provide unique kidneys' function parameters, split renal function, and gfrs. the gfrs measured by renal scintigraphy alone or with other static and dynamic clinical variables may have a predictive value for stratification and clinical events in critically ill patients. fig. 1 dynamic renal scintigraphy for a critical patient by picc. a 65-year-old man with absence of urine for 3 days; he was diagnosed with aki stage 3, lung infection, atelectasis, electrolyte disorders, and coagulopathy, and the crrt was initiated. on the fifth day, the patient was performed with endotracheal intubation and ventilator-assisted mechanical ventilation due to dyspnea and hypoxemia. a dynamic renal scintigraphy of 99mtc-dtpa was performed by picc in this critical patient with aki and artificially assisted ventilation. the relative renal uptake of the right kidney was 22,737 counts, the left kidney was 40,310 counts, the right kidney gfr was 14.6 ml/min, and the left kidney gfr was 25.9 ml/min. the bilateral renal blood flow significantly reduced and the renogram curves shown a renal failure pattern; the relative renal uptake of each kidney indicated the split renal function, respectively. these findings were most consistent with renal causes of acute renal failure determining the optimal time for liberation from renal replacement therapy in critically ill patients: a systematic review and meta-analysis (done rrt) estimating and measuring glomerular filtration rate: methods of measurement and markers for estimation the snmmi and eanm practice guideline for renal scintigraphy in adults acr appropriateness criteria(®) radiologic management of central venous access publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions gw, zhu contributed to the designing, drafting, and reviewing the paper. z, gao contributed equally with gw, zhu; h, liu and abdoul rachid participated in the data analysis. all authors approved the final manuscript. availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord-004299-ydm6j046 authors: lu, yifang; chen, tenggao title: new-onset atrial fibrillation can be falsely associated with increased length of stay in icu due to immortal time bias date: 2020-02-06 journal: crit care doi: 10.1186/s13054-020-2757-2 sha: doc_id: 4299 cord_uid: ydm6j046 nan new-onset atrial fibrillation can be falsely associated with increased length of stay in icu due to immortal time bias yifang lu 1 and tenggao chen 2* dear editor, in a recent study published in critical care, fernando sm and colleagues investigated the impact of new-onset atrial fibrillation (noaf) on clinical outcomes in critically ill patients [1] . they performed univariate analysis and found that the length of stays (los) in icu and hospital was both longer in the noaf group versus non-noaf group. they then concluded that noaf was associated with increased los in icu and increased total costs. while the conclusion appeared intuitive and statistically sound, it could be the result of immortal time bias. immortal time is a span of cohort follow-up during which, because of exposure definition, the outcome under study could not occur [2] . the noaf can happen at any time during icu stay and patients live longer in the icu can have more chance to report noaf. for example, a patient can have noaf on day 4 and the outcome such as icu discharge or death cannot happen before day 4. in this situation, the period from days 1 to 3 are considered as immortal time because if the outcome happens during the period, the patient cannot experience noaf. the immortal time is incorrectly attributed to the exposure of noaf, but actually, the noaf do not contribute to the survival time. the same applies to the mortality outcome. the authors used binary logistic regression model to adjust for confounding effect and found there was no independent association of noaf and mortality [3] . the truth could be that noaf is associated with increased mortality risk, but since patients who lived longer can have more chances to experience noaf, the neural effect reported in the paper was actually the result of the true adverse effect and the bias towards beneficial effect. potential solutions to control for the immortal time bias are as follows: (1) perform analysis by restricting to patients who had noaf on day 1 and compare to those without noaf, (2) consider the time of noaf and include noaf as timevarying covariate in the cox proportional hazard model [4] , and (3) perform time-dependent propensity score matching by including covariates that can influence the onset of noaf [5] . the authors would like to thank drs. lu and chen for their comments on our recent article related to outcomes and costs associated with new-onset atrial fibrillation (noaf) in critically ill adults [1] . drs. lu and chen suggest caution in the interpretation of our study results, particularly as they relate to the length of stay and costs, due to the possibility of immortal time bias. indeed, the use of time-dependent covariates (such as noaf) has the potential to confound multivariate models [2] . however, as seen in our original study, the majority of patients who developed noaf did so on the first day of hospital admission, consistent with previous studies in this population [6, 7] . as suggested by drs. lu and chen, we conducted sensitivity analyses of our data, restricting the noaf population to only those who developed noaf on the first day of hospital admission (n = 962, 62.4% of the original noaf population). indeed, our original results persist, with patients with developing noaf on the first day of admission still experiencing prolonged hospital stay, as compared to patients who did not develop noaf (table 1) . we similarly repeated our generalized linear model restricted to this select population, in order to determine if noaf was still associated with total hospital costs ( table 2 ). we found that noaf was indeed a predictor of total hospital costs, even when only considering patients who developed noaf on the first day of admission. these findings support the notion that our results were not markedly influenced by immortal time bias. finally, we would like to clarify that total hospital costs are not inferred as a multiple of hospital length of stay, as drs. lu and chen suggest. in fact, all direct costs are linked directly to the patient identification number, and while they may be associated with length of stay (e.g., a person who stays in hospital for a longer length of time is likely to have increased testing and therapies, translating to higher costs), they are not obtained through a multiplication of length of stay, but rather reflect the direct resource use for each individual patient [8] . new-onset atrial fibrillation and associated outcomes and resource use among critically ill adults-a multicenter retrospective cohort study problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes model building strategy for logistic regression: purposeful selection time-varying covariates and coefficients in cox regression models propensity score matching with time-dependent covariates new-onset atrial fibrillation in adult critically ill patients: a scoping review new-onset atrial fibrillation in the critically ill outcomes and costs of patients admitted to the icu due to spontaneous intracranial hemorrhage none authors' contributions qj conceived the idea and drafted the manuscript. wl helped interpret the results. both authors read and approved the final manuscript. availability of data and materials no data for the work ethics approval and consent to participate not applicable consent for publication not applicable the authors declare that they have no competing interests. received: 15 january 2020 accepted: 30 january 2020 key: cord-007550-2b62zaur authors: buchtele, nina; staudinger, thomas; schwameis, michael; schörgenhofer, christian; herkner, harald; hermann, alexander title: feasibility and safety of watershed detection by contrast-enhanced ultrasound in patients receiving peripheral venoarterial extracorporeal membrane oxygenation: a prospective observational study date: 2020-04-02 journal: crit care doi: 10.1186/s13054-020-02849-y sha: doc_id: 7550 cord_uid: 2b62zaur nan in bifemoral venoarterial extracorporeal membrane oxygenation (va ecmo), the transition point at which the antegrade pulsatile output from the left ventricle and the retrograde non-pulsatile ecmo output collide is referred to as watershed [1] . currently, no standard method is available to determine its location. occasionally, contrast-enhanced computed tomography (ct) or angiography has been used [1] [2] [3] . both techniques, however, bear disadvantages including radiation exposure and use of iodinated contrast media. we assessed the feasibility and safety of contrast-enhanced ultrasound (ceus) to detect the watershed at the bedside in patients on bifemoral va ecmo at three icus of a european tertiary care facility. ceus was performed as soon as possible after ecmoinitiation (cardiohelp, maquet, germany) using sono-vue contrast media (bracco, italy). transesophageal echocardiography (x7-2t probe) and transabdominal sonography (3-5 mhz curvilinear probe) were performed concomitantly to display mid-esophageal aortic valve, ascending, descending aorta, and upper esophageal aortic arch long-axis views as well as longitudinal views of the proximal (below diaphragm), mid (level of renal arteries), and distal (above iliac bifurcation) abdominal aorta. the mechanical index was set to 0.05-0.10 field of view. prior to ceus, the arterial bubble sensor activating zero-flow mode was disabled. the acoustic alarm was kept active. the presence or absence of pulsatility in the left radial artery was documented. one milliliter of sonovue was administered via the venous drainage cannula, followed by a flush of 10 ml normal saline. the obtained images were evaluated qualitatively. if a watershed area was not able to be visualized, contrast-enhanced blood flow was classified into "pulsatile" or "continuous" to discriminate between cardiac and ecmo blood flow. the feasibility of ceus was assessed based on qualitative image evaluation, the amount of contrast media administered, and the rate of bubble detection. secondary outcomes were safety and frequency of radial arterial pulsatility. safety variables included ecmo settings, hemodynamics, and neurologic assessment and were obtained over a 6-h period after ceus. the variables are presented as absolute values (n), relative frequencies (%), and median (25-75% iqr). we used random-effects general linear regression models to estimate mean changes for each safety variable (mean ± sd). between august 2018 and april 2019, ten patients were enrolled (table 1) . qualitative detection of watershed location by ceus was feasible using 1 ml contrast media. in five patients, the watershed could be clearly shown in the abdominal aorta, seconds after contrast media administration (fig. 1 ). in the remaining five patients, contrast-enhanced continuous blood flow was visible throughout the abdominal and thoracic aorta indicating watershed location close to the aortic root. the pulsatility of the left radial arterial waveform and opening of the aortic valve was present in all patients. acoustic bubble detection occurred in all patients after ceus. no changes in the safety variables related to ceus occurred (table 1) . ct imaging of the brain (8/10 patients) showed no cerebral lesions suggesting particle embolism. this study assessed the feasibility of ceus for watershed detection at the bedside in patients on bifemoral va ecmo. ceus was apparently safe and provided realtime assessment of the watershed or contrast-enhanced continuous blood flow in the aorta. increasing evidence indicates that ceus is safe in critically ill patients, and application areas are ever-expanding [4] [5] [6] . in bifemoral va ecmo, ceus may help to identify patients at risk for differential hypoxia, given that left radial arterial pulsatility was present in all study patients, including those in whom the watershed was located near the aortic root. transthoracic suprasternal echocardiography may be useful to localize the watershed in the aortic arch but has not been tested. furthermore, no reference imaging technique has been used to assess the performance of ceus, because no standard method for the detection of the watershed is available, and no repeated measurements were performed. abbreviations ceus: contrast-enhanced ultrasound; ct: computed tomography; va ecmo: venoarterial extracorporeal membrane oxygenation fig. 1 visualization of contrast-enhanced retrograde non-pulsatile ecmo blood flow. the watershed is marked with an arrow and located distal to the superior mesenteric artery extracorporeal membrane oxygenation watershed heart against venoarterial ecmo: competition visualized hemodynamic changes in patients with extracorporeal membrane oxygenation (ecmo) demonstrated by contrast-enhanced ct examinations -implications for image acquisition technique safety and feasibility of contrast echocardiography for ecmo evaluation safety and feasibility of contrast echocardiography for lvad evaluation acute kidney injury is associated with a decrease in cortical renal perfusion during septic shock publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we gratefully thank our collaborators gerhard ruzicka, christoph weiser, hans domanovits, alexander o. spiel, peter schellongowski, andja bojic, anne merrelaar, and monika schmid for their valuable help with patient recruitment, performing ultrasound and study flow throughout the study. we thank sarah ely for the thorough revision of the manuscript. authors' contributions nb, ms, and ts designed the study. nb, ms, cs, and ah enrolled the study patients and/or performed the ultrasound. nb, ms, and cs collected the data together with the trained study nurses. nb, ms, and ts analyzed and interpreted the data. hh did the statistical analysis. nb and ms wrote the first draft of the manuscript and drew the figure and table. all authors critically revised the manuscript for important intellectual content and approved its current version. all authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. the manuscript has not been previously published and is not under consideration for publication in the same or substantially similar form in any other peerreviewed media. this study was supported by the austrian society for internal medicine and general intensive care and emergency medicine (ögiain). the datasets analyzed during the current study are available from the corresponding author on reasonable request. complete results from safety data are available with the main manuscript. exemplary ultrasound loops are available from the corresponding author on request. the study was approved by the ethics committee of the medical university of vienna (ec#1177/2018) and conducted in accordance with helsinki declarations. according to austrian law regulations, prior to the study enrolment, a waiver was obtained and patients were informed about their participation after regaining consciousness. the authors declare that they have no competing interests. key: cord-001536-ta1i0ata authors: nair, girish b; niederman, michael s title: year in review 2013: critical care respiratory infections date: 2014-10-29 journal: crit care doi: 10.1186/s13054-014-0572-3 sha: doc_id: 1536 cord_uid: ta1i0ata infectious complications, particularly in the respiratory tract of critically ill patients, are related to increased mortality. severe infection is part of a multiple system illness and female patients with severe sepsis have a worse prognosis compared to males. kallistatin is a protective hormokine released during monocyte activation and low levels in the setting of septic shock can predict adverse outcomes. presepsin is another biomarker that was recently evaluated and is elevated in patients with severe sepsis patients at risk of dying. the centers for disease control and prevention has introduced new definitions for identifying patients at risk of ventilator-associated complications (vacs), but several other conditions, such as pulmonary edema and acute respiratory distress syndrome, may cause vacs, and not all patients with vacs may have ventilator-associated pneumonia. new studies have suggested strategies to identify patients at risk for resistant pathogen infection and therapies that optimize efficacy, without the overuse of broad-spectrum therapy in patients with healthcare-associated pneumonia. innovative strategies using optimized dosing of antimicrobials, maximizing the pharmacokinetic and pharmacodynamic properties of drugs in critically ill patients, and newer routes of drug delivery are being explored to combat drug-resistant pathogens. we summarize the major clinical studies on respiratory infections in critically ill patients published in 2013. critically ill patients with respiratory infections have been the continued focus of investigation over the last several years. infections, mostly nosocomial, are a major cause of mortality in hospitalized patients related to an increased risk of infection with multi-drug resistant (mdr) pathogens and the widespread use of indiscriminate broad-spectrum antibiotics. the frequency and epidemiology of mdr pathogens show regional variation, however, with several studies pointing out that the risk of mdr pathogens in healthcare-associated pneumonia (hcap) is variable and hence there is a need for accurate risk scoring in this category of patients. obtaining meaningful data and monitoring trends of preventative strategies have become ever more important, with the centers for disease control and prevention (cdc) recently publishing new surveillance definitions. newer biomarkers are becoming part of the increasing armamentarium in the field of critical care medicine and antibiotic stewardship using biomarkers has been studied robustly. antibiotic use in the critically ill, with dosing to attain better pharmacokinetic and pharmacodynamic results, was part of several research studies. we summarize the findings from the major clinical research studies published in 2013 on respiratory infections, with a focus on infections in critically ill patients. respiratory infection continues to be the most common cause of sepsis and septic shock. the past decade has seen increased awareness in recognizing patients with sepsis and several guidelines, including the 'surviving sepsis campaign' , have published a detailed framework on the approach to patients with severe sepsis. in a large, prospective, french, multicenter, observational study as part of the episs study cohort, investigators examined the epidemiology of septic shock in 1,495 patients [1] . in this study, 53.6% of patients had respiratory tract infection as the cause of septic shock and 83.9% required invasive mechanical ventilation (mv), with gram-negative bacilli being the most common pathogens identified. although most patients received initial appropriate antibiotic therapy (n = 898), the in-hospital mortality rate was still high, up to 48.7%. a higher sequential organ failure assessment (sofa) score, age and chronic health status score and the presence of immunosuppression were independent risk factors for short-term mortality. in a follow-up study of the same cohort of patients, 3-month mortality was 52.2%. severity of illness, indicated by a higher sofa score early after septic shock, impacted mortality the most, while co-morbid conditions such as cirrhosis, nosocomial infection and age influenced mortality after hospitalization [2] . in another prospective observational cohort of 1,000 patients with severe sepsis, phua and colleagues studied the characteristics and outcomes of patients with a positive microbial culture (58.5%) compared with those whose culture was negative (41.5%) [3] . respiratory infection was the most common cause of sepsis in both groups, and a lung source was determined as the primary cause of sepsis more often in patients with a negative culture than in patients with a positive culture (74.5% versus 59.9, p <0.001). of all the pathogens identified, infection with pseudomonas aeruginosa (pa) was associated with increased mortality (odds ratio (or) 2.02, 95% confidence interval (ci) 1.08 to 3.79, p = 0.03). patients with culture-negative sepsis had fewer comorbidities; these patients were more often women and had lower severity of illness than those with culture-positive sepsis. although patients with positive culture had higher mortality, it was not an independent predictor of mortality on logistic regression analysis. sakr and colleagues [4] studied the influence of gender on 3,902 patients with severe sepsis and found the frequency of severe sepsis and septic shock was lower in women than in men (6.0% versus 8.9%, p = 0.001) and the overall icu mortality was not different in both sexes (20.1% versus 19.8%, p = 0.834). in the subset of patients with severe sepsis, however, female patients had worse survival than men (63.5% versus 46.4%, p = 0.007). further studies on the impact of gender-specific hormonal and immunologic profile differences may uncover an explanation for these findings. cognitive dysfunction has been noted in patients following severe illness. in a study including 5,888 participants, the authors tested the hypothesis that a bidirectional relationship exists between pneumonia and dementia, with subclinical changes in cognition increasing the risk of pneumonia hospitalization and an accelerated decline in cognitive dysfunction occurring after pneumonia [5] . three trajectories were identified longitudinally based on teng's modified mini mental state examination -no decline, minimal decline and severe decline. a low cognitive score prior to hospitalization increased the risk of pneumonia -a 10 point lower modified mini mental state score increased the hazard of pneumonia by 8.4%. patients who had at least one episode of pneumonia had a higher risk of developing subsequent dementia than those without pneumonia (hazards ratio 2.24, 95% ci 1.62 to 3.11, p = 0.01). of the total population, 6.8% had severe sepsis and similar cognitive decline as was seen with pneumonia. neurotoxicity related to elevated cytokine levels and other co-morbid conditions with severe illness, such as delirium, could be a plausible explanation for the cognitive decline. however, the population in this study who developed pneumonia were slightly older and had abnormal scores on mini mental state examination and potentially were identified earlier in their course with longitudinal screening. enteral feeding is the desired mode of nutritional supplementation in critically ill patients, but patients receiving enteral nutrition may have gastroparesis and gastroesophageal reflux, putting them at risk for aspiration; therefore, measurement of gastric residual volume (grv) is recommended in ventilated patients. reignier and associates [6] in a randomized, non-inferiority, open-label, multicenter trial studied whether grv monitoring every 6 hours and adjusting enteral feeding rates if the volume exceeded 250 ml would prevent ventilator-associated pneumonia (vap). in this study, there was no difference in vap incidence between patients who had grv measured (n = 227) compared with the group (n = 222) who did not (16.7% versus 15.8%), and all the clinical outcomes, including mortality, were similar in both groups. patients in whom grv was not measured had a higher incidence of vomiting, but also a higher proportion of this group achieved the calorie target and had lower use of prokinetic agents. although the study was done well, it was underpowered to determine the harmful effects related to vomiting and included mostly patients in the medical icu and excluded patients with gastrointestinal bleeding. in a meta-analysis of 19 randomized controlled trials including 1,394 patients, alhazzani and colleagues [7] reviewed the risk of pneumonia in patients receiving small bowel feeding compared to gastric feeding. small bowel feeding was associated with reduced risk of pneumonia (relative risk 0.70, 95% ci 0.55 to 0.90, p = 0.004), but there was no difference in mortality, ventilator days or icu length of stay (los) between the two groups. the study is limited, however, because the individual trials had small sample sizes, included severe pancreatitis patients and patients not in the icu and used variable definitions of pneumonia. insertion of the small bowel feeding tube can be technically difficult if done blindly and may need additional training with fluoroscopy and endoscopy procedures. even though oropharyngeal bacterial translocation seems a likely cause of the development of vap, it is unclear if monitoring gastric reserve volume or advancing the feeding tube to the small intestine clearly prevents vap. another identified risk factor for ventilator-associated respiratory infection (including vap and ventilator-associated tracheobronchitis) is iatrogenic immune suppression (or 3.34), a risk factor that has frequently been excluded in prior studies [8] . shorr and colleagues [9] studied the factors leading to 30-day readmission in 977 culture-proven non-nosocomial pneumonia patients who survived to discharge following initial hospitalization to any of the nine participating hospitals in the same geographical area. the readmission rate was 19.3% (n = 149) within the 30-day period and was related to non-pneumonia causes such as chronic obstructive pulmonary disease (25%) and congestive heart failure (chf) (22%). while pneumonia accounted for only 7.4% (n = 11) of readmissions, patients with hcap were re-admitted more often than those with communityacquired pneumonia (cap) (24.4% versus 4.1%, p <0.001) and had more comorbid conditions. the four independent variables associated with readmission on logistic regression analysis were long-term care admission prior to index hospitalization (or = 2.15, p = 0.001), immunosuppressed state (or = 1.93, p = 0.001), previous antibiotics (or = 1.74, p = 0.009) and previous 90-day hospitalization (or = 1.66, p = 0.014). these data suggest that readmission rates differ among groups of patients with pneumonia, and that patients with hcap and those with baseline poor functional status have a higher likelihood of being readmitted than uncomplicated cap patients. clinical algorithms based on biomarkers help with antibiotic de-escalation and possibly limit antibiotic over-exposure in patients with pneumonia, but their use in clinical practice has been variable. procalcitonin (pct), an inflammatory hormokine, is elevated in bacterial infection and helps with antibiotic stewardship, and risk stratification, particularly for respiratory infections. presepsin (scd14-st) is another novel biomarker (soluble amino-terminal fragment of the cluster of differentiation (cd) marker protein cd14) in sepsis that is released into the circulation during monocyte activation. kallistatin is an endogenous serine proteinase inhibitor that has a strong affinity to tissue kallikrein and is thought to have a protective role with a higher consumption in patients with severe sepsis. in a prospective observational study of 54 severe cap patients admitted to icu, lin and colleagues [10] determined the prognostic value of serum kallistatin and its correlation to other biomarkers; 17 healthy patients were included as controls. plasma kallistatin and antithrombin iii were significantly lower on days 1 and 4 in patients who did not survive (24%) compared to those who did, possibly indicating greater consumption of these factors in the severely ill. the plasma kallistatin levels were significantly reduced in patients with septic shock and in those who developed acute respiratory distress syndrome (ards). a cutoff level of day 1 kallistatin <6.5 μg/ml can discriminate between survivors and non-survivors with an area under the curve (auc) of 0.683, p = 0.04 ( figure 1 ). thus, decreased plasma kallistatin level on day 1 of icu admittance is independently associated with mortality and severity of disease in cap patients in this study. in a multicenter, case-control study, masson and colleagues [11] compared presepsin and pct levels in 50 survivors and 50 nonsurvivors who were admitted to icu with severe sepsis. the presepsin levels were significantly higher on day 1 of enrollment in patients who died compared with survivors and remained significantly elevated on day 7 as well. presepsin was independently associated with short-term icu and 28-day mortality and had good prognostic accuracy similar to the sofa score for long-term mortality at 90 days. pct on the other hand was not related to mortality and the levels declined on day 7 in both survivors and non-survivors. chf may cause gut translocation of bacteria and potentially lead to elevated pct levels. wang and colleagues [12] studied the diagnostic value of serum pct levels in 4,698 patients with different types of chf. patients were grouped into chf (n = 1,364), chf with infection (n = 1,183), infection only (n = 1,703) and healthy controls (n = 448). the pct levels in patients with chf were significantly elevated compared with healthy controls, while those with infection and chf had higher levels than both the infection alone and chf alone group ( figure 2 ). in patients with increasing severity of chf, the positive predictive value of pct decreased significantly (90.9 in class ii chf with infection to 68.6 in class iv chf). if the pct was negative, however, the finding was good for ruling out infection in class iv chf patients (negative predictive value of 89). hence, elevated pct should not be taken at face value in patients with chf and a higher cutoff should be used to define infection, depending on the severity of heart failure. in a meta-analysis of seven studies including 1,075 patients, prkno and colleagues [13] studied the safety of using a pct-based regimen in patients with severe sepsis or septic shock. the 28-day mortality based on results from four included studies was not different between the pct-based regimen and standard treatment groups, but the pct group had a shorter duration of antimicrobial therapy based on five included studies. the studies included in the meta-analysis had substantial differences in design and cutoff values for pct and included both medical and surgical patients, but the common theme was that therapy based on pct leads to more de-escalation and a shorter duration of antibiotic therapy, with no adverse impact on mortality. the stop antibiotics on guidance of procalcitonin study (saps) is an ongoing, multicenter, randomized dutch study of daily pct versus standard therapy , currently finishing enrollment, and will be the largest icu-based trial evaluating the early stopping of antibiotics based on pct [14] . healthcare bundles in the form of daily goal sheets and educational sessions have been shown to reduce the incidence of vap and related complications, but variable practices and different vap definitions limit their use. the cdc recently introduced a step-wise approach for 'objective' surveillance of ventilator-associated events and includes ventilator-associated complications (vacs), infection-related ventilator-associated complications (ivacs), as well as possible and probable vap. muscedere and associates [15] studied the clinical impact and preventability of vacs and ivacs using prospectively collected data on 1,320 patients from another series and determined the relationship to vap. over four study periods, vacs developed in 10.5% of patients (n = 139), ivacs in 4.9% (n = 65) and vap was noted in 11.2% (n = 148); 39 patients had both a vac or ivac and vap. patients who had vacs were more likely to develop vap than those who did not have vacs (28.1% versus 9.2%, p <0.001). patients with vacs or ivacs had significantly more ventilator days, hospital days, and antibiotic days and higher hospital boxes represent interquartile range, and whiskers the 5th and 95th percentiles in each category. hf, heart failure; pct, procalcitonin. adapted from wang and colleagues [12] . mortality compared with patients who did not develop vacs or ivacs. when prevention efforts were undertaken, they were able to reduce the incidence of vacs and vap, but not ivacs, over subsequent periods. in another study, hayashi and colleagues [16] compared 153 patients with vacs to 390 without vacs and noted that patients who developed vacs had a longer icu los (22 versus 11 days), duration of mv (20 versus 5 days) and use of antibiotics but no difference in overall icu mortality and hospital los. vac definitions identified a 'potential vap' (a vac with positive culture of respiratory pathogens in respiratory specimens plus antibiotic prescription with intention to treat as vap) in 30.7% of cases, but it was not specific for vap and included atelectasis in 16.3% of patients, acute pulmonary edema in 11.8%, and ards in 6.5%. using electronic records to identify complications related to ventilation is easy and identifies sick patients, but many patients with vap were not identified in both studies and therefore vacs and ivacs may be different diseases with different pathobiological causes than vap. sinuff and associates [17] studied the impact of a 2-year multi-faceted intervention via educational sessions supplemented with reminders and led by local opinion leaders on improving concordance with vap prevention and treatment guidelines and assessed sustainable behavior changes in the icu. over time, there was more improvement in prevention strategies than in therapy approaches, and, overall, a significant increase in guideline concordance (aggregate concordance (mean (standard deviation)): 50.7% (6.1), 54.4% (7.1), 56.2% (5.9), 58.7% (6.7); p = 0.007). they also observed a reduction in vap rates (events/330 patients: 47 (14.2%), 34 (10.3%), 38 (11.5%), 29 (8.8%); p = 0.03) over the study period, but icu mortality and length of icu stay were unchanged, despite adjustments for age and sofa score. the best concordance rate achieved was only 58.7% and highlights the potential barriers to guideline implementation and variable practices that exist within the community despite multiple reinforcements. in another study, including 350 patients, investigators using data from electronic medical records compared the incidence and outcomes in vap patients using various definitions, including the new cdc ventilator-associated event algorithm, before and after a vap bundle was introduced in their institution (pre-bundle period january 2003 to december 2006 (n = 213); post-bundle period january 2007 to december 2009 (n = 137)) [18] . unlike the previous study, vap and vac incidence remained unchanged and was not affected by the implementation of the vap bundle despite good compliance. however, mortality adjusted for severity of illness was less in the post-bundle period (23% versus 18%, p <0.0001), although the duration of mv, icu and hospital los did not change post-bundle introduction. the lack of reduction in vap and vac incidence could have been due to continuous quality improvement interventions that were already underway prior to guideline implementation, but interestingly the newer ventilator-associated event definitions did not recognize vap in all patients, similar to findings from the studies by muscedere and colleagues [15] and hayashi and colleagues [16] discussed above. luna and associates [19] , in a prospective study of 283 ventilated patients, analyzed if an antibiotic prescription strategy based on routine endotracheal aspirate (eta) culture was better than empiric antibiotic therapy for vap, as outlined by the american thoracic society (ats)/infectious disease society of america (idsa) guidelines. eighty-three patients had vap and the eta and bronchoalveolar lavage (bal) cultures had concordance in only 52 culture pairs. sensitivity for eta to predict a bal-obtained pathogen was 62.4% (78/125 microorganisms cultured) and was better if done within 3 days of vap onset and in recurrent vap. antibiotic decisions made according to the ats/idsa guidelines led to appropriate therapy in 97.9% of patients compared with 77.4% based on eta culture, with fewer antibiotic days using the eta-based culture. hence, using a strategy for vap diagnosis and treatment decisionmaking based on eta cultures alone could result in inappropriate therapy but possibly helps with de-escalation and leads to fewer antibiotic days. recent studies have confirmed the significant heterogeneity among hcap patients and also that the risk for mdr pathogens has regional differences. in a study including 519 patients with cap and 419 with hcap, the authors compared the performance of pneumonia severity index (psi) and curb-65 risk scores for predicting 30-day mortality [20] . hcap patients were sicker, had more frequent icu admission, longer length of icu stay and higher mortality than cap patients in this cohort. the discriminatory power for 30-day mortality, using both psi and curb-65, was lower in hcap patients than cap patients (auc for psi = 0.679, curb-65 = 0.599 in hcap group versus auc for psi = 0.835, curb 65 = 0.79; p = 0.009). thus, both scoring systems were less effective for predicting mortality in hcap than in cap patients, but if used, the psi scoring system performed better than curb-65. in a prospective study including 1,413 patients (887 cap and 526 hcap), shindo and associates [21] determined the risk factors for pathogens resistant to macrolides, beta-lactams and respiratory fluoroquinolones (cap-drps). hcap patients had a higher frequency of cap-drps than cap patients (26.6% versus 8.6%) and a higher 30-day mortality rate (20.3% versus 7.0%). independent risk factors for cap-drps were similar in both cap and hcap groups, and included prior hospitalization, immunosuppression, previous antibiotic use, gastric acid-suppressive agents, tube feeding, and non-ambulatory status. the higher the number of risk factors, the greater the chance of cap-drps (auc 0.79, 95% ci 0.74 to 0.84). they also identified risk factors for methicillin-resistant staphylococcus aureus (mrsa), which included dialysis within 30 days, prior mrsa isolation within the past 90 days, antibiotics in the past 90 days, and gastric acid-suppressive therapy. however, the presence of a high frequency of resistant pathogens in this study group limits generalization and further studies are needed for external validity of the model. in another study, aliberti and colleagues [22] used probabilistic risk scores for prediction of mdr pathogens in two independent cohorts admitted to the hospital from the community (n = 3,474) to validate the previously reported shorr and aliberti risk scores. the prevalence of mdr pathogens was 7.6% in barcelona and 3.3% in edinburgh and the two scores performed consistently better than the traditional hcap classification in both centers. maruyama and colleagues [23] , in a prospective study of 425 patients (cap = 124, hcap = 321), applied a therapeutic algorithm based on the presence of mdr risk factors (immunosuppression, hospitalization within the last 90 days, poor functional status indicated by a barthel index score <50, and antibiotic therapy within the past 6 months) and severity of illness (need for icu admission or requiring mv) to determine its impact on outcomes. hcap patients with no or one risk factor were treated with cap therapy and those with two or more risk factors were treated with a hospital acquired pneumonia regimen based on the ats/idsa 2005 guidelines. hcap patients with two or more risk factors had a higher incidence of mdr pathogens and higher mortality than cap patients (27.1% versus 2%, p <0.001, and 13.7% versus 5.6%, p = 0.017, respectively). although only 53% of hcap patients received broad-spectrum antibiotics, using the algorithm the majority (92.9%) received appropriate therapy for the identified pathogens. thus, using this approach, broad-spectrum antibiotic use can be limited, even in patients with hcap. lacroix and associates [24] investigated the role of early fiberoptic bronchoscopeguided distal protected small volume bronchoalveolar lavage (mini-bal) in 54 hcap patients. mini-bal helped identify causative pathogens more efficiently than blood culture (46.3% versus 11.1%, p <0.01), up to 72% in patients who did not receive prior antibiotics. thus, a strategy based on mini-bal might help with early identification, but the authors did not compare length of antibiotic days, development of resistance or mortality between an empiric regimen and patients who had mini-bal. the practicality of this approach in the non-intubated hcap population needs to be validated. sicot and colleagues [25] evaluated the characteristics of 161 patients with panton-valentine leucocidin (pvl) community-acquired s. aureus pneumonia from a french registry, based on methicillin resistance. both pvl-mrsa (n = 37, 23%) and pvl-methicillin-sensitive staphylococcus aureus (pvl-mssa; n = 124, 77%) occurred in younger patients (median age 22.5 years) with no underlying comorbidities. airway hemorrhage was more frequent in pvl-mssa necrotizing pneumonia compared with pvl-mrsa (44.2% versus 24.1%, p = 0.056) but there was no significant difference in mortality (39.4% versus 37.9%), icu admission, severity of disease or use of antibiotics between the two groups. interestingly, methicillin resistance was not associated with increased mortality, but patients with airway hemorrhage had a three-fold increase in 7-and 30-day mortality (or 3.75 and 3.68, respectively) and patients treated with an anti-toxin regimen (clindamycin, linezolid, or rifampicin) had a better chance of survival (mortality rate 6.1% versus 52.3%, p <0.001) even though the timing of therapy was not available. this study is one of the largest series on necrotizing community-acquired staphylococcal infection and shows that, despite the resistance pattern, pvl-associated s. aureus infection can be a severe disease with high mortality in young patients from the community and that the use of anti-toxin therapy in suspected patients is associated with a potential survival advantage. choi and associates [26] studied the role of viruses in 198 patients with severe pneumonia (64 with cap and 134 with hcap) using rt-pcr and bal fluid (58.1%) or nasopharyngeal swab (84.1%). of the patients, 35.9% (n = 71) had positive bacterial culture, 36.4% (n = 72) had viral infections, and 9.1% (n = 18) had bacterialviral co-infections. rhinovirus was the most commonly identified virus (23.6%), followed by parainfluenza virus (20.8%) and human metapneumovirus (18.1%). bacterial coinfection was more common with parainfluenza and influenza viruses and less common with respiratory syncitial virus and rhinoviruses. there was no difference in mortality between each group, but of those patients with viral infection, rhinovirus was associated with the highest mortality (52.9%), followed by influenza virus (33.3%). this is an interesting study and shows that polymicrobial infection with viruses and bacteria is not uncommon in patients with severe pneumonia. however, some study participants had antibiotics prior to bal and therefore the negative bacterial cultures may not have been an accurate finding. in contrast to the discussion above, bacterial infection commonly complicates viral respiratory infection and is often associated with higher morbidity and mortality. muscedere and colleagues [27] evaluated the risk of coexistent or secondarily acquired bacterial respiratory tract or bloodstream-positive cultures in 681 patients with influenza a (h1n1) infection during the 2009 outbreak. they noted that 38% of patients (n = 259) had at least a positive blood or respiratory culture during their icu stay (29.7% had co-existent and 44.4% had icu-acquired infection; 15.4% had both) despite almost all patients receiving antibiotics. patients with any positive culture had higher morbidity with more days on the ventilator, longer icu and hospital los and higher hospital mortality (24.7% versus 19.9%, p = 0.15). the interesting finding from this study is that influenza infection (h1n1) is not as mild as previously thought; the majority of icu patients required mv and the morbidity and mortality were high even in patients without bacterial co-infection. hung and colleagues [28] in a double-blind, randomized controlled trial evaluated the use of hyperimmune iv immunoglobulin (h-ivig) fractionated from convalescent plasma of patients who had 2009 h1n1 infection (n = 17) versus normal iv immunoglobulin (n = 18) in 35 patients with severe h1n1 infection. patients who received h-ivig had significantly lower viral loads post-treatment and, if treatment was given within 5 days of onset, had mortality benefit (or 0.14, 95% ci 0.02 to 0.92, p = 0.04). although the study is limited by a relatively small sample size, the h1n1 antibody present in the convalescent h-ivig, if used early, offers potential benefit in the treatment of h1n1 infection. the ats/idsa guidelines recommend antibiotic therapy based on the risk for mdr pathogens with early onset infection (within 5 days of admission), generally using a narrow-spectrum antibiotic regimen. restrepo and colleagues [29] examined the microbial cultures of 496 vap patients from 2 large prospective, randomized, open-label studies, classifying patients as early-(<5 days since hospitalization, n = 248) and late-onset vap (>5 days, n = 248). late-onset vap patients had a higher overall frequency of gram-negative pathogens (84.3% versus 75.4%, p = 0.02) and more significant antibiotic exposure in the prior month (85.5% versus 68.5%, p <0.01). however, both early-and late-onset vap patients had similar rates of mdr pathogens (27.8% and 32.3%, respectively, p = 0.33). investigators from the eu-vap study divided 485 patients with microbiology-confirmed nosocomial pneumonia into two groups; group 1 was early-onset with no mdr risk factors (n = 152) and group 2 was early-onset with mdr risk factors or late-onset pneumonia [30] . the presence of severe sepsis/septic shock (or = 3.7) and pneumonia that developed in a center with greater than a 25% prevalence of resistant pathogens (or = 11.3) was independently associated with the presence of resistant pathogens in group 1 patients. these findings suggest that most patients with vap are at risk for mdr pathogens, and that very few can safely receive narrow-spectrum empiric therapy. tumbarello and associates [31] analyzed the impact of multi-drug resistance on outcomes in 110 patients admitted to icu with culture-confirmed pa pneumonia. forty-two cases (38%) involved mdr pa, and 9 (8.1%) were colistin-only susceptible pa. the initial antimicrobial regimen was inadequate in 56 patients (50.9%) and more often inadequate among those with mdr pa. patients who had initial inappropriate antibiotics had a higher mortality than those who had appropriate therapy (64.2% versus 24.7%, p = 0.001) and mdr pa patients treated with empiric combination therapy had a lower risk of initial inappropriate antibiotics than those treated with monotherapy. in a similar study, pena and colleagues [32] looked at the impact of mdr in 91 patients with pa vap, of which 60 cases were caused by mdr strains, 42 (70%) of which were extensively drug-resistant. as with the previous study, vap patients with susceptible pa received adequate empiric antibiotic coverage more often, both empiric and definitive, than patients with mdr pathogens (68% versus 30%, p <0.001). although inadequate antibiotics were an independent risk factor for early mortality (or 4.27, p = 0.052) and patients with susceptible strains had more adequate coverage, those with inadequate therapy had a higher mortality that could be related to severity of illness more than to resistance. the outcomerea data on pa pneumonias include 393 pa-vap episodes with multi-drug resistance defined as resistance to two antibiotics (piperacillin, ceftazidime, imipenem, colistin, and fluoroquinolones) [33] . mdr was not related to treatment failure or relapses but was associated with longer icu los. fluoroquinolone use prior to the first episode was associated with increased risk of treatment failure probably related to the induction of resistance, but when used in the treatment regimen, fluoroquinolones decreased the risk of treatment failure. in another study of 143 confirmed pseudomonal pneumonia patients, serotypes o6 and o11 were more prevalent, but mortality was higher with o1 (40%) and lower with o2 (0%); clinical resolution tended to be better with o2 (82%) compared with other serotypes. higher acute physiology and chronic health evaluation ii score was associated with worse outcomes among all serotypes [34] . clinically feasible and simple to use predictors of icu outcome in patients with icu-acquired pneumonia are important in clinical practice. in a prospective observational study, esperatti and colleagues [35] determined the usefulness of a set of predictors of adverse outcomes (paos) in 355 icu-acquired pneumonia patients and determined their correlation with serum inflammatory markers and clinical prognostic scores. the paos were determined 72 to 96 hours after starting antibiotics (evolutionary criteria), and were considered positive if there was: 1) no improvement in partial pressure of oxygen in arterial blood/fraction of inspired oxygen ratio since the onset of pneumonia and in the absence of other causes of worsening oxygenation; 2) requirement for intubation despite antibiotics for 24 hours; 3) persistence of fever or hypothermia together with purulent secretions; 4) a 50% or greater increase in pulmonary infiltrates on chest radiograph; 5) development of septic shock or multi-organ dysfunction not present on day 1. fifty percent of patients had at least one pao, and had a higher 28-day mortality (45% versus 19%, p = 0.001), less mean ventilator-free days (10 versus 12, p = 0.001) and elevated serum inflammatory markers such as pct and c-reactive protein compared with those who did not have any paos. the trend remained significant in patients who developed vap, as well as those who had nonventilator icu-acquired pneumonia. the failure to improve oxygenation (partial pressure of oxygen in arterial blood/ fraction of inspired oxygen) and a worsening sofa score over 5 days were independently associated with mortality in a multivariate analysis. the 2007 ats/idsa guidelines recommend using combination antibiotic therapy in patients with severe cap admitted to the icu. adrie and colleagues [36] examined the impact of dual (β-lactam plus macrolide or fluoroquinolone (n = 394)) versus monotherapy (β-lactam alone (n = 471)) in immunocompetent severe cap patients, using a large prospective database. they found no significant difference in 60-day mortality between patients who had dual therapy compared to monotherapy, and in those who received dual therapy, there was no survival advantage between the macrolide and fluoroquinolone subgroups (subdistribution hazard ratio 1.45, 95% ci 0.78 to 2.70, p = 0.24). interestingly, patients who had initial adequate antibiotic therapy had a survival advantage (subdistribution hazard ratio 0.63, 95% ci 0.42 to 0.94.00, p = 0.02) and those who received dual therapy had a higher frequency of initial adequate antibiotics, which did not translate into improved survival. further, subgroup analysis did not reveal a survival benefit even in patients with septic shock or streptococcus pneumoniae infection receiving dual therapy, but dual therapy did not increase the development of mdr pathogens or nosocomial pneumonia. in a similar study including 3,203 hospitalized patients, guideline concordant therapy (defined as macrolides/β-lactams or respiratory fluoroquinolone monotherapy) did not have a mortality benefit compared with discordant therapy, but a composite endpoint of death or icu admission was lower in the concordant group (14.7% versus 29.0%; adjusted or 0.44, 95% ci 0.36 to 0.54, p <0.0001) [37] . most patients received levofloxacin monotherapy in the guideline-concordant group (70%) and there was no significant difference in mortality between patients who received macrolide/β-lactam antibiotics versus those who had fluoroquinolone/β-lactams (adjusted or 0.75, 95% ci 0.395 to 1.42, p = 0.38). the findings from these studies contradict previous reported studies, but lack of randomization and possible misclassification bias limits interpretation. antibiotic dosing in critically ill patients is challenging due to deranged drug metabolism and elimination that can lead to suboptimal dosing. extended infusion of antibiotics with a time-dependent killing mechanism, such as beta-lactams, has been proposed as a means to overcome the pharmacokinetic/pharmacodynamic (pk/pd) alterations in severely ill patients in order to optimize the time that drug concentration exceeds the minimum inhibitory concentration (mic) of the target organism. carlier and colleagues [38] studied the effect of augmented renal clearance on extended infusion of meropenem or piperacillin/tazobactam (pip/tazo) in 61 patients with sepsis and normal creatinine clearance [38] . patients received a loading dose (1 g for meropenem and 4.5 g for pip/tazo) followed by extended infusion usually over 3 hours every 6 hours for pip/tazo and 8 hours for meropenem. only 55% of patients achieved a predefined pk/pd target, and of patients who had augmented renal clearance (48%), the majority did not achieve the target (76%). augmented renal clearance with a clearance >130 ml/ minute was an independent predictor of not achieving the pk/pd target, but the study was not designed to look at outcome and treatment failures, and the pk/pd target may have been set too high. dulhunty and colleagues [39] , in a double-blind randomized controlled trial, compared continuous versus intermittent bolus dosing of pip/tazo, meropenem, and ticarcillin-clavulanate in 60 patients with severe sepsis. patients in the intervention arm received active infusion and placebo boluses and controls received placebo infusion and active boluses. the concentration exceeded the mic more often in the intervention group than in controls (81.8% versus 28.6%, p = 0.001; most with meropenem and least with ticarcillinclaculanate) and the patients in the intervention group had a higher clinical cure rate, but there was no difference in icu or hospital los or mortality. the study reinforces the dosing options available for critically ill patients based on pk characteristics, but did not have the statistical power to determine a mortality benefit, although there was a trend towards better survival in the intervention arm. with the growing development of resistance to beta-lactams, aminoglycosides are advocated for patients with severe sepsis as part of combination therapy, especially with pa infection and the bactericidal activity of aminoglycosides is dependent on peak concentration (cpeak) relative to mic. as noted above, the concentration of aminoglycoside can change in critically ill patients due to variations in drug clearance. in a study of 63 patients with severe sepsis (50% with lung infection) requiring amikacin, investigators used therapeutic drug monitoring and dose adjustments to optimize serum concentration [40] . microbiological eradication and clinical cure were higher in patients who achieved initial optimal cpeak/mic and were proportionately higher with higher target concentration. patients who achieved the target concentration after 3 days had a worse clinical cure and microbiological eradication than those who achieved this goal on the first day. renal failure was seen in 24% of patients and was more likely in those with impaired clearance and higher minimum concentration. inhalation antibiotics have the potential advantage of achieving high alveolar concentrations with minimal systemic side effects. in a matched 1:1 case control study, tumbarello and colleagues [41] studied aerosolized colistin (given via jet nebulizer or ultrasonic nebulizer) as an adjunctive treatment to intravenous therapy with the same drug in 208 vap patients with positive cultures for gram-negative mdr pathogens susceptible only to colistin. patients receiving aerosolized therapy in conjunction with intravenous colistin had a higher clinical cure rate compared with controls (69.2% versus 54.8%, p = 0.03) and fewer days on the ventilator after onset of vap (8 versus 12 days, p = 0.001), but no difference in overall mortality or icu los. also, there was no difference in the rate of new-onset kidney failure between the two groups. the study results are in contrast to previous reports with aerosolized colistin providing only modest benefits. in this study the medication was delivered in the majority of patients using conventional ventilators with jet nebulizers and the local concentration of antibiotics could not be determined. in view of the reported increased incidence of drug-resistant pathogens causing vap and the potential treatment alternative with aerosolized colistin, further randomized controlled studies are needed prior to generalization of the results. in a study looking at factors influencing antibiotic de-escalation in 229 patients admitted to icu with sepsis, only 51.1% of patients had the number of antibiotics reduced or switched to a narrower spectrum [42] . however, there was no difference in mortality rate, icu los or duration of mv between patients who had de-escalation compared with those with no de-escalation. in those patients who did not have de-escalation, 15% had no de-escalation despite meeting criteria. narrowspectrum initial antibiotic therapy (or 0.1, 95% ci 0.0 to 0.1, p <0.001) and infection with an mdr bacteria (or 0.2, 95% ci 0.1 to 0.7, p = 0.006) were factors preventing de-escalation. duration of antibiotic treatment for nosocomial pneumonia is not clearly defined, and previous studies have shown that a short duration may be as clinically effective as a longer duration (>14 days) and more cost-effective. a meta-analysis of four randomized controlled trials (including 883 patients) comparing short (7 to 8 days) with long (10 to 15 days) duration regimens in patients with vap showed no difference in mortality, icu los or mv between the two groups, and more antibioticfree days in the short course group [43] . there was a trend towards more relapses due to non-fermenting gram-negative bacilli in the shorter duration antibiotic cohort. in another observational study, including 89 suspected vap patients with negative bal results, investigators compared the effects of early discontinuation (antibiotics stopped within 1 day of final negative quantitative bal culture results) with late discontinuation of antibiotics (more than 1 day after negative final bal cultures) [44] . there was no difference in mortality between early discontinuation (25.0%) and late discontinuation (30.6%) patients (p = 0.642). clinical resolution as noted by clinical pulmonary infection score was similar in both groups and patients with late discontinuation had a longer duration of antibiotic therapy (9 versus 4 days, p <0.001). interestingly, patients with early discontinuation developed less frequent superinfections compared with late discontinuation patients (22.5% versus 42.9%, p = 0.008). these results add credence to the value of de-escalation for vap patients and to the possibility that longer antibiotic courses may cause microbial persistence and selection pressure leading to the development of microbial resistance. prophylactic systemic antibiotics have a role in preventing early-onset vap in closed head injury patients. valles and colleagues [45] evaluated the role of single-dose antibiotics within 4 hours of intubation (ceftriaxone 2 g intravenously; 1 g ertapenem in those with hypersensitivity to beta-lactam; 500 mg levofloxacin in those with anaphylaxis to beta-lactam) in the prevention of early-onset vap or ventilator-associated tracheobronchitis in comatose patients. they compared 71 patients who received prophylaxis to 58 historical cohorts. the patients who received prophylaxis had fewer microbiologically confirmed cases of vap (7% versus 27.6%, or 0.11, p = 0.009), less mv days, and shorter icu los. however, there was no difference in mortality or hospital los between the two groups. although there was no increased incidence of mdr pathogens in the prophylaxis group with lateonset vap, the study patients did not have surveillance cultures and hence the rate of colonization is unknown. prophylactic antibiotic at the time of intubation in high-risk patients at risk for vap is an interesting concept and further prospective randomized controlled studies are required prior to generalization of the results. statins have possible anti-inflammatory and immunomodulatory effects and their use in patients with pneumonia had previously been reported to lead to beneficial outcomes. papazian and associates in a double-blind, parallel-group study, randomized vap patients (defined as having a clinical pulmonary infection score >5) to receive simvastatin (60 mg) or placebo [46] . the authors planned to enroll 1,002 patients, but the study was stopped prematurely because of futility after enrolling 153 in the intervention arm and 147 in the control group. there was no significant difference in 28-day mortality (6% absolute increase with simvastatin) or other secondary outcomes, including duration of mv, coronary events, ards, or adverse side effects between the two groups. however, of those patients naive to prior statin use, the 28-day mortality was higher in the placebo arm (28% versus 5%, p = 0.01). although this trial was underpowered to highlight any marginal beneficial effects of statins, the results are similar to another recent trial exploring the role of statins in sepsis that also did not find any difference in levels of interleukin-6, but possible beneficial effects in continuing chronic statin therapy [47] . probiotics may restore non-pathogenic gut flora and the value of their use in critically ill patients has been inconclusive. barraud and associates [48] conducted a meta-analysis including 13 randomized studies with 1,439 patients to evaluate the use of probiotics (most with lactobacillus sp.) in the icu. probiotic use did not have a significant impact on mortality or the duration of mv. however, probiotic use resulted in a significant decrease in nosocomial pneumonia even after adjustment for heterogeneity (or 0.54, 95% ci 0.36 to 0.79) and also led to a shorter icu los. use of probiotics could potentially prevent gastric colonization by pathogenic bacteria and might explain the beneficial effects seen with icu-acquired pneumonia. whether this should be added to vap prevention measures is still to be determined and will need further large trials, with vap as the primary end point. respiratory infections remain the most common cause of sepsis and septic shock, with gram-negatives being slightly more common than gram-positives. some patients have sepsis with negative cultures and these patients may have a better prognosis than those with positive cultures. severe infection is part of a multiple system illness, and some recent data have examined the relationship of pneumonia to cognitive impairment, showing that infection can lead to cognitive decline, possibly related to inflammatory cytokines, while at the same time patients who develop pneumonia may be more cognitively impaired than those without pneumonia. many episodes of pneumonia result from gastric aspiration, but recent investigations have shown that development of vap could not be prevented even with enteral feeding and close attention to gastric residual volume. one alternative is to place feeding tubes directly into the small bowel, which may reduce pneumonia risk but not have an impact on mortality. biomarkers may help us guide the need for therapy, the duration of therapy for pneumonia, and the prognosis for survival, but most data have been collected with serum pct measurements. recent studies suggest that kallistatin is a protective hormokine, and that, in the setting of septic shock, low levels may predict adverse outcomes such as ards and death. another biomarker, presepsin, is elevated in severe sepsis patients who die. pct has been used to separate patients with infection from those without infection, but in the presence of chf new data suggest that low levels may rule out infection, but that severe heart failure itself can falsely elevate levels. the diagnosis of vap remains confusing, and new data have shown the limited value of the cdc definition of vacs. vacs include a number of non-infectious diagnoses, and many patients with vap do not have a vac. some data suggest that vacs can be prevented, but there are also studies showing that the currently available ventilator bundles cannot prevent them. in the management of cap and vap, it is important to account for mdr pathogens in empiric therapy. outside the hospital, there are patients who develop hcap and many of these are also at risk for mdr pathogens. new studies have suggested strategies to identify patients at risk for resistant pathogen infection, and therapies that optimize efficacy, without the overuse of broad-spectrum therapy. the optimal therapy of mdr pathogens is being explored, but for mrsa cap, the use of anti-toxin therapy may improve outcome. in vap, the role of resistance in determining outcome is uncertain, but most studies suggest an interaction between drug susceptibility and disease severity. optimizing the therapy of mdr pathogens is being explored in a number of ways, including the use of modified dosing regimens, and inhaled antibiotics for pneumonia. our enhanced understanding of altered renal clearance in severe infection has led to renewed efforts to provide enough antibiotic to seriously ill patients, and to avoid the use of too low a dose of an effective agent. in the future, we will continue our efforts at pneumonia prevention, but this will require a continued understanding of disease pathogenesis, the use of prevention bundles and the application of standard therapies in novel ways (as demonstrated with studies of statins). note: this article is part of a collection of year in review articles in critical care. other articles in this series can be found at [49] . acute respiratory distress syndrome cap: community-acquired pneumonia; cdc: centers for disease control and prevention; chf: congestive heart failure; ci: confidence interval peak concentration; eta: endotracheal aspirate; grv: gastric residual volume; hcap: healthcare-associated pneumonia; h-ivig: hyperimmune iv immunoglobulin; idsa: infectious disease society of america; ivac: infection-related ventilator-associated complication mdr: multi-drug resistant; mic: minimum inhibitory concentration methicillin-sensitive staphylococcus aureus; mv: mechanical ventilation; ofa: sequential organ failure assessment; or: odds ratio pao: predictors of adverse outcome; pcr: polymerase chain reaction pct: procalcitonin; pip/tazo: piperacillin/tazobactam; pk/pd: pharmacokinetic/pharmacodynamic; psi: pneumonia severity index pvl: panton-valentine leucocidin; rt: reverse transcriptase; vac: ventilator-associated complication; vap: ventilator-associated pneumonia the epidemiology of septic shock in french intensive care units: the prospective multicenter cohort episs study profile of the risk of death after septic shock in the present era: an epidemiologic study characteristics and outcomes of culture-negative versus culture-positive severe sepsis the influence of gender on the epidemiology of and outcome from severe sepsis bidirectional relationship between cognitive function and pneumonia effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials suspected ventilator-associated respiratory infection in severely ill patients: a prospective observational study readmission following hospitalization for pneumonia: the impact of pneumonia type and its implication for hospitals plasma kallistatin levels in patients with severe community-acquired pneumonia presepsin (soluble cd14 subtype) and procalcitonin levels for mortality prediction in sepsis: data from the albumin italian outcome sepsis trial procalcitonin testing for diagnosis and short-term prognosis in bacterial infection complicated by congestive heart failure: a multicenter analysis of 4,698 cases procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock -a systematic review and meta-analysis stop antibiotics on guidance of procalcitonin study (saps): a randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients -calculated sample size: 1816 patients the clinical impact and preventability of ventilator-associated conditions in critically ill patients who are mechanically ventilated toward improved surveillance: the impact of ventilator-associated complications on length of stay and antibiotic use in patients in intensive care units implementation of clinical practice guidelines for ventilator-associated pneumonia: a multicenter prospective study temporal trends of ventilator-associated pneumonia incidence and the effect of implementing health-care bundles in a suburban community is a strategy based on routine endotracheal cultures the best way to prescribe antibiotics in ventilator-associated pneumonia? performances of prognostic scoring systems in patients with healthcare-associated pneumonia risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia multidrug-resistant pathogens in hospitalised patients coming from the community with pneumonia: a european perspective a new strategy for healthcare-associated pneumonia: a 2-year prospective multicenter cohort study using risk factors for multidrug-resistant pathogens to select initial empiric therapy evaluation of early mini-bronchoalveolar lavage in the diagnosis of health care-associated pneumonia: a prospective study methicillin resistance is not a predictor of severity in community-acquired staphylococcus aureus necrotizing pneumonia -results of a prospective observational study viral infection in patients with severe pneumonia requiring intensive care unit admission the occurrence and impact of bacterial organisms complicating critical care illness associated with 2009 influenza a(h1n1) infection hyperimmune iv immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza a (h1n1) infection comparison of the bacterial etiology of early-onset and late-onset ventilator-associated pneumonia in subjects enrolled in 2 large clinical studies potentially resistant microorganisms in intubated patients with hospital-acquired pneumonia: the interaction of ecology, shock and risk factors clinical outcomes of pseudomonas aeruginosa pneumonia in intensive care unit patients impact of multidrug resistance on pseudomonas aeruginosa ventilator-associated pneumonia outcome: predictors of early and crude mortality pseudomonas aeruginosa ventilator-associated pneumonia. predictive factors of treatment failure pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes validation of predictors of adverse outcomes in hospital-acquired pneumonia in the icu initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance impact of guideline-concordant antibiotics and macrolide/beta-lactam combinations in 3203 patients hospitalized with pneumonia: prospective cohort study meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial therapeutic drug monitoring of amikacin in septic patients effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients short-vs long-duration antibiotic regimens for ventilator-associated pneumonia: a systematic review and meta-analysis early antibiotic discontinuation in patients with clinically suspected ventilatorassociated pneumonia and negative quantitative bronchoscopy cultures efficacy of single-dose antibiotic against early-onset pneumonia in comatose patients who are ventilated effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial a multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis impact of the administration of probiotics on mortality in critically ill adult patients: a meta-analysis of randomized controlled trials cite this article as: nair and niederman: year in review 2013: critical care -respiratory infections the authors declare that they have no competing interests.author details key: cord-029991-0sy417j0 authors: longhini, federico; bruni, andrea; garofalo, eugenio; ronco, chiara; gusmano, andrea; cammarota, gianmaria; pasin, laura; frigerio, pamela; chiumello, davide; navalesi, paolo title: chest physiotherapy improves lung aeration in hypersecretive critically ill patients: a pilot randomized physiological study date: 2020-08-03 journal: crit care doi: 10.1186/s13054-020-03198-6 sha: doc_id: 29991 cord_uid: 0sy417j0 background: besides airway suctioning, patients undergoing invasive mechanical ventilation (imv) benefit of different combinations of chest physiotherapy techniques, to improve mucus removal. to date, little is known about the clearance effects of oscillating devices on patients with acute respiratory failure undergoing imv. this study aimed to assess (1) the effects of high-frequency chest wall oscillation (hfcwo) on lung aeration and ventilation distribution, as assessed by electrical impedance tomography (eit), and (2) the effect of the association of hfcwo with recruitment manoeuvres (rm). methods: sixty critically ill patients, 30 classified as normosecretive and 30 as hypersecretive, who received ≥ 48 h of imv, underwent hfcwo; patients from both subgroups were randomized to receive rm or not, according to two separated randomization sequences. we therefore obtained four arms of 15 patients each. after baseline record (t0), hfcwo was applied for 10 min. at the end of the treatment (t1) or after 1 (t2) and 3 h (t3), eit data were recorded. at the beginning of each step, closed tracheobronchial suctioning was performed. in the rm subgroup, tracheobronchial suctioning was followed by application of 30 cmh(2)o to the patient’s airway for 30 s. at each step, we assessed the change in end-expiratory lung impedance (δeeli) and in tidal impedance variation (δtiv), and the center of gravity (cog) through eit. we also analysed arterial blood gases (abgs). results: δtiv and cog did not differ between normosecretive and hypersecretive patients. compared to t0, δeeli significantly increased in hypersecretive patients at t2 and t3, irrespective of the rm; on the contrary, no differences were observed in normosecretive patients. no differences of abgs were recorded. conclusions: in hypersecretive patients, hfcwo significantly improved aeration of the dorsal lung region, without affecting abgs. the application of rm did not provide any further improvements. trial registration: prospectively registered at the australian new zealand clinical trial registry (www.anzctr.org.au; number of registration: actrn12615001257550; date of registration: 17th november 2015). mucociliary clearance of secretion is the primary innate protective mechanism of the respiratory tract to remove inhaled particles and microorganism from the tracheobronchial system; it depends from the interaction between ciliated columnar cells and the viscoelastic properties of bronchial secretions [1] . the presence of an endotracheal tube impairs the bronchial mucus velocity transport in anaesthetized dogs [2] ; in critically ill patients undergoing invasive mechanical ventilation (imv), it seriously impairs cough reflex and mucociliary escalator function [3, 4] , promoting the accumulation of tracheobronchial secretions, leading to sequestration and densification of secretions in the lower airways and increasing the risk of pneumonia [5] and lung atelectasis [6] . usual care of the intubated patient includes direct suction applied through the endotracheal tube, which clears a small portion of the airway, is ineffective for clearing secretions in the peripheral airways, and leaves the patient dependent on mucociliary clearance rather than on cough clearance [7] . in intubated patients, the application of various combinations of chest physiotherapy techniques is a commonly used intensive care procedure [8] . there is supportive evidence that various combinations of chest physiotherapy assist in the re-expansion of atelectatic lung [9] , confer short-term improvement in total lung-thorax compliance [10] and expiratory flow rates [11] , and reduce the incidence of ventilator-associated pneumonia [12] . oscillating devices have been repeatedly shown to improve mucus clearance in patients with chronic retention of airway secretions such as cystic fibrosis [13] [14] [15] . on the opposite, little is known about their effects on patients with acute respiratory failure (arf) undergoing imv. high-frequency chest wall oscillation (hfcwo) is an airway clearance technique by which external forces are applied to the chest through an inflatable wrap connected to a device that generates vibrations at variable frequency and intensity. various mechanisms of action have been proposed for hfcwo: (1) augmentation of the expiratory flow, which increases the annular flow of mucus towards the oropharynx when exceeding by more than 10% the inspiratory peak flow [16] [17] [18] ; (2) improvement of mucus rheological (spinnability and viscoelastic) properties [19, 20] ; (3) increase of ciliary motility by reflected stimulation of vagus nerve, in particular when the applied oscillations range between 11 and 15 hz [21] ; and (4) enhancement of the gasliquid transport [16, 22] . recent findings showed that hfcwo, when compared to conventional physiotherapy, improves the amount of aerated lung regions and oxygenation of intubated patients in intensive care unit (icu) [23, 24] . electrical impedance tomography (eit) has been introduced in icu clinical practice as a non-invasive bedside monitoring system able to evaluate the aeration and ventilation of different lung regions [25] . this technique is based on the injection of small currents and voltage measurements through multiple electrodes placed around the chest of the patient. the recorded currents generate a cross-sectional image representing the change of impedance throughout the patient's respiration and, therefore, the lung ventilation [25] . the aim of this pilot randomized physiological study is assessing the effects of hfcwo on lung aeration and ventilation distribution, as assessed by eit, in normosecretive and hypersecretive mechanically ventilated patients. in addition, we also evaluate the association of hfcwo with recruitment manoeuvres (rm). this four-arms randomized study was conducted in the sant'andrea hospital of vercelli (italy) after local ethical committee approval (ethical committee approval number aslvc.rian.14.03, on 11th september 2014). it included patients who required more than 48 h of imv and who satisfied eligibility criteria. all enrolled patients underwent hfcwo and were randomized to receive a rm or not. the primary outcome of the study was the variation in end-expiratory lung impedance. secondary outcomes were the tidal impedance and arterial partial pressure of oxygen (pao 2 ) variations among groups. the following variables were collected: socio-demographic characteristics, body mass index (bmi), comorbidities, reason for icu admission, acute physiology and chronic health disease classification system ii score (apacheii), sequential organ failure assessment (sofa), and simplified acute physiology score (saps2). changes in vital parameters and arterial blood gas analysis (abgs) were also recorded. all participants provided written informed consent. this trial followed the consolidated standards of reporting trials (consort) reporting guidelines and was prospectively registered in the australian new zealand clinical trial registry (actrn12615001257550; www.anzctr.org.au, date of registration 17th november 2015). we considered eligible any patient ≥ 18 years who was admitted to the icu and received more than 48 h of imv with heated humidification. exclusion criteria were as follows: (1) life-threatening cardiac arrhythmias or signs of ischaemia, (2) pneumothorax, (3) haemoptysis, (4) acute spinal injury, (5) need for vasopressors, (6) brain injury, (7) pulmonary embolism, (8) recent chest trauma or burn, (9) recent surgery, (10) pregnancy, (11) enrolment in other research protocols, and (12) denied consent. eligible patients were classified as "normosecretive" or "hypersecretive". definition of "normosecretive" or "hypersecretive" was based on the criteria adopted in previously published studies [26] [27] [28] [29] . briefly, patients who required two or more broncoaspirations/hour in the previous 8 h were considered "hypersecretive". suction occurred only if auscultation revealed secretions in the larger airway, if the airway pressure waveform indicated fluid in the system and/or the peak airway pressures increased [30] . an equal number of patients were enrolled from the hypersecretive and normosecretive group. two separate randomization sequences were computer-generated (one for each subpopulation) and sealed in opaque numbered envelopes. in practice, a total of 60 patients were randomized in this four-arms pilot physiological study. among them, 30 patients belonged to the normosecretive group and 30 patients to the hypersecretive one. each patient was randomized to receive rm or not. therefore, we obtained four groups of 15 patients: normosecretive not receiving rm (n rm −), normosecretive receiving rm (n rm+), hypersecretive not receiving rm (h rm−), and hypersecretive receiving rm (h rm+) (fig. 1) . after randomization, one silicon eit belt of proper size with 16 electrodes was placed around the patient's chest between the 4th and 6th intercostal space and connected to an eit device (pulmovista 500; draeger medical gmbh, lübeck, germany) [25, 31, 32] . quality of signal was ascertained through a dedicated tool of the eit device. eit belt positioning was therefore marked on the skin, in order to avoid its displacement during the whole study period. patients were switched to receive imv by a ventilator connected to the eit device through a rs232 interface (v500; draeger medical gmbh, lübeck, germany); a heated humidifier (mr850 heated fig. 1 flowchart of the study. the figure depicts the study flowchart, which includes four arms humidifier; fisher & paykel, auckland, new zealand) was also used. ventilatory mode and settings were those clinically indicated by the attending physicians, while heated humidifier was set at 37°c and relative humidity at 100% (i.e. 44 mg/l of absolute humidity). ventilator settings and analgo-sedation regimen were not modified throughout the entire study protocol and no supportive measures such as instillation of isotonic or hypertonic saline were used. subsequently, a dedicated inflatable wrap garment of proper size was placed around the patient's chest and connected to a generator of pressure and oscillation (the vest 105 system, hill rom, st. paul, mn, usa). finally, tracheobronchial suctioning was assured throughout a closed aspiration system (kimvent, turbo-cleaning closed suction system, kimberly-clark, roswell, ga, usa). after eit baseline record (t0), hfcwo was applied for 10 min with an oscillation frequency of 12 hz [33, 34] . soon after the end of the treatment (t1) or after 1 (t2) and 3 h (t3), eit data were recorded for 10 min. at the beginning of each step of the protocol, closed tracheobronchial suctioning was performed. in the subgroup of patients randomized to receive rm, tracheobronchial suctioning was followed by application of 30 cmh 2 o to the patient's airway for 30 s. predefined criteria for protocol interruption were as follows: (1) onset of haemodynamic instability, (2) lifethreatening arrhythmias or electrocardiographic signs of ischaemia, and (3) worsening of oxygen saturation (sato 2 ), as assessed by pulse oxymetry. detailed information about data acquisition and analysis is provided in the supplemental material (supplemental material). briefly, we computed the tidal impedance variation (tiv) as the difference of impedance between the end of inspiration and expiration [31] , and changes in tiv (δtiv, ml) and in end-expiratory lung impedance (δeeli, ml), which is a surrogated measure of the endexpiratory lung volume [31, 32, 35] . we also defined two contiguous regions of interest (rois) of the same size (ventral and dorsal) and computed tiv, δtiv, and δeeli for both [32, 35] . the amount of pixel of nonventilated area was also calculated and expressed as percentage of the pixel number. we also computed the centre of gravity (cog), which expresses the distribution of tiv in ventral to dorsal direction, calculated by dividing the dorsal by the overall tiv, expressed as percentage [36] . because of the lack of previous similar studies and given the descriptive and physiologic purpose of our pilot randomized study, we arbitrarily decided to enrol a sample of 60 patients, 30 for each subpopulation (i.e. normosecretive and hypersecretive patients). normally distributed continuous data were described as means and standard deviation (sd) and non-normal distributed data were described as median and interquartile range [25th-75th interquartile range]. normality of continuous data was assessed through the kolmogorov-smirnov test. comparisons between groups were performed by using the student t test or the mann-whitney u test, for the continuous variables normally or non-normally distributed, respectively. categorical variables were reported as numbers and percentages. categorical data were compared with a chi-square test or fisher test, when required. to assess the effects of the "amount of secretions", "application of a rm" and their interaction with the "time after hfcwo application", continuous variables were analysed with the analysis of variance (anova) or friedman test, according to the gaussian distribution of data. furthermore, positive endexpiratory pressure (peep) values between the four groups were compared through a one-way anova test. post hoc bonferroni test was applied for pair-wise multiple comparisons, when indicated. we considered significant two-sided p values < 0.05. statistical analysis was performed using the sigmaplot v. 12.0 (systat software inc., san jose, ca). thirty normosecretive and 30 hypersecretive patients were enrolled between december 2015 and june 2016. all patients completed the study protocol without any complication and were included in data analysis. demographic, anthropometric, and clinical characteristics of included patients are presented in table 1 . no differences in percentage of not ventilated areas, tiv, δtiv, and centre of gravity were found between normosecretive and hypersecretive patients at all time points. hypersecretive patients showed higher δeeli at t2 and t3, as opposed to the respective time points in normosecretive patients (table 2 ; fig. 2 ). eit parameters did not differ between patients randomized to receive or not rm (table 3) . when compared to n rm− patients, the h rm− group showed higher overall dorsal and ventral δeeli. similarly, both overall dorsal and ventral δeeli values were higher in h rm+, as compared to n rm+. on the contrary, no differences in δtiv were recorded. (table e1 , supplemental material). vital parameters and abgs were not different between any subgroup. our study shows that chest physiotherapy by hfcwo may improve lung aeration of hypersecretive mechanically ventilated patients, without affecting gas exchange. on the contrary, it does not produce any significant changes in normosecretive patients. in addition, our study shows that the application of rm does not add any further advantage, both in normosecretive and hypersecretive groups of patients. in the last years, mechanical assisted cough devices have been increasingly used in the acute setting; however, these devices aim to remove secretions from the large airways to the airway opening, through a sequential application of positive and negative (sub-atmospheric) pressure to the airway [37] . differently, hfcwo aims to mobilize secretions from the smallest and deepest airways towards the upper and larger airways. to date, only a few data exist on the application of hfcwo in mechanically ventilated patients. in fact, most of the published studies mainly refer to the application of this technique in different populations. esguerra-gonzales et al. proved the efficacy of hfcwo in oxygenation improvement in 45 non-intubated recipients of lung transplantation, as compared to the conventional physiotherapy treatment [38] . accordingly, kuyrukluyildiz et al. showed that the application of hfcwo in intubated icu patients provided more secretion mobilization, translating in better oxygenation after 72 h of repeated applications [23] . on the contrary, clinkscale et al. did not find any benefit in hypersecretive patients treated with hfcwo, although this latter was better tolerated by patients than conventional physiotherapy [39] . similar results were reported in patients with chronic obstructive pulmonary disease [40] , neuromuscular disorders [41] [42] [43] , and after lung resection surgery [44] . since mucus retention can occlude distal and smaller airways, inducing atelectasis of the alveoli [45] , we decided to randomize some normosecretive and hypersecretive patients to receive a rm after hfcwo and closed suction. in fact, after application of hfcwo and suctioning, sputum and airway obstruction were supposed to be removed, while distal and smaller airways to be reopened. furthermore, suctioning may induce a loss of end-expiratory lung volume and atelectasis [46] . therefore, the application of rms should have reopened the lung, which was subsequently kept open by positive the findings of the present study are of potential clinical interest. first, our results suggest that during mechanical ventilation, hfcwo should be applied only in hypersecretive patients. this is important in order to save time and workload for nurses and/or physiotherapists. furthermore, we observed a significant increment of δeeli, which is a surrogated measure for the functional residual capacity. in principle, lung recruitment, increasing functional residual capacity, should be coupled with improved oxygenation [23, 31] . surprisingly, we did not observe such an improvement. these findings could be explained by a correction of the ventilation-perfusion mismatch, rather than a reduction of the intrapulmonary shunt, as also indirectly confirmed by the lack of effect produced by rm. in this manner, the oxygenation enhancement would be masked/covered/obscured by oxygen administration, which occurred in all patients (mean fio 2 0.40 ± 0.09 in the hypersecretive group). secondarily, since the physiological benefits we observed tended to reduce after 3 h from the application of hfcwo, we might hypothesize that the treatment should be repeated every 4 h. however, further studies are necessary to support this hypothesis. before drawing our conclusions, some limitations deserve discussion. first, we arbitrarily defined normosecretive and hypersecretive patients according to the number of tracheal-bronchial aspiration per hour in the prior 8 h, which is definitely a gross and simplistic criterion. the same criterion was adopted in previously published studies [26] [27] [28] and, worth remarking, allowed us to differentiate two subpopulations with different physiologic outcomes. in another previous study, a single operator assessed the amount of secretions, who classified patients as producing either no, mild, moderate, or abundant endotracheal secretions based on personal observations in the preceding 4 to 6 h [29] . however, this method is quite subjective and opened to criticisms. in addition, no standardized bronchoaspiration protocol was applied and nurse subjectivity might have generated a bias in patients' selection. moreover, the number of patients enrolled was small. worth remarking, however, several studies aimed to assess modifications in eit parameters in response to different interventions t0 baseline assessment, t1 assessment soon after the end of the treatment, t2 assessment 1 h after the end of the treatment, t3 assessment 3 h after the end of the treatment, tiv tidal impedance variation, δtiv difference of tiv from t0, δeeli difference of end-expiratory lung impedance from t0, paco 2 arterial partial pressure of carbon dioxide, pao 2 /fio 2 ratio between arterial partial pressure and inspired fraction of oxygen *p < 0.05 normosecretive vs. hypersecretive within the same time point a p < 0.05 t0 vs. t2 within the same subpopulation b p < 0.05 t0 vs. t3 within the same subpopulation. all data are expressed as mean (standard deviation) enrolled similar, or even lower, number of patients [26, 28, 41, 42] . although the great effect size we observed suggests the appropriateness of the sample, our study has to be considered as hypothesis generating. in addition, this is a physiologic study and we cannot provide any information about the clinical implications of our finding. knowledge of pathophysiologic mechanisms and physiologic consequences of any intervention are fundamental for designing meaningful randomized, controlled trials. finally, the vast majority of patients were ventilated in pressure support ventilation, which is an assisted modality. although ventilator settings were not modified throughout the entire study protocol, the tidal volume might have been changed. in fact, not only the inspiratory airway pressure participates in the tidal volume generation, but also respiratory muscle activation and respiratory mechanics [47, 48] . in the attempt to optimize the control of these variables, we also kept the analgosedation regimen unmodified, since analgesics and sedatives may influence the respiratory drive and/or pattern [49] [50] [51] . as a result, δtiv did not change throughout the study protocol, either between normosecretive and hypersecretive patients or between patients randomized to receive or not a rm. authors' contributions f.l. was responsible for the conception and design of the study; and the acquisition, analysis, and interpretation of the data; and for drafting and revising the article for final approval of the version to be published. a.b. was responsible for the conception and design of the study; for the acquisition, analysis, and interpretation of data; and for drafting and revising the article for final approval of the version to be published. e.g. was responsible for the conception and design of the study; for the acquisition, analysis, and interpretation of data; and for drafting and revising the article for final approval of the version to be published. c.r. was responsible for the acquisition of data and for revising the article for final approval of the version to be published. a.g. was responsible for the acquisition of data and for revising the article for final approval of the version to be published. g.c. was responsible for the acquisition of data and for revising the article for final approval of the version to be published. l.p. was responsible for analysis and interpretation of the data and for drafting and revising the article for final approval of the version to be published. p.f. was responsible for analysis and interpretation of the data and for drafting and revising the article for final approval of the version to be published. d.c. participated in the design of the study; the analysis of the data, and in revising the article for final approval of the version to be published. p.n. was responsible for the conception and design of the study and the analysis and interpretation of rm recruiting manoeuvre, t0 baseline assessment, t1 assessment soon after the end of the treatment, t2 assessment 1 h after the end of the treatment, t3 assessment 3 h after the end of the treatment, tiv tidal impedance variation, δtiv difference of tiv from t0, δeeli difference of end-expiratory lung impedance from t0, paco 2 arterial partial pressure of carbon dioxide, pao 2 /fio 2 ratio between arterial partial pressure and inspired fraction of oxygen data, as well as for drafting and revising the article for important intellectual content and final approval of the version to be published. hill-rom provided the vest 105 system used for the study. draeger provided the ventilator and the eit system used for the study. the authors will share all of the individual participant data collected during the trial after de-identification, to researchers who provide a methodologically sound proposal. the full protocol and raw data are available at longhini.federico @gmail.com ethics approval and consent to participate the study was approved by the local ethics committees of alessandria, italy (approval number aslvc.rian.14.03, on 11th september 2014). written informed consent was obtained from each participant before inclusion in the study, according to the local regulations and principles outlined in the helsinki declaration. all patients gave consent for data publication according to national regulations. all authors read the final manuscript and approved the submitted version. dr. navalesi's research laboratory has received equipment and grants from maquet critical care, draeger, and intersurgical s.p.a. he also received honoraria/speaking fees from maquet critical care, orionpharma, philips, resmed, msd, and novartis. dr. navalesi contributed to the development of the helmet next, whose licence for patent belongs to intersurgical s.p.a., and receives royalties for that invention. dr. longhini and dr. navalesi contributed to the development of a new device (not discussed in the present study), whose patent is in progress (european patent application number ep20170199831). the remaining authors have no conflict of interest to disclose. author details airway epithelial differentiation and mucociliary clearance effect of cuffed endotracheal tubes on tracheal mucous velocity ventilator-associated pneumonia or endotracheal tube-associated pneumonia? an approach to the pathogenesis and preventive strategies emphasizing the importance of endotracheal tube clearance of mucus from 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management in the mechanically ventilated patient bronchoscopic suctioning may cause lung collapse: a lung model and clinical evaluation end-inspiratory airway occlusion: a method to assess the pressure developed by inspiratory muscles in patients with acute lung injury undergoing pressure support neurally adjusted ventilatory assist remifentanil effects on respiratory drive and timing during pressure support ventilation and neurally adjusted ventilatory assist effects of propofol on patient-ventilator synchrony and interaction during pressure support ventilation and neurally adjusted ventilatory assist effects of dexmedetomidine and propofol on patient-ventilator interaction in difficult-to-wean, mechanically ventilated patients: a prospective, open-label, randomised, multicentre study springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations part of the results of this study was presented in abstract form at the european respiratory society held in london (uk) from 3rd to 7th september 2016. we are in debt with rosalba lembo for the support provided for the statistical analysis. chest physiotherapy by hfcwo significantly improves aeration of the dorsal region of the lung in hypersecretive mechanically ventilated patients without affecting gas exchange. the application of rm does not add any further benefit. hfcwo did not produce any effect in normosecretive patients. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03198-6.additional file 1: table e1 . data from the 4 subgroups of patients stratified according the amount of secretions and application of recruiting manoeuvres. key: cord-254287-8q2gdy5n authors: azoulay, elie; de waele, jan; ferrer, ricard; staudinger, thomas; borkowska, marta; povoa, pedro; iliopoulou, katerina; artigas, antonio; schaller, stefan j.; shankar-hari, manu; pellegrini, mariangela; darmon, michael; kesecioglu, jozef; cecconi, maurizio title: international variation in the management of severe covid-19 patients date: 2020-08-05 journal: crit care doi: 10.1186/s13054-020-03194-w sha: doc_id: 254287 cord_uid: 8q2gdy5n background: there is little evidence to support the management of severe covid-19 patients. methods: to document this variation in practices, we performed an online survey (april 30–may 25, 2020) on behalf of the european society of intensive care medicine (esicm). a case vignette was sent to esicm members. questions investigated practices for a previously healthy 39-year-old patient presenting with severe hypoxemia from covid-19 infection. results: a total of 1132 icu specialists (response rate 20%) from 85 countries (12 regions) responded to the survey. the survey provides information on the heterogeneity in patient’s management, more particularly regarding the timing of icu admission, the first line oxygenation strategy, optimization of management, and ventilatory settings in case of refractory hypoxemia. practices related to antibacterial, antiviral, and anti-inflammatory therapies are also investigated. conclusions: there are important practice variations in the management of severe covid-19 patients, including differences at regional and individual levels. large outcome studies based on multinational registries are warranted. there is little evidence to support the optimal management of severe covid-19 patients [1, 2] . to document whether there is a variation in practices, we performed an online survey (april 30-may 25, 2020) on behalf of esicm. in this online survey, a case vignette (https://www.surveymonkey.com/r/f2ffc6s) was sent to icu specialists who are members of esicm. questions investigated practices for a previously healthy 39-year-old patient presenting with severe hypoxemia from covid-19 infection ( table 1 ). the 85 participating countries were grouped into 12 different regions [3] : continuous variables are described as median (interquartile range [iqr] ) and are compared between groups using the non-parametric wilcoxon rank-sum test. categorical variables are described as frequency (percentages) and are compared between groups using fisher's exact test. statistical analyses were performed with r statistical software, version 3.4.3 (available online at http://www.rproject.org/). a p value < 0.05 was considered significant. response rate was 20% (n = 1132 intensive care (icu) specialists from 85 countries, including 1001 complete answers). respondents (median 45 years [iqr, 39-53], 34% women) were from middle europe (25%), south europe (23%), the united kingdom (uk) (12%), south america (9%), north europe (8.1%), eastern europe (5.3%), middle-east (5%), north america (4.7%), asia (3.3%), india (2.7%), australia-new zealand (1.3%), or africa (0.6%); 54% were living in a large city (> 1 million inhabitants), and 55% were working in university-affiliated hospitals. the median (iqr) number of icu beds was increased from 20 (11-36) to 35 (20-60) during the pandemic surge. as the patient had 88 (peripheral oxygen saturation) spo 2 on 9 l/min of oxygen, direct icu admission was reported in 56% (30-90%) of the respondents, with significant variation across regions ( fig. 1, p < 0 respondents were then asked about the first-line oxygenation strategy, which varied significantly across regions (fig. 2, p < 0.0001) . first-line high flow nasal cannula (hfnc) was used by 22.9% of the respondents (0% in australia-new zealand, 38% in eastern europe). noninvasive ventilation was used by 25.5% of the respondents (5.4% in north america, 43.6% in the uk). interestingly, 8% of the respondents were using first-line intubation (0% in australia-new zealand, 23% in asia). women less frequently initiated hfnc (32% vs. 42%, p = 0.02). the availability of an intermediate care unit influenced the use of hfnc or non-invasive ventilation (niv) (32.8% vs. 21.7%, p = 0.03). along this line, a higher number of icu beds (24 (12-40) vs. 18 (10-30) beds, p = 0.0009) was associated with the use of hfnc and niv. interestingly, 37.5% were using prone positioning in awake nonventilated patients. to assess whether hfnc or niv should be continued, icu specialists relied on spo 2 (85.7%), respiratory rate (71.4%), followed by dyspnea (47.1%), and comfort (45.4%). criteria for intubation included clinical signs of respiratory distress (94%), high oxygen flow to maintain a spo 2 of 95% (33.5%), or low spo 2 only (25.6%). following intubation, the patient had a partial pressure of oxygen/fraction of inspired oxygen (p/f) ratio of 84 mmhg. although prone positioning (71.2%) and neuromuscular blockade (59.7%) were often used to optimize oxygenation, the practice varied significantly across countries. for instance, prone positioning was performed in 70-85% of the cases in asia, india, eastern europe, middle europe, south america, south europe, and the uk, whereas africa, australia-new zealand, middle east, north america, and scandinavia were in the 50-70% range (fig. 3, p < 0 antibiotic prescribing was routine for all patients in 44.2% of the respondents and biomarker-guided in 36.5%, without significant variation across regions. routine antibiotics were more frequently used by respondents working in university-affiliated hospitals (48.3% vs. 40.9%, p = 0.03) and those living in large cities (49.3% vs. 40.2%, p = 0.01). biomarker-guided antibiotic therapy was less frequent in large cities (47.3% vs. 57.4%, p = 0.007). regarding antiviral therapy, 48.9% reported not prescribing antivirals, 42.6% were giving hydroxychloroquine, 17% lopinavir-ritonavir, and 15% remdesivir. figure 4 displays significant variation in antiviral prescriptions across regions (p < 0.0001 women (41.7% vs. 28.2%, p < 0.0001). there was significant variation in the use of interleukin-6 (il-6)/il-1 blockade or of corticosteroids across countries (p < 0.0001 for both tests). other collected variables were not associated with the use of antiinflammatory drugs. this survey highlights important practice variations in the management of severe covid-19 patients, including differences at regional and individual levels. this illustrates that neither idsa nor surviving sepsis guidelines did recommend any of these treatments, but instead encouraged inclusion of patients into trials [1, 4, 5] . since the publication of these guidelines, no more evidence has been made available to ascertain that these specific covid-19 therapies should be included in the standard of care. learning from this heterogeneity will not only raise hypothesis on optimal patient's management, but also serves as a tool to suggest personalized management for each clinical phenotype [6, 7] . this study has several limitations. first, the study suffers from a nonresponse bias of 80%. second, even though only physicians have responded, we cannot ascertain that all of them had the clinical expertise and the experience of managing covid-19 patients. last, questions about specific treatments did not take into account the fact that the level of evidence has changed over time. as no management guidelines have allowed to guide practices for the covid-19 pandemic, heterogeneous behaviors are reported. large charité -universitätsmedizin berlin, corporate member of freie references surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (covid-19) randomized clinical trials and covid-19: managing expectations changes in end-of-life practices in european intensive care units from 1999 to 2016 infectious diseases society of america guidelines on the treatment and management of patients with covid-19 managing icu surge during the covid-19 crisis: rapid guidelines prothrombotic phenotype in covid-19 severe patients clinical phenotypes of critically ill covid-19 patients publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are indebted to dominique de boom, nicolas vander elst, and guy francois from the esicm office for their fast and high-quality support to prepare this survey and its diffusion. all authors contributed to the design, the development of the instrument, and interpretation of data. all authors have approved the submitted manuscript. availability of data and materials fully available upon request.ethics approval and consent to participate all participants agreed online to complete the survey. all participants consented. the authors declare no conflict of interest in relation to this survey. key: cord-004263-m1ujhhsc authors: koekkoek, w. a. c.; menger, y. a.; van zanten, f. j. l.; van dijk, d.; van zanten, a. r. h. title: the effect of cisatracurium infusion on the energy expenditure of critically ill patients: an observational cohort study date: 2020-02-03 journal: crit care doi: 10.1186/s13054-020-2744-7 sha: doc_id: 4263 cord_uid: m1ujhhsc background: both overfeeding and underfeeding of intensive care unit (icu) patients are associated with worse outcomes. a reliable estimation of the energy expenditure (ee) of icu patients may help to avoid these phenomena. several factors that influence ee have been studied previously. however, the effect of neuromuscular blocking agents on ee, which conceptually would lower ee, has not been extensively investigated. methods: we studied a cohort of adult critically ill patients requiring invasive mechanical ventilation and treatment with continuous infusion of cisatracurium for at least 12 h. the study aimed to quantify the effect of cisatracurium infusion on ee (primary endpoint). ee was estimated based on ventilator-derived vco(2) (ee in kcal/day = vco(2) × 8.19). a subgroup analysis of septic and non-septic patients was performed. furthermore, the effects of body temperature and sepsis on ee were evaluated. a secondary endpoint was hypercaloric feeding (> 110% of ee) after cisatracurium infusion. results: in total, 122 patients were included. mean ee before cisatracurium infusion was 1974 kcal/day and 1888 kcal/day after cisatracurium infusion. multivariable analysis showed a significantly lower ee after cisatracurium infusion (md − 132.0 kcal (95% ci − 212.0 to − 52.0; p = 0.001) in all patients. this difference was statistically significant in both sepsis and non-sepsis patients (p = 0.036 and p = 0.011). non-sepsis patients had lower ee than sepsis patients (md − 120.6 kcal; 95% ci − 200.5 to − 40.8, p = 0.003). body temperature and ee were positively correlated (spearman’s rho = 0.486, p < 0.001). hypercaloric feeding was observed in 7 patients. conclusions: our data suggest that continuous infusion of cisatracurium in mechanically ventilated icu patients is associated with a significant reduction in ee, although the magnitude of the effect is small. sepsis and higher body temperature are associated with increased ee. cisatracurium infusion is associated with overfeeding in only a minority of patients and therefore, in most patients, no reductions in caloric prescription are necessary. targeting optimal nutrition concerning energy goals is essential in critically ill patients, as both underfeeding and overfeeding have been associated with increased morbidity and mortality [1] . ideally, the target is based on energy expenditure (ee). however, due to the pathophysiological response to critical illness, iatrogenic interventions, and differences in body composition, ee is highly variable in and between critically ill patients [2] . frequent monitoring of ee may circumvent this problem and help to adjust the optimal amount of calories on an individual basis. at present, indirect calorimetry is considered the gold standard. however, frequently, this technique is not available and often unfeasible [3] . to optimize nutritional targets without frequent monitoring of ee, it is essential to know which factors are associated with either an increase or decrease in ee. specific conditions expected to influence ee have been studied such as sepsis [4] [5] [6] , burns [4, 7] , trauma [4, 8] , cerebrovascular accidents [4, 9] , pregnancy [10] , body temperature [4] , administration of sedatives [11] , and therapeutic hypothermia [4, 12] . an increased ee has been reported in patients with sepsis, trauma, burns, fever, and pregnancy. therapeutic hypothermia and the administration of sedatives are associated with a decrease in ee [4] . however, limited information is available on the effects of neuromuscular blocking agents (nmbas) on ee. furthermore, it is not known whether nmba administration affects the ee in sepsis patients similarly compared with non-sepsis patients and in relation to the baseline temperature. this study aimed to quantify the effect of cisatracurium infusion on ee of adult critically ill patients. also, we analyzed the effects of body temperature and sepsis on ee. secondary endpoint was hypercaloric feeding as a consequence of muscle relaxation. we performed a retrospective observational study in patients treated with cisatracurium at the mixed medicalsurgical adult intensive care unit of the gelderse vallei hospital, ede, the netherlands, between january 1, 2011, and october 31, 2016. patients were included when they met with the following inclusion criteria: adult critically ill patients (≥ 18 years) requiring invasive mechanical ventilation and treatment with cisatracurium for at least 12 h. exclusion criteria were pregnancy, hypothermia induced by therapeutic temperature management, burns, and malignant hyperthermia because these conditions have a substantial effect on ee. patients were also excluded when data on vco 2 were incomplete. in patients with multiple icu admissions during the study period, data from readmissions were excluded. an icu admission was considered readmission when the patient was admitted within 6 months from the primary icu admission. cisatracurium is the nmba of choice for sustained neuromuscular blockade during critical illness in gelderse vallei hospital. cisatracurium was administered when indicated according to the international clinical practice guidelines for the sustained neuromuscular blockade in the adult critically ill patient [13] . an infusion was started at doses of 3 μg/kg per minute and then adjusted by assessment of the train-of-four (tof) using a peripheral nerve stimulator (tof-watch® s, dublin, ireland). according to the hospital protocol, tof measurements were performed every hour, and dosage adjustments were made to achieve a tof level of 1 or lower. the electrodes of the tof-watch® were placed on the other wrist daily to prevent skin lesions. the primary endpoint was the total ee, expressed as kcal/day, which was measured before and during cisatracurium infusion. indirect calorimetry was not routinely available during the study period. ee was, therefore, estimated by an adjusted version of weir's equation using the ventilator-derived vco 2 (eevco 2 ). eevco 2 = 3.941 × vco 2 (l/min) / respiratory quotient + 1.11 × vco 2 (l/min) × 1440. the respiratory quotient was considered to be a fixed value of 0.86 [14] [15] [16] . the mechanical ventilator measured the vco2 (hamilton-s1, hamilton medical ag, bonaduz, switzerland), and every minute, data are automatically sent to our electronic patient data management system (metavision; imdsoft metavision®, tel aviv, israel). for each patient, the vco 2 was collected during the 12 h before and during the 12 h after the start of cisatracurium infusion. when patients were not admitted to the icu 12 h before the start of cisatracurium infusion, the parameters of the available hours were used. the eevco 2 was calculated every 2 h using the mean vco 2 measurements from the previous 2 h. secondary endpoint was hypercaloric feeding (> 110% of ee) after cisatracurium infusion. we also evaluated icu length of stay (los) and in-hospital mortality in patients receiving hypercaloric versus regular or hypocaloric feeding. the world health organization/food and agricultural organization of the united nations (who/fao) formulas were used to calculate caloric and protein targets by our computerized feeding protocol [17] . according to bmi, the actual (bmi < 27), corrected (bmi 27-30; regression to bmi of 27), or ideal body weight (bmi > 30; regression to bmi 21 in women and bmi 22.5 in men) was used. an addition to the resting ee (ree) of 20% was used to correct for disease activity [18] . most parameters were routinely collected into an extensive icu database during standard clinical care. data extraction was performed using sas enterprise guide queries (version 7.12hf1) searching our patient data management system (metavision; imdsoft metavision®, tel aviv, israel, and neozis®, electronic medical record, mi consultancy, katwijk, the netherlands). data to calculate the charlson comorbidity index (cci) [19] were obtained from the quality management system for hospital mortality registration. data verification was performed manually. collected data were de-identified and stored on a secure hospital computer. there were no identifiable paper documents. descriptive data are reported as means and standard deviation (sd) or median and interquartile range in case of skewed distributions, or as frequencies and percentages when appropriate. for the primary analysis, comparing the ee before and after cisatracurium infusion, a general linear mixed model analysis for repeated measures was performed with an autoregressive covariance structure. in this analysis, we corrected for body temperature, sedative and noradrenaline dosages, ph, peep, and fio 2 and repeated measurements. we performed a subgroup analysis of septic and nonseptic patients. we also evaluated the effects of body temperature on ee with the pearson or spearman rank correlation tests. the effects of sepsis on ee were analyzed through general linear mixed models, correcting for the following confounders: cisatracurium, temperature, nutric score, gender, bmi, admission type, and repeated effects. finally, we evaluated the effect of hypercaloric feeding vs. normocaloric and hypocaloric feeding on in-hospital mortality and icu length of stay (los) by chi-square test and one-way anova, respectively. a p value of < 0.05 was considered statistically significant. the data analyses were performed using ibm corp. spss statistics for windows (version 24.0, released 2015 new york, usa). during the study period, 4247 patients were admitted to the icu, of which 179 received cisatracurium for at least 12 h and therefore were eligible for inclusion. we excluded 57 patients according to the exclusion criteria. in total, 122 patients were enrolled in this study (fig. 1) . baseline characteristics and nutritional parameters are shown in tables 1, 2, and 3. the median age was 65.5 years, and 36.1% were female. the median sofa and apache ii scores on admission were 8 and 22, respectively. most patients were septic (58.2%) and admitted to the icu because of medical reasons (73%). a median icu and hospital los of 15 and 23 days were found. the in-hospital mortality was 28.7%. the mean ee was 1974 kcal/day before cisatracurium infusion (= control period) and 1888 kcal/day during cisatracurium infusion resulting in a mean difference of in the subgroup of sepsis patients, cisatracurium reduced ee from 2058 kcal/day to 1932 kcal/day (mean difference of − 125.7 kcal; 95% ci − 243.0 to − 8.4; p = 0.036). in the subgroup of non-sepsis patients, cisatracurium reduced ee from 1932 kcal/day to 1795 kcal/day (mean difference − 137.2 kcal; 95% ci − 243.0 to − 31.4; p = 0.011). in both analyses, adjustment for body temperature, sedative and noradrenaline dosages, ph, peep, and fio 2 were performed. a significant non-linear positive association between body temperature and ee was found (spearman's rho = 0.486, p < 0.001; fig. 3 ). mean ee was 1805 kcal (95% ci 1721-1888) in nonseptic patients and 1909 kcal (95% ci 1838-1978) in septic patients (p = 0.062). in mixed-model multivariable analysis, a significantly lower ee was observed in nonseptic patients than in septic patients (mean difference − 120.6 kcal, 95% ci − 200.5 to − 40.8; p = 0.003). only seven patients (5.7%) received > 110% of their caloric target (estimated by eevco 2 ) on the first day of cisatracurium infusion. twenty patients (16.4%) received between 80 and 110% of their caloric target, while 95 patients (77.9%) were fed hypocalorically (< 80% of caloric target). because of the small number of patients with hypercaloric intake, no associations between hypercaloric intake and icu los or mortality were calculated. we studied the effect of cisatracurium infusion on ee in a cohort of 122 adult critically ill patients. cisatracurium infusion lowered ee as estimated by the vco 2 method by 6.6%. nmbas act by interfering with the binding of acetylcholine to the motor endplate in the synaptic cleft of the neuromuscular junction, thereby ultimately preventing muscle contraction. indications for the continuous infusion of nmbas during critical illness comprise severe acute respiratory distress syndrome (ards) (pao 2 /fio 2 < 150), overt shivering during therapeutic hypothermia, and other life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise in case of failure of other measures such as deep sedation [13] . cisatracurium is one of the most widely used nmbas for continuous infusion as it can also be used in patients with hepatic or renal insufficiency [21] . due to the blocking of muscle contractions and as a consequence of the subsequent lower muscular heat production, nmbas should conceptually reduce ee. however, this hypothesis has not been studied in icu patients with the previously described indications for the use of continuous nmba infusion. overall, only one earlier study has evaluated the effects of nmbas on ee in adults, reporting a significant increase in ee of 18.6% after discontinuation of pancuronium in patients with severe head injury [22] . additionally, one study investigated the effects of nmba infusion (vecuronium, pancuronium, and atracurium) in 20 critically ill children reporting a significant reduction of 10.3% of ee 1 h after infusion of nmbas [23] . we observed a non-linear positive association between body temperature and ee. four small previous studies reported an association between body temperature and ee in critically ill patients [4, 24, 25] . a reduction of 6.6% of ee per 1°c decrease at temperatures below 36°c and an increase of 8.2% per 1°c at temperatures above 37°c have been reported [24, 25] . we observed a higher ee in septic patients than in nonseptic patients. this was in line with our expectations based on previous studies in which ee in septic patients was 102-198% of ee in non-septic patients [4] . however, a recent observational study in 205 patients found no differences in ee between septic and nonseptic patients (1434 vs. 1430 kcal/day) [20] . this is the largest cohort of critically ill patients in which the effects of nmbas on ee have been studied. the effects of nmbas, especially cisatracurium, in this specific patient population have not been studied before. a large number of patient variables were available with few missing data, providing enough data to perform rigorous multivariable and repeated measure analyses. however, our study has several limitations. indirect calorimetry was not routinely available during the study period. therefore, ee was calculated using vco 2 obtained from the mechanical ventilator. calculation of ee from vco 2 has been demonstrated to be more accurate than predictive equations, but less than indirect calorimetry. finally, limitations related to the retrospective design may potentially have introduced bias and residual confounding. as cisatracurium reduces ee, reduction of caloric intake after the start of nmbas should be considered, especially in those patients that are on full feeding or considered to reach this target soon, because they are at risk of hypercaloric feeding and associated harm. before we designed the study, we expected, due to the drop in ee induced by the nmba, that some of the patients would be overfed. based on the results, we noticed that a reduction of ee by nmba could induce an almost 10% overfeeding risk in individual patients. in daily practice, this did not occur as the patients were not on nutrition target. thus, for most patients, adjustment may not be necessary as in our analysis the reduction of ee found was only 6.6% and hypercaloric feeding was only present in 5.7%, while most other patients were fed (77.9%) hypocalorically after initiation of cisatracurium infusion. although not the focus of our present study, it should be noted that the recent rose trial, studying the effect of early neuromuscular blockade (48-h continuous infusion of cisatracurium) with concomitant heavy sedation, compared with usual care, did not result in a significant mortality difference at 90 days in patients with moderate to severe acute respiratory distress syndrome in contrast to an earlier rct [26, 27] . this trial was stopped early at the second interim analysis for futility. this study may lead to reevaluation of the use of nmbas in severe respiratory failure. our data suggest that continuous infusion of cisatracurium in mechanically ventilated icu patients is associated with a significant reduction in ee as estimated by the vco 2 method, although the magnitude of the effect is small. sepsis and higher body temperature are associated with increased ee. cisatracurium infusion is associated with overfeeding in only a minority of patients, and therefore, in most patients no reductions in caloric prescription are necessary. resting energy expenditure, calorie and protein consumption in critically ill patients: a retrospective cohort study the use of indirect calorimetry in the intensive care unit introducing a new generation indirect calorimeter for estimating energy requirements in adult intensive care unit patients: feasibility, practical considerations, and comparison with a mathematical equation energy expenditure in different patient populations on intensive care: one size does not fit all resting energy expenditure and oxygen consumption in critically ill patients with vs without sepsis predicting energy expenditure in sepsis: harris-benedict and schofield equations versus the weir derivation reliability of resting energy expenditure in major burns: comparison between measured and predictive equations energy expenditure in patients with severe head injury: controlled normothermia with sedation and neuromuscular blockade resting energy expenditure in critically ill patients with spontaneous intracranial hemorrhage variations in resting energy expenditure: impact on gestational weight gain quantitative analysis of the relationship between sedation and resting energy expenditure in postoperative patients resting energy expenditure and substrate oxidation rates correlate to temperature and outcome after cardiac arrest -a prospective observational cohort study clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient validation of carbon dioxide production (vco2) as a tool to calculate resting energy expenditure (ree) in mechanically ventilated critically ill patients: a retrospective observational study ventilator-derived carbon dioxide production to assess energy expenditure in critically ill patients: proof of concept can calculation of energy expenditure based on co2 measurements replace indirect calorimetry? crit care effects of implementation of a computerized nutritional protocol in mechanically ventilated critically ill patients: a single-centre before and after study insights into energy requirements in disease a new method of classifying prognostic comorbidity in longitudinal studies: development and validation identifying critically-ill patients who will benefit most from nutritional therapy: further validation of the "modified nutric" nutritional risk assessment tool use of cisatracurium in critical care: a review of the literature effect of neuromuscular blockade on energy expenditure in patients with severe head injury effect of neuromuscular blockade on oxygen consumption and energy expenditure in sedated, mechanically ventilated children effect of cooling on oxygen consumption in febrile critically ill patients optimal temperature for the management of severe traumatic brain injury: effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism early neuromuscular blockade in the acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors wish to thank johannes kars, data specialist, and dick van blokland, icu it application specialist, for their support with data collection. all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, key: cord-004422-oep1grwq authors: li, yuting; li, hongxiang; zhang, dong title: comparison of t-piece and pressure support ventilation as spontaneous breathing trials in critically ill patients: a systematic review and meta-analysis date: 2020-02-26 journal: crit care doi: 10.1186/s13054-020-2764-3 sha: doc_id: 4422 cord_uid: oep1grwq background: the effect of alternative spontaneous breathing trial (sbt) techniques on extubation success and other clinically important outcomes is uncertain. a systematic review and meta-analysis was performed to clarify the preferable sbt (t-piece or pressure support ventilation [psv]). methods: we searched the pubmed, cochrane, and embase databases for randomized controlled trials (rcts) from inception to the 31st of july 2019. we included rcts involving adult patients (> 18 years) who underwent at least two different sbt methods. all authors reported our primary outcome of successful extubation rate and clearly compared ps versus t-piece with clinically relevant secondary outcomes (rate of reintubation, icu and hospital length of stay, and icu and hospital mortality). results were expressed as odds ratio (or) and mean difference (md) with accompanying 95% confidence interval (ci). results: ten rcts including 3165 patients were included. the results of this meta-analysis showed that there was no significant difference in the successful extubation rate between the t-piece group and ps group (odds ratio [or] = 0.91; 95% ci, 0.78–1.07; p = 0.27; i(2) = 79%). in addition, compared with the ps group, the t-piece group showed no significant difference in the rate of reintubation (odds ratio [or] = 0.99; 95% ci, 0.78–1.26; p = 0.95; i(2) = 5%), icu mortality (odds ratio [or] = 1.22; 95% ci, 0.83–1.80; p = 0.30; i(2) = 0%), hospital mortality (odds ratio [or] = 1.36; 95% ci, 0.99–1.87; p = 0.06; i(2) = 19%), icu length of stay (mean difference = − 0.10; 95% ci, − 0.59 to 0.39; p = 0.69; i(2) = 13%), and hospital length of stay (mean difference = − 0.82;95% ci, − 2.2 to 0.55; p = 0.24; i(2) = 0%). conclusions: t-piece and psv as sbts are considered to have comparable predictive power of successful extubation in critically ill patients. the analysis of secondary outcomes also shows no significant difference in the rate of reintubation, icu and hospital length of stay, and icu and hospital mortality between the two groups. further randomized controlled studies of sbts are still required. t-piece and psv as sbts are considered to have comparable predictive power of successful extubation in critically ill patients. further randomized controlled studies of sbts are still required to confirm our results. mechanical ventilation is often required in patients with critical illness, but after recovery from the acute illness, several problems can impair the successful separation of the patient from the ventilator [1] . weaning from mechanical ventilation is one of the most important and challenging problems for most intensive care unit (icu) patients. it is well known that weaning failure is associated with longer use of mechanical ventilation, higher infection rate, longer icu stay, longer hospital stay, and higher mortality rate [2] . a spontaneous breathing trial (sbt) is most often performed to assess the ability of a patient to sustain spontaneous breathing when extubated [3] . the most common modes of sbt are t-piece ventilation and pressure support ventilation (psv), lasting between 30 min and 2 h [4] [5] [6] . discontinuation of mechanical ventilation should be accomplished when the patient's ability to breathe unassisted is identified. both premature and delayed ventilator discontinuation are associated with significant morbidity. daily spontaneous breathing trials (sbts) are the current evidence-based standard of care in determining the time of ventilator discontinuation. when patients are ready to wean, the weaning process should be initiated with the first sbt as soon as possible. nevertheless, about 15-30% of the patients will be re-intubated even if they are able to tolerate (or pass) the sbt [7] . a recent meta-analysis suggested that patients undergoing ps (vs t-piece) sbts appear to be 6% more likely to be extubated successfully and, if the results of an outlier trial are excluded, 6% more likely to pass an sbt [8] . another meta-analysis found that psv might be superior to t-piece with regard to weaning success for simple-towean subjects. for the prolonged-weaning subgroup, however, t-piece was associated with a shorter weaning duration [9] . a latest large-scale multicenter randomized controlled trial found that an sbt consisting of 30 min of psv, compared with 2 h of t-piece ventilation, led to significantly higher rates of successful extubation [10] . moreover, the latest american thoracic society guidelines for weaning recommend psv sbts with moderate-quality evidence [11] . thus, further research is needed to determine the best approach for sbts. in this study, we conducted a meta-analysis, which extracted results from published randomized controlled trials (rcts) to evaluate the effectiveness and safety of two strategies, a t-piece and psv, for weaning adult patients with respiratory failure that required mechanical ventilation, measuring extubation success and other clinically important outcomes. this systematic review and meta-analysis is reported according to the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines [12] . ethical approval was not necessary for this study because it was a review of the published literature. we searched the pubmed, cochrane, and embase databases for rcts from inception to the 31st of july 2019 using the following search terms: spontaneous breathing trial, t-piece, t-tube, pressure support ventilation, pressure support, weaning, ventilator weaning, mechanical ventilation. the search was slightly adjusted according to the requirements of the different databases. the authors' personal files and reference lists of relevant review articles were also reviewed. the flow chart of the search strategies is summarized in fig. 1 . the primary outcome was successful extubation rate, and successful extubation was defined as remaining free of invasive mechanical ventilation 72 h after the first sbt [10] . secondary outcomes were rate of reintubation among patients who were extubated after the sbt, icu, and hospital length of stay, and icu and hospital mortality. weighted means were calculated based on the number of patients in each study. the inclusion criteria were as follows: (1) randomized controlled trials; (2) adult patients (> 18 years) who underwent at least two different sbt methods; (3) all authors reported our primary outcome of successful extubation rate; (4) clearly comparing ps versus t-piece with clinically relevant secondary outcomes. we excluded nonrandomized controlled trials and studies without clear comparisons of the outcomes. in addition, we excluded studies evaluating sbt methods in patients with tracheotomy and in patients receiving noninvasive ventilation. two reviewers (yl and hl) independently performed quality assessment using the cochrane collaboration's tool for assessing risk of bias [13] . the specific elements were adequacy of the methods used to minimize bias through: (1) randomization sequence (selection bias), (2) allocation concealment (selection bias), (3) blinding of study personnel and participants (performance bias), (4) blinding of outcome assessors (performance bias), (5) complete reporting of data without arbitrarily excluded patients and with low to minimal loss to follow-up (attrition bias), (6) selective reporting bias, and (7) other sources of bias. satisfactory performance, unclear performance, and unsatisfactory performance of each domain from the tool is denoted by green, yellow, and red colors respectively. the risk of bias summary is presented in fig. 2 ; the risk of bias graph is presented in fig. 3 . statistical analyses were performed using review manager version 5.3 (revman, the cochrane collaboration, oxford, uk). risk ratio (rr) with 95% confidence intervals (ci) was calculated for dichotomous variables. as to the continuous variables, mean difference (md) and 95% ci was estimated as the effect result. a random-effects model was used to pool studies with significant heterogeneity, as determined by the chi-squared test (p < 0.10) and inconsistency index (i 2 ≥ 50%) [14] . some of the selected continuous variables were represented by the median (interquartile range). we calculated their mean and standard deviation according to the sample size with a calculator [15] , and then performed meta-analysis. a p value < 0.05 was set as the threshold of statistical significance. the search strategy identified 2090 studies, and the data were from 10 rcts comprising 3165 patients (table 1 ) [10, [16] [17] [18] [19] [20] [21] [22] [23] [24] . the characteristics of the included studies are shown in table 1 . a total of 10 eligible studies were published between 1997 and 2019. among these studies, 2 studies were conducted in spain, 2 studies were conducted in croatia, 2 studies were conducted in brazil, 1 study was conducted in korea, 1 study was conducted in switzerland, 1 study was conducted in thailand, and 1 study was conducted in china. of these studies, three were multi-center studies [10, 23, 24] and seven were single-center studies [15] [16] [17] [18] [19] [20] [21] [22] . the interventions of ps and t-piece included in the meta-analysis are outlined in table 2 . a total of 10 rcts including 3165 patients were included, and the successful extubation rate was about 74.0% (1166/1592 in the t-piece group and 1176/1573 (fig. 4) . a funnel plot was used to assess the publication bias (fig. 5) . five of included studies were analyzed to assess the rate of reintubation. the rate of reintubation was about 14.1% (171/1205 in the t-piece group and 167/ 1184 in the ps group). there was no statistically significant difference in the rate of reintubation between 2 groups (odds ratio [or] = 0.99;95% ci, 0.78-1.26; p = 0.95; chi 2 = 4.20; i 2 = 5%) (fig. 6) . three of the included studies were analyzed to assess the icu mortality. there was no statistically significant difference in the icu mortality between 2 groups (odds ratio [or] = 1.22; 95% ci, 0.83-1.80; p = 0.30; chi 2 = 1.73; i 2 = 0%) (fig. 7) . three of included studies were analyzed to assess the hospital mortality. there was no statistically significant difference in the hospital mortality between 2 groups (odds ratio [or] = 1.36; 95% ci, 0.99-1.87; p = 0.06; chi 2 = 2.48; i 2 = 19%) (fig. 8) . four of included studies were analyzed to assess the icu length of stay. there was no statistically significant (fig. 9 ). four of included studies were analyzed to assess the hospital length of stay. there was no statistically significant difference in the hospital length of stay between 2 groups (mean difference = − 0.82; 95% ci, − 2.2 to 0.55; p = 0.24; chi 2 = 0.63; i 2 = 0%) (fig. 10 ). this systematic review and meta-analysis of ten unique rcts including 3165 patients compared tpiece and pressure support ventilation as spontaneous breathing trials in critically ill patients. we found that the overall successful extubation rate was about 74.0% and there was no significant difference of successful extubation rate between the t-piece group and ps group. extubation failure may occur because of upper-airway obstruction, ineffective cough, and excessive respiratory secretions that cannot be managed by the patient [2] . another potential reason for extubation failure is loss of positive pressure in the chest after extubation in subjects weaned to psv [25] . psv allows patients to retain control over respiratory rate and timing, inspiratory flow rate, and tidal volume. in addition, physicians can modulate a satisfactory workload for the patients by monitoring breathing frequency and accessory muscle activity during psv. because of these potential advantages, the value of psv as a technique to gradually withdraw ventilator support is generally recognized for patients who have weaning difficulties [17] . sklar et al. [3] recently pointed out that psv significantly reduces the work of breathing and pressure-time product compared to the t-piece, which could, in turn, more closely represent the post-extubation scenario. however, noninvasive mechanical ventilation (niv) dissemination as an adjunctive for extubation makes clinical interpretation of these data difficult [24] . the major finding of our study suggests that both spontaneous breathing using t-piece and psv are suitable methods for successful extubation of patients with critical illness from mechanical ventilation. the main goal of a weaning trial is to identify patients who are able to breathe without a ventilator with the minimum risk of extubation failure and its potential complications [26] . daily screening of respiratory function by sbt is associated with a shorter duration of mechanical ventilation [27] . after a successful sbt and extubation, 10 to 25% of patients require reintubation, and reintubation is associated with higher mortality [28, 29] . in this meta-analysis, the reintubation rate was not significantly different between the 2 groups (about 14.1%), which is lower than the 17% in the first study by esteban et al. [16] and similar to the 13% in their second study [30] . conversely, the reintubation rate was higher than in a study by perren et al. [31] (9% for short sbts and 4% for long sbts), but that study has a singlecenter design and the small sample size precludes direct comparison. hospital mortality and icu mortality were not statistically significant different between 2 groups. icu or hospital mortality may be not directly related to the sbt technique which is the intervention that is applied for a very short period during the course of icu admission. patient mortality is associated with prolonged intubation or unsuccessful weaning and they significantly increased medical costs because of extended hospitalization. besides this, we also found that hospital length of stay and icu length of stay were not statistically significant different between 2 groups. this finding can be explained by the reintubation rate, apache ii score at admission, and the overall successful extubation rate, which were not significantly different between the 2 groups. a variety of workers have indicated that continuous positive airway pressure of 5 cm h 2 o, typically considered as minimal support, decreases patient work of breathing by as much as 40%. pressure support of 5 cm h 2 o also decreases patient work of breathing by 30 to 40% [32, 33] . the vast majority of patients can cope with a 40 to 60% increase in work of breathing at the point of extubation, but a fragile patient may not [34] . the small population of marginal patients will likely require reintubation. reintubation is associated with a significant mortality rate. it is necessary to look for the high-risk patient and treat all patients as vulnerable and assess their ability to breathe. our meta-analysis has several characteristics: (1) we conducted a systematic search of several databases to identify all rcts comparing t-piece and psv sbt techniques in weaning subjects. (2) we employed standardized techniques to assess risk of bias and overall quality of evidence. this meta-analysis is associated with several limitations. first, the number of included studies is small. further randomized clinical trials should be conducted in order to assess whether or not psv is safer and more effective compared to the t-piece method for achieving relevant clinical outcomes among adult patients with at least 24 h of invasive ventilation. second, many of the secondary outcomes such as hospital length of stay or hospital mortality were not included in all of the studies examined in this meta-analysis. third, the rate of sbt success is also very important because successful extubation after passing the sbt will be also related to upper airway patency and adequacy of secretion clearance. only if the patients have the above conditions can they pass the sbts. however, not all of included studies showed this data. fourth, there was substantial heterogeneity among the included studies. therefore, our findings should be interpreted with caution. t-piece and psv as sbts are considered to have comparable predictive power of successful extubation in critically ill patients. the analysis of secondary outcomes also shows no significant difference in the rate of reintubation, icu and hospital length of stay, and icu and managing the apparent and hidden difficulties of weaning from mechanical ventilation extubation failure after successful spontaneous breathing trial: prediction is still a challenge! respir care effort to breathe with various spontaneous breathing trial techniques. a physiologic meta-analysis mechanical ventilation international study group. characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study characteristics and outcomes of ventilated patients according to time to liberation from mechanical ventilation evolution of mechanical ventilation in response to clinical research outcomes of extubation failure in medical intensive care unit patients trials directly comparing alternative spontaneous breathing trial techniques: a systematic review and meta-analysis spontaneous breathing trials with t-piece or pressure support ventilation effect of pressure support vs t-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical trial liberation from mechanical ventilation in critically ill adults: executive summary of an official preferred reporting items for systematic reviews and meta-analyses: the prisma statement cochrane handbook for systematic reviews of interventions the exact distribution of cochran's heterogeneity statistic in one-way random effects meta-analysis estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range extubation outcome after spontaneous breathing trials with t-tube or pressure support ventilation. the spanish lung failure collaborative group effect of an additional 1-hour t-piece trial on weaning outcome at minimal pressure support extubation after breathing trials with automatic tube compensation, t-tube, or pressure support ventilation comparison of pressure support and t-tube weaning from mechanical ventilation: randomized prospective study chronic obstructive pulmonary disease and weaning of difficult-to-wean patients from mechanical ventilation: randomized prospective study comparison of pressure support ventilation and t-piece in determining rapid shallow breathing index in spontaneous breathing trials comparison of proportional assist ventilation plus, t-tube ventilation, and pressure support ventilation as spontaneous breathing trials for extubation: a randomized study an open label randomized controlled trial to compare low level pressure support and t-piece as strategies for discontinuation of mechanical ventilation in a general surgical intensive care unit pressure-support ventilation or t-piece spontaneous breathing trials for patients with chronic obstructive pulmonary disease -a randomized controlled trial weaning from mechanical ventilation outcome of reintubated patients after scheduled extubation effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously weaning from the ventilator and extubation in icu risk factors and outcomes for airway failure versus non-airway failure in the intensive care unit: a multicenter observational study of 1514 extubation procedures spanish lung failure collaborative group. effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation protocol-directed weaning from mechanical ventilation: clinical outcome in patients randomized for a 30-min or 120-min trial with pressure support ventilation extubation and the myth of "minimal ventilator settings pressure-time product during continuous positive airway pressure, pressure support ventilation, and t-piece during weaning from mechanical ventilation physiologic basis of mechanical ventilation not applicable. this work was supported by the project of natural science foundation of jilin province (no.20160101142jc). all data generated or analyzed during this study are included in this published article. authors' contributions yl searched the scientific literature and drafted the manuscript. hl contributed to the conception and design and data interpretation. hl also helped to collect the data and performed the statistical analyses. dz contributed to the conception and design, data interpretation, manuscript revision for critical intellectual content, and supervision of the study. all authors read and approved the manuscript.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord-029183-3aotgq6m authors: monard, céline; pehlivan, jonathan; auger, gabriel; alviset, sophie; tran dinh, alexy; duquaire, paul; gastli, nabil; d’humières, camille; maamar, adel; boibieux, andré; baldeyrou, marion; loubinoux, julien; dauwalder, olivier; cattoir, vincent; armand-lefèvre, laurence; kernéis, solen title: multicenter evaluation of a syndromic rapid multiplex pcr test for early adaptation of antimicrobial therapy in adult patients with pneumonia date: 2020-07-14 journal: crit care doi: 10.1186/s13054-020-03114-y sha: doc_id: 29183 cord_uid: 3aotgq6m background: improving timeliness of pathogen identification is crucial to allow early adaptation of antibiotic therapy and improve prognosis in patients with pneumonia. we evaluated the relevance of a new syndromic rapid multiplex pcr test (rm-pcr) on respiratory samples to guide empirical antimicrobial therapy in adult patients with community-acquired pneumonia (cap), hospital-acquired pneumonia (hap), and ventilator-acquired pneumonia (vap). methods: this retrospective multicenter study was conducted in four french university hospitals. respiratory samples were obtained from patients with clinical and radiological signs of pneumonia and simultaneously tested using conventional microbiological methods and the rm-pcr. a committee composed of an intensivist, a microbiologist, and an infectious diseases specialist retrospectively assessed all medical files and agreed on the most appropriate antimicrobial therapy for each pneumonia episode, according to the results of rm-pcr and blinded to the culture results. the rm-pcr-guided antimicrobial regimen was compared to the empirical treatment routinely administered to the patient in standard care. results: we included 159 pneumonia episodes. most patients were hospitalized in intensive care units (n = 129, 81%), and episodes were hap (n = 68, 43%), cap (n = 54, 34%), and vap (n = 37, 23%). conventional culture isolated ≥ 1 microorganism(s) at significant level in 95 (60%) patients. the syndromic rm-pcr detected at least one bacteria in 132 (83%) episodes. based on the results of the rm-pcr, the multidisciplinary committee proposed a modification of the empirical therapy in 123 (77%) pneumonia episodes. the modification was a de-escalation in 63 (40%), an escalation in 35 (22%), and undetermined in 25 (16%) patients. in microbiologically documented episodes (n = 95), the rm-pcr increased appropriateness of the empirical therapy to 83 (87%), as compared to 73 (77%) in routine care. conclusions: use of a syndromic rm-pcr test has the potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empirical antibiotic therapy in adult patients with pneumonia. inadequate and delayed empirical treatments are strong predictors of mortality in sepsis [1, 2] . therefore, in pneumonia patients, international guidelines state that an attempt should be made to obtain respiratory samples and recommend to start early empirical treatment while awaiting for the results of culture and antimicrobial susceptibility testing (ast) [3] . for severe patients or those with risk factors of multidrug-resistant organisms (mdro), the empirical treatment should include a broad-spectrum antibiotic [4, 5] . however, conventional microbiological techniques have a low sensitivity, particularly on microbiological samples collected in non-intubated patients and in case of prior exposure to antibiotics [6, 7] . the lack of a reliable microbiological diagnosis thus prevents from deescalating the empirical regimen in a large proportion of patients [8] . identification of causative microorganisms provides the potential to target antibiotic therapy, but the turnaround time from microbiological sampling to ast usually requires at least 48 h. new molecular diagnostic tools aim at shortening this time. syndromic rapid multiplex pcr (rm-pcr) can be used for simultaneous detection of multiple organisms and resistance markers in a specific clinical context, within a few hours [9] . alongside with antimicrobial stewardship (ams), the use of rm-pcr has been shown to significantly decrease time-to-appropriate therapy and optimize clinical and economic outcomes [10, 11] . during a previous evaluation in community-acquired pneumonia, a rm-pcr assay achieved pathogen detection in 87% of patients compared to 39% using culture-based methods [12] . in addition, in this population, molecular testing had the potential to lead to a de-escalation in the number and/or spectrum of initial empirical antibiotics in 77% of patients. the biofire® filmarray® pneumonia panel (biomerieux s.a., marcy-l'etoile, france) is a novel assay able to simultaneously identify 27 of the most common pathogens involved in lower respiratory tract infections (semi-quantitative results for 11 gram-negative and 4 gram-positive bacteria, qualitative results for 3 atypical bacteria and 9 viruses) as well as 7 antibiotic resistance genes (fig. 1) . two studies have found excellent agreement between this molecular method and standard culture [13, 14] . our main objective was to estimate the potential impact of this new syndromic rm-pcr assay on early adaptation of empirical antimicrobial therapy in adult patients with pneumonia. between july and december 2018, 11 french university hospitals participated in a pre-commercialization evaluation of the investigative-use-only (iuo) version of the rm-pcr biofire® filmarray® pneumonia panel (biomerieux s.a., marcy-l'etoile, france). a total of 515 respiratory samples (sputa, endotracheal aspirations (eta), blind bronchial sampling (bbs), and bronchoalveolar lavages (bal)) were tested simultaneously, using conventional techniques and the rm-pcr. the syndromic rm-pcr demonstrated high agreement with conventional culture in this panel of patients [14, 15] . four centers (bichat-paris, cochin-paris, rennes, and lyon) were further selected to participate in the present sub-study. criteria for patient inclusion were as follows: (1) age ≥ 18 years and (2) presence of clinical and radiological criteria for pneumonia according to the idsa guidelines: new lung infiltrate on a chest x-ray and evidence that the infiltrate was of an infectious origin, i.e., at least two of three clinical features (fever greater than 38°c, leukocytosis or leukopenia, and purulent secretions) [16] . criteria for pneumonia were evaluated by two clinical investigators in each center. communityacquired pneumonia (cap), hospital-acquired pneumonia (hap), and ventilator-associated pneumonia (vap) were included. hap was defined as pneumonia occurring 48 h or more after admission, which was not incubating at the time of admission and not associated with mechanical ventilation [4] . vap referred to pneumonia arising > 48 h after endotracheal intubation [4, 16] . cap included all episodes of pneumonia acquired outside of the hospital setting. even if not strictly included in the most recent definition of cap [17] , we also included patients with immunocompromising conditions. respiratory specimens were routinely analyzed in each local microbiology laboratory according to current recommendations of the french standard guidelines in medical microbiology (remic) [18] . in brief, sputum and eta samples were digested and diluted according to sample types. then, they were streaked on recommended plates according to semi-quantitative patterns and incubated for 2 days in co 2 and aerobic conditions. results of standard culture were expressed in colony-forming unit (cfu)/ml. the thresholds for positivity on culture were ≥ 10 3 cfu/ml for bbs, ≥ 10 4 cfu/ml for bal, ≥ 10 5 cfu/ml for eta, and ≥ 10 7 cfu/ml for sputa [19] . diagnostic tests for viruses and atypical bacteria were conducted only if requested by the physician in charge. respiratory samples were simultaneously tested with the iuo version of the biofire® filmarray® pneumonia panel according to the manufacturer's instructions directly on native respiratory samples. the iuo version is identical to the final fda-cleared and ce-marked version. the system integrates sample preparation, nucleic acid extraction and purification, amplification, detection, and analysis, with a total run time of about 1 h. results of the syndromic rm-pcr are expressed as semiquantitative results (10 4 to ≥ 10 7 ) in dna-copies/ml for commonly culturable bacteria and as qualitative results (presence/absence) for resistance genes, viruses, and atypical bacteria. bacteria found under the threshold of 10 3.5 copies/ml are not reported on the final rm-pcr report. clinical and demographical data were retrospectively obtained from the electronic medical records of each patient. investigators collected demographic characteristics (age, gender) and medical data such as medical history, classification of pneumonia (vap, hap, or cap), severity scores, and antibiotics prescribed. in each study center, a multidisciplinary committee composed of an intensivist, an infectious diseases specialist, and a clinical microbiologist was formed. during a face-to-face meeting, the local multidisciplinary committee retrospectively reviewed medical files of all pneumonia patients, including patients' medical history, previous antimicrobial treatments received, previous microbial colonization and risk factors for mdro carriage, clinical parameters (e.g., fever, hemodynamics, and respiratory parameters), results of standard biological analyses, and chest imaging. for each episode, the result of the syndromic rm-pcr was presented to the committee, blinded to (1) the direct examination of the sample, (2) the results of the standard culture and ast, and (3) the empirical therapy administered in routine care. guided by the rm-pcr results, the multidisciplinary committee agreed on the most appropriate antimicrobial therapy for each pneumonia episode. the antimicrobial therapy proposed by the multidisciplinary committee based on syndromic rm-pcr results (pcr-guided therapy) was compared to the empirical therapy actually delivered to the patient in routine care (empirical therapy). the primary endpoint was the number of pneumonia episodes in which pcr-guided therapy differed from empirical therapy. the secondary endpoints were as follows: (1) the number of de-escalations of the antibiotic regimen based on syndromic rm-pcr results and (2) the number of episodes in which pcrguided therapy would be active on pathogens isolated at significant threshold on culture. both primary and secondary endpoints were evaluated by an independent central committee composed of an intensivist and an infectious disease specialist from two different university hospitals (sk and cm). de-escalation was defined according to previous studies as discontinuation of any companion drug and/or switch of the pivotal drug to a narrower-spectrum antibiotic [20, 21] . ranking of pivotal drugs was determined according to their antibacterial spectrum and putative ecological impact and defined either within the same antibiotic family or from a family to another (e.g., vancomycin to oxacillin). β-lactams were categorized into six groups, as previously described by weiss et al. [22] (fig. 2) . in several cases (e.g., switch from piperacillin/tazobactam to a fourth-generation cephalosporin), as hierarchy of antibiotics could not be established, the antibiotic change was qualified as "undetermined." if a companion drug was stopped but a new one was started, the antibiotic change was also considered as "undetermined." definitive results of standard culture and ast were considered by the central committee to state on the susceptibility of pathogens to the pcr-guided therapy. this secondary endpoint was evaluated only in microbiologically documented pneumonia episodes. only pathogenic microorganisms cultured at significant levels on culture were considered as documentation. coagulase-negative staphylococci (cons) and enterococcus spp. were considered as non-pathogenic. all data were anonymously collected and stored on a secured database. descriptive analysis was performed using the r software (3.3.2, r foundation for statistical computing, vienna, austria). due to relatively small numbers and the retrospective design of our study, we did not perform a formal statistical analysis, but rather present the description of data. for each variable, when data were missing, they were excluded from the calculation of percentages. according to the french legislation, this study was approved by the ethics committee of the french society of infectious diseases (société de pathologie infectieuse de langue française), n°2019-0902, and declared to the french national data protection commission (commission nationale de l'informatique et des libertés, cnil), n°19-213. among 170 pneumonia episodes included in the precommercialization evaluation in the four investigating centers, 159 were retained for final analysis. exclusion criteria were as follows: age < 18 years (n = 2) and criteria for pneumonia not fulfilled (n = 9). a total of 129 patients (81%) were hospitalized in intensive care units (icus) at inclusion, and their median [iqr] sofa score was 6 [2.5-8.5 ]. overall in-hospital mortality was 28% (45/159). pneumonia episodes were classified as hap (n = 68, 43%), cap (n = 54, 34%), and vap (n = 37, 23%). microbiological samples were as follows: eta (n = 71, 45%), sputum samples (n = 33, 21%), bal (n = 34, 21%), and bbs (n = 21, 13%). other demographic data are reported in table 1 . conventional culture isolated ≥ 1 microorganism(s) at significant level in 95 episodes (60%): 27/54 (50%) in cap, 40/68 (59%) in hap, and 28/37 (76%) in vap. the syndromic rm-pcr detected at least one bacteria in 132 (83%) episodes; a viral co-infection was detected in 16 episodes and a virus without bacteria in 6 episodes. among the 64 undocumented episodes on culture, the syndromic rm-pcr identified a microorganism in 21 episodes (bacteria in 19 episodes and viruses in 2 episodes). the main pathogens identified on culture were gramnegative bacilli (escherichia coli (24), pseudomonas aeruginosa (23), enterobacter cloacae complex (14), klebsiella pneumoniae (12), haemophilus influenzae (11)) and gram-positive cocci (staphylococcus aureus (28), streptococcus pneumoniae (8)) ( table 2) . results of the microbiological analyses according to sample type are described in the supplementary material (supplementary table 1 ). multiple microorganisms were detected in 33% of episodes using culture and 43% using the syndromic rm-pcr method. no influenza virus was found, neither using standard methods nor the syndromic rm-pcr. the syndromic rm-pcr identified 16 antibiotic resistance genes: 11 bla ctx-m and 5 meca/c-mrej genes. all pathogens identified as harboring an extended-spectrum β-lactamase on ast (n = 10) were found positive for the bla ctx-m by the rm-pcr. the 2 staphylococcus aureus strains resistant to methicillin on ast were detected by the rm-pcr, which detected 2 more methicillin-resistant staphylococcus aureus strains that were not found on culture. six enterobacteriaceae probably had an overproduction of ampc β-lactamase, which could not be detected by the rm-pcr. the empirical therapy included a β-lactam in 147 (92%) pneumonia episodes: third-generation cephalosporin (n = 35, 22%), amoxicillin/clavulanate (n = 27, 17%), piperacillin/tazobactam (n = 29, 18%), or fourth-generation cephalosporin (n = 19, 12%), and carbapenems (n = 27, 17%). a companion molecule was prescribed in 79 (50%) episodes: mainly macrolides (n = 20, 13%), imidazoles (n = 17, 11%), and aminoglycosides (n = 15, 9%; table 3 ). based on the results of the rm-pcr, the multidisciplinary committee proposed a modification of the routine empirical therapy in 123 (77%) pneumonia episodes: deescalation in 63 (40%) and escalation in 35 (22%; table 4 ). the proportion of antibiotic modifications was higher in vap (32/37, 87%), as compared to hap (54/ 68, 79%) and cap (37/54, 69%). de-escalation consisted in change of the pivotal drug to a narrower spectrum antibiotic (n = 37, 23%) and/or discontinuation of a companion drug (n = 37, 23%), or discontinuation of all antibiotics (n = 9, 6%). sputum samples were associated with less antimicrobial modifications (21/33, 64%) compared to other sample types (58/71, 82%; 27/34, 80%; 17/21, 81%; for eta, bal, and bbs respectively). modifications in the sputum group were escalation and de-escalation in the same number of cases, whereas there was more de-escalation compared to escalation in the other type of samples (supplementary table 2 ). in microbiologically documented episodes (n = 95), pathogens were susceptible to the empirical therapy in 73 (77%) episodes and to the pcr-guided therapy in 83 (87%) episodes. the proportion of the empirical and pcr-guided therapies that were active on the documented pathogens did not statistically differ between cap, hap, and vap (data not shown). when the pcrguided therapy differed from the empirical therapy, pathogens were susceptible to pcr-guided therapy in 85% [28/33] of the de-escalations and 88% [22/25] of the escalations. for 14 (9%) patients, the pcr-guided therapy was active against documented pathogens, whereas the empirical routine therapy was non-active. conversely, 4 patients had an active empirical therapy, and the multidisciplinary committee proposed a non-active pcr-guided therapy. in 1 patient, the syndromic rm-pcr was negative and the committee proposed to discontinue antibiotics, whereas standard culture grew up 10 7 cfu/ml morganella morganii (not included in the panel). of note, gram-negative bacilli were identified on direct examination of the respiratory sample (bal), but this information was not considered by the multidisciplinary committee. in 2 other patients treated with fourth-generation cephalosporin as empirical therapy, the committee proposed a treatment with piperacillintazobactam. these 2 patients had a syndromic rm-pcr positive for enterobacter cloacae complex confirmed by culture, consequently found resistant to piperacillintazobactam due to overexpression of the naturally produced ampc β-lactamase. the fourth patient was empirically treated with ceftolozane-tazobactam, and the committee proposed to treat him with ceftazidime. both syndromic rm-pcr and conventional culture identified pseudomonas aeruginosa, which was phenotypically confirmed as resistant to ceftazidime. of note, this patient was already known to be colonized with a p. aeruginosa of this particular phenotype. details on all inadequate antibiotic therapies (either empirical or pcr-guided) are available in the supplementary material (supplementary table 3 ). acinetobacter calcoaceticus-baumannii complex 1 --1 legionella pneumophila 1 1 -conventional techniques include culture for all pathogens presented, apart from legionella pneumophila which was detected using molecular techniques. only pathogens cultured at pre-defined levels are presented (≥ 10 3 cfu/ml for blind bronchial sampling, ≥ 10 4 cfu/ml for bronchoalveolar lavage, ≥ 10 5 cfu/ml for endotracheal aspiration, and ≥ 10 7 cfu/ml for sputum samples) a immunosuppression was defined as leucopenia < 1 giga/l, hiv infection, history of solid organ or stem cell transplantation, and immunosuppressive treatment including corticosteroids over 10 mg/day of equivalent prednisone for more than 15 days b chronic pulmonary condition included patients with history of chronic obstructive pulmonary disease, severe bronchiectasis, cystic fibrosis, and chronic respiratory insufficiency overall, as described in table 3 , compared to routine empirical therapy, the syndromic rm-pcr would have theoretically led to avoid 27 prescriptions of β-lactams in this retrospective multicenter study, a syndromic rm-pcr approach with semi-quantitative results had the potential to lead to a change in empirical antimicrobial therapy in 77% of pneumonia episodes in adult patients. the most frequent intervention was a de-escalation, which occurred in almost half of the patients. using standard culture and ast as the reference method, pcr-guided antibiotic treatment was more frequently adequate when compared to the empirical treatment. as observed in previous studies, microbiological documentation was almost twice as high using the rm-pcr compared to the standard method [14] . if this higher sensitivity is an advantage for patients treated with antibiotics prior to sampling, it also implies a very cautious interpretation of results. the test might detect nucleic acids from pseudomonas aeruginosa 23 28 enterobacter cloacae complex 13 22 klebsiella pneumoniae group 13 14 acinetobacter calcoaceticus-baumannii complex 3 4 enterobacter aerogenes 5 7 serratia marcescens 3 5 proteus spp. moraxella catarrhalis 1 5 klebsiella oxytoca 1 5 gram-positive cocci streptococcus pneumoniae 8 1 6 streptococcus pyogenes 0 0 streptococcus agalactiae 0 0 legionella pneumophila 1 1 mycoplasma pneumoniae 0 1 chlamydophila pneumoniae 0 0 resistance meca 5 targets not included in the rm-pcr panel citrobacter sp. others* 11 -conventional techniques include culture for all pathogens presented, apart from legionella pneumophila which was detected using molecular techniques rm-pcr real-time multiplex polymerase chain reaction *acinetobacter junii (n = 1), actinomyces odontolyticus (n = 1), corynebacterium sp. (n = 1), coagulase-negative staphylococcus (n = 4), enterococcus faecium (n = 1), enterococcus faecalis (n = 6), lactobacillus reuteri (n = 1), streptococcus alpha (n = 1), streptococcus pseudopneumoniae (n = 1) in the present report, we did not evaluate the correlation between culture quantification (in cfu/ml) and molecular semi-quantification (in dna copies/ml). this question is currently under investigation [15] . meanwhile, clinicians should be aware that molecular diagnosis is highly sensitive and the use of thresholds established for conventional culture to guide interpretation of the rm-pcr is not straightforward and may lead to misinterpretation. it should also be kept in mind that even if it detects a large panel of microorganisms, the test is not exhaustive and several important pathogens (such as morganella spp., citrobacter spp., hafnia alvei, stenotrophomonas maltophilia, or pneumocystis jirovecii) are not included. the same issue can be raised for the resistance genes, especially esbl-encoding genes for which only the most frequent ones (i.e., bla ctx-m ) are included in the panel. thus, when a pathogen is identified by the test, the absence of resistance genes does not predict with certainty its phenotypic susceptibility. when a gene encoding for a resistance marker is detected alongside with different bacteria, it is not possible to link the resistance to one of the detected microorganisms. also, overexpression of intrinsic resistance genes (such as ampc β-lactamase) is not detected by the panel. from this perspective, rm-pcr should not be considered as a sufficient diagnostic test for pneumonia but rather as a complementary tool in adjunction to standard culture and ast, to allow for an earlier pathogen-directed therapy. multidisciplinary discussion of the results is a prerequisite for optimal use. in our experience, the rare errors (4 over 159 episodes) in the choice of pcr-guided therapy were linked to (1) amp-c overproduction in enterobacter sp. in 2 cases, (2) isolation of pathogens not included in the panel (i.e., morganella morganii) in 1 case, and (3) isolation of a multi-drug-resistant p. aeruginosa (that was previously isolated in this particular patient) in 1 case. in this last case, it is important to note that interpretation of the rm-pcr in light of the previous microbial documentation could have prevented this error. our intervention was based on a multidisciplinary approach with physicians from different specialties interpreting the results of the rm-pcr together and agreeing on an optimal therapy. the success of this approach is concordant with previous studies where strategies combining rapid diagnostic testing and ams interventions in bloodstream infections showed a significant and synergistic impact on early antibiotic de-escalation, mortality, and costs [23] [24] [25] [26] . moreover, implementation of ams programs, led by dedicated multidisciplinary teams, is strongly encouraged to improve the quality of antibiotic prescriptions [27] [28] [29] . interestingly, the use of rapid diagnostic tests without active ams intervention failed to provide the expected benefits in patients [26, [30] [31] [32] . it is uncertain whether the same results would have been observed if only one clinician, non-expert of the diagnostic methods, had to choose alone a therapy guided by the rm-pcr results. another strength of the present study is its multicenter character, as it improves the generalizability of the results, but also because the multidisciplinary committees were local and therefore aware of the ecology of their hospitals. the present study presents some limitations. its retrospective and observational design did not allow comparison of clinical outcomes with the rm-pcr versus standard treatment approach. second, although we included a large panel of pneumonia patients (severe icu patients with vap or hap and non-severe cap patients from the emergency room), it remains unclear what group of patients will benefit most from the syndromic rm-pcr diagnosis. further studies should evaluate this new test in more selected groups of patients. however, most patients herein were severe patients hospitalized in icus with complicated microbiological histories, and results suggest the rm-pcr could help to choose the antimicrobial treatment even in this particular group of results are presented as n (%) cap community-acquired pneumonia, hap hospital-acquired pneumonia, vap ventilator-associated pneumonia patients. also, even if we tried to give the multidisciplinary committee as much information as needed to choose the antibiotic treatment, in some cases, important data may have been missing. as an example, this might explain why the clinician chose a ceftolozane-tazobactambased treatment for a patient with a past history of infection with piperacillin-tazobactam-resistant p. aeruginosa, whereas the committee decided to use piperacillintazobactam despite identification of p. aeruginosa by the rm-pcr. again, this reinforces the necessity to carefully interpret the rm-pcr report, in light of the clinical and historical microbiological data. in our panel of cap patients, only half had microbiological documentation on conventional culture. this is in accordance with previous studies that highlighted a low rate of documentation in cap, due to difficulties to obtain contributive microbiological samples and to previous exposure to antibiotics [6] . in the 27 cap patients with positive microbiology results, we identified 10 pathogens frequently involved in cap (staphylococcus aureus, haemophilus influenzae, streptococcus pneumoniae) and 12 gram-negative bacilli (4 escherichia coli, 3 pseudomonas aeruginosa, 2 klebsiella pneumoniae, 2 enterobacter sp., 1 raoultella). the number of gram-negative bacteria isolated is likely related to the profile of patients included in our study. indeed, all participating centers were tertiary university hospitals, referral centers for specific comorbidities as highlighted in table 1 : among cap patients, 35% had chronic respiratory conditions and 20% immune suppression. the gold standard used herein for microbiological diagnosis was culture with ast. in certain cases, the syndromic rm-pcr detected pathogens that were not detected by culture. this finding questions the choice of culture as the gold standard for microbial identification, notably in case of antibiotic treatment before sampling. because the molecular diagnostic methods are probably more sensitive than cultures, the present results would have been even more favorable for pcr-guided therapy if we had also considered as documentation the organisms identified by rm-pcr and not by culture. as an example, one patient had a staphylococcus aureus (10 5 copies/ml), a moraxella catarrhalis (10 4 copies/ ml), and a meca/c-mrej gene found by rm-pcr while the culture remained negative and was therefore considered as "undocumented." also, because two thirds of our samples were non-protected (eta and sputum), this could have led to an over-identification of bacteria [33] . however, since we used the culture and validated the significance thresholds for interpretation, this bias was minimized. the high proportion of non-invasive samples reflects the heterogeneity of practices between icus and is consistent with the idsa guidelines which suggest noninvasive sampling with semi-quantitative cultures to diagnose vap, rather than invasive sampling [4] . many questions regarding the syndromic rm-pcr still remain unanswered and should be addressed in future evaluations. the cost-effectiveness ratio of the syndromic rm-pcr needs to be evaluated in order to justify its use in particular subgroups of patients. to date, no studies addressed this medico-economic outcome in lower respiratory tract infections, but a syndromic rm-pcr developed for the higher tract respiratory infections was found to decrease the length of hospital stay, duration of antibiotic therapy, and time in isolation, therefore decreasing related costs [34, 35] . as previously discussed, thresholds for interpretation of rm-pcr results cannot be directly derived from those established for culture and must be more precisely defined. because of these limits, physicians should be aware of the test's drawbacks and the present results highlight the need for a close cooperation between infectious disease specialists, clinical microbiologists, and clinicians for the interpretation of results. we also suggest that the results of the test should be included in a decision algorithm, alongside with the suspected pathogens, the history of the patient, and their personal risk factors for mdro infection. we recommend that decision regarding antibiotic treatment based on rm-pcr results should consider clinical presentation, local epidemiology, direct smear of the sample, and historical microbiological data in each patient. as a guidance for use in clinical practice and based on our experience, we may recommend to (1) consider the semi-quantitative result regarding the type of sample, in order to discriminate between colonization and infection (future results should be available soon to precise the significance thresholds); (2) if a microorganism is identified and thought to be pathogenic, the antimicrobial therapy should be chosen considering colonization of the patient, previous microbial documentations, and risk factors for mdro; (3) if a pathogen of the group 3 is detected, an amp-c overproduction cannot be excluded and therefore treatment with cefepim or meropenem should be considered; (4) oseltamivir should not be prescribed in the absence of influenza detection; (5) a companion molecule such as macrolide could be discontinued for community-acquired pneumonia without identification of atypical bacteria; and (6) identification of a resistance gene should always be considered. to date, the rm-pcr should not be considered as a sufficient diagnostic test for pneumonia but rather as a complementary tool in adjunction to standard culture and ast, to allow for an earlier pathogen-directed therapy. controlled randomized trials evaluating the impact of rm-pcr on patient's outcomes are currently ongoing, and their results will be of major help to precise the impact of the rm-pcr on infection control, length of stay, and resistance selection. results suggest that early use of rm-pcr in pneumonia could reduce unnecessary antimicrobial exposure without compromising the appropriateness of the treatment. together with an expert advice, this promising diagnostic tool could improve the quality of care and participate in the reduction of broad-spectrum antimicrobial agents' use. prospective randomized controlled trials are needed to confirm these results, identify categories of patients that would most benefit from the test, and define precise guidelines to appropriately adjust the empirical therapy based on the results. supplementary information 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the authors thank all research teams and laboratory teams that participated in the study in each center. the authors thank philip robinson/verena landel for participating in manuscript preparation. the authors thank all the members from the adapt study group: agathe becker, julien charpentier, julien textoris, claude-alexandre gustave, grégory destras, françois vandenesch, bruno lina, jean sebastien casalegno, manon lejeune, philippe montravers, claire poyart, hugo tête, jean-françois timsit, and thomas uberti. authors' contributions cm and sk elaborated the study protocol, had full access to all of the data, did the analysis, and take responsibility for the integrity of the data and the accuracy of the data analysis. cm, od, vc, lal, and sk drafted the paper. all authors critically revised the manuscript and gave final approval for the version to be published. not applicable. the datasets used during the current study are available from the corresponding author on reasonable request. according to the french legislation, this study was approved by the ethics committee of the french society of infectious diseases (société de pathologie infectieuse de langue française), n°2019-0902, and declared to the french national data protection commission (commission nationale de l'informatique et des libertés, cnil), n°19-213. competing interests biomerieux sa provided iuo tests for the study. biomerieux sa did not interfere with data collection and analysis, nor with manuscript preparation. dr. julien textoris participated in the elaboration of the protocol. sk declares grants from biomérieux and lecture fees and conference invitations from biomérieux, msd, and accelerate diagnostics. cm received lecture fees from biomerieux sa. atd and ng report no conflicts of interest. vc reports personal fees from accelerate diagnostics, astellas, biomérieux, correvio, curetis, eumédica, menarini, mylan, pfizer, and sanofi. la received lecture fees from pfizer, msd, biocodex, and biomerieux. all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed.author details key: cord-001322-7xmxcm35 authors: walden, andrew p; clarke, geraldine m; mckechnie, stuart; hutton, paula; gordon, anthony c; rello, jordi; chiche, jean-daniel; stueber, frank; garrard, christopher s; hinds, charles j title: patients with community acquired pneumonia admitted to european intensive care units: an epidemiological survey of the genosept cohort date: 2014-04-01 journal: crit care doi: 10.1186/cc13812 sha: doc_id: 1322 cord_uid: 7xmxcm35 introduction: community acquired pneumonia (cap) is the most common infectious reason for admission to the intensive care unit (icu). the genosept study was designed to determine genetic influences on sepsis outcome. phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe cap admitted to icus across europe. methods: kaplan-meier analysis was used to determine mortality rates. a cox proportional hazards (ph) model was used to identify variables independently associated with 28-day and six-month mortality. results: data from 1166 patients admitted to 102 centres across 17 countries was extracted. median age was 64 years, 62% were male. mortality rate at 28 days was 17%, rising to 27% at six months. streptococcus pneumoniae was the commonest organism isolated (28% of cases) with no organism identified in 36%. independent risk factors associated with an increased risk of death at six months included apache ii score (hazard ratio, hr, 1.03; confidence interval, ci, 1.01-1.05), bilateral pulmonary infiltrates (hr1.44; ci 1.11-1.87) and ventilator support (hr 3.04; ci 1.64-5.62). haematocrit, ph and urine volume on day one were all associated with a worse outcome. conclusions: the mortality rate in patients with severe cap admitted to european icus was 27% at six months. streptococcus pneumoniae was the commonest organism isolated. in many cases the infecting organism was not identified. ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and ph on admission were independent predictors of a worse outcome. community acquired pneumonia (cap) is common, affecting between 5 and 11 individuals per 1,000 of the adult population each year [1, 2] and is the commonest cause of sepsis, severe sepsis and septic shock [3] . between 22 and 42% of patients require hospital admission [1, 2, 4] of whom 5 to 10% will be admitted to an icu [5] [6] [7] . hospital and icu admission rates for cap are increasing for all ages [8] . an ageing, more vulnerable population, earlier recognition of deteriorating patients and better availability and use of intensive care beds may in part explain this increase. a number of investigators have examined the clinical and microbiological factors that might affect the outcome from severe cap [5] [6] [7] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] , but these studies have often been relatively small, with considerable heterogeneity in both the inclusion criteria and outcome measures. as a consequence reported mortality rates have varied and there has been uncertainty regarding the most important risk factors for death. a number of more recent, larger studies have focussed on identifying patients with cap at increased risk of severe sepsis and death, as well as those who may require ventilator or vasopressor support [3, [24] [25] [26] . one of these studies provides outcome data at 90 days for the smaller subgroup of patients with severe sepsis admitted to the icu [3] , and another [24] reports microbiological findings and 90-day mortality in a subgroup of 170 patients admitted to the icu. the aim of the study reported here was to define the clinical characteristics, microbiological aetiology, outcomes and independent risk factors for mortality in a large, contemporary cohort of patients with severe cap admitted to icus across europe. by using such a large database with clear censor data for mortality we hoped to overcome some of the deficiencies of previous studies. the genosept study was conceived by the european critical care research network (eccrn), the research arm of the european society for intensive care medicine (esicm) with the aim of defining genetic influences on the host response and outcomes in patients with sepsis. genosept is a pan-european study that has recorded comprehensive phenotypic data and obtained dna from a large cohort of patients admitted to icu with sepsis due to cap, peritonitis, meningococcal disease or pancreatitis. ethics approval was granted nationally, for individual centres, or for both. written, informed consent was obtained from all patients or a legal representative. patients reported here were recruited into genosept from 102 centres across 17 countries (see additional file 1 for contributors) over a 4-year period between september 2005 and october 2009. inclusion criteria were as follows: admission to a high dependency unit (hdu) or icu with cap, and age over 18 years. the diagnosis of cap was defined as a febrile illness associated with cough, sputum production, breathlessness, leucocytosis and radiological features of pneumonia acquired in the community or within less than 2 days of hospital admission [24] . the diagnosis of sepsis was based upon the international consensus criteria published in 2003 [27] . patients were further sub-classified according to the criteria for severe sepsis and septic shock. exclusion criteria were as follows: patient or legal representative unwilling or unable to give consent; patient under 18 yrs of age; patient pregnant; advanced directive to withhold or withdraw life-sustaining treatment or admitted for palliative care only (please see also additional file 1). patients were observed until death or for a maximum of 6 months. in those who had died between icu discharge and 6-month follow-up the date of death was recorded. specific data was recorded in the electronic case report form (ecrf) to allow calculation of the acute physiology and chronic health evaluation ii (apache ii) and sequential organ failure assessment (sofa) scores [28, 29] . the infectious diseases society of america/american thoracic society (idsa/ats) criteria were used for the diagnosis of severe cap [30] . co-morbidities were recorded according to the modified charlson scoring system [31] . chest radiograph appearances were recorded as: 1) lobar, 2) localised or 3) diffuse bilateral. investigators were also asked to consider the differential diagnosis of cardiogenic pulmonary oedema in those with diffuse pulmonary infiltrates. microbiological investigations were performed according to local policies and practices. investigators recorded the microbiological findings, including the organism(s) isolated, the source of the organism and the use of serology. mortality at 28 days and at 6 months were chosen as primary endpoints. univariate analysis was performed using a cox proportional hazards model, adjusted for age and gender. variables considered by the investigators to be clinically relevant were chosen for analysis (see additional file 1). a test for proportional hazards using the schoenfeld residuals was performed, and for covariates indicating evidence of non-proportionality, spline smooth estimates of time-dependent hazard ratios (hrs) with point-wise confidence bands were calculated [32] . variables that were significant in the univariate analysis after bonferroni adjustment for multiple testing (p-value <0.05/k where k is the number of variables tested) were entered into a multivariate cox proportional hazards model to determine independent risk factors for death. a final set of predictors for each of 28-day and 6-month mortality was selected from these variables via a stepwise cox proportional hazards regression model. r software version 2.11.1 was used for all data analysis. between 29 september 2005 and 13 october 2009, 1,170 patients were enrolled. four individuals were excluded because of missing or inconsistent data. patient characteristics are shown in table 1 . on admission, 1,135 patients (97%) met idsa/ats criteria for severe cap, 991 on major criteria and 146 on minor criteria. median age was 64 years (range 18 to 101, iqr 51 to 71): 62% were male, 81% were caucasian and 13% mediterranean, and 509 patients were hospitalised for more than 24 hours prior to icu admission. of these the mean time from hospital admission to icu admission was 1.04 days. median length of stay in the icu was 11 days (iqr 6 to 23); median length of stay in hospital was 22 days (iqr 13 to 40) ( table 1) . a total of 718 (62%) patients had one or more co-morbid conditions, with cardiac and respiratory disease affecting 458 and 531 patients, respectively. chronic obstructive pulmonary disease was documented in 278 (23.8%) patients, diabetes mellitus in 19.6% and a chronic neurological condition in 13.1%. on the day of admission 884 (76%) patients required mechanical ventilation, with the number increasing to 962 patients (84%) within the first week of admission ( table 2 ). median duration of mechanical ventilation was 7 days: 573 patients (49%) satisfied the criteria for septic shock. the median duration of inotrope/vasopressor support was 3 days. renal replacement therapy was required during the first week of admission in 10% of patients. median sofa score on admission was 6 (iqr 4 to 9) and median apache ii score was 20 (iqr 15 to 25). chest radiograph appearances were recorded as lobar consolidation in 43.7%, patchy localised consolidation in 25.0% and diffuse, bilateral changes in 29.3%. a total of 316 (27.3%) patients had died within 6 months of enrolment, 222 (19.0%) in the icu, 63 in hospital after icu discharge and 31 between hospital discharge and 6 months following icu admission. the in-hospital mortality rate was 24.4% and the 28-day mortality rate was 17.3% (see table 3 and figure 1 ). mortality was higher in mechanically ventilated patients, (24.9% at 28 days and 33.6% at 6 months) and in patients with septic shock receiving haemodynamic support with inotropes or vasopressors (28.8% and 38.6% respectively). the standardised mortality ratio derived from the apache ii score was 0.69 (95% ci 0.68, 0.70) [28] . no causative organism was identified in over a third of patients (table 4) . streptococcus pneumoniae (pneumococcus) was the most commonly isolated organism (29% of cases), positive microbiology was obtained from lung secretions/lavage in 47% of cases; blood culture in 22%; urinary antigen testing in 17%; blood serology in 10%; pleural fluid in 2.3% and other methods in 2%. bacteraemia was present in 241 (22%) of patients and pleural infection/empyema in 32 (3%). pneumococcus was the commonest organism causing bacteraemia and empyema, accounting for 119 episodes (49%) and 25 episodes (60%) respectively. atypical organisms and viruses were rarely identified. isolation of staphylococcus aureus, presence of septic shock, need for mechanical ventilation and renal replacement therapy all showed a strong association with outcome (table 5) . the factors most strongly associated with 28-day mortality were the apache ii score calculated on day 1 (hr = 1. [5] [6] [7] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] . the considerable heterogeneity in admission policies, study design, guidelines compliance [21] , and severity scoring in these studies probably accounts for the wide range of reported mortality rates and makes meaningful comparisons difficult. most of these studies have used icu admission rather than severity scores to indicate severe disease. only three studies [12, 18, 21] defined censor points for death, which is important as in-hospital mortality increases following icu discharge by between 15 and 27% [33] . admission practices in different countries may also lead to large ranges in mortality. take for instance one study of 395 patients admitted to a spanish respiratory icu in the 1990s the mortality rate was 5% but with rates of mechanical ventilation and septic shock of 9% and 2% respectively [14] , whereas in a uk study published in 1997 the mortality rate was 58%, with mechanical ventilation and septic shock rates of 96% and 16% respectively [11] . the mortality rates reported here are more in keeping with other recent, large cohorts. the capuci group analysed 529 patients admitted to over 30 spanish icus between 2000 and 2002 and found icu mortality rates of 28% with associated apache ii scores of 19 [21] . they included both immunocompetent and immunosuppressed patients. in the 459 immunocompetent individuals the rate of death at icu discharge was slightly lower at 25%, a figure that is closer to the 19% seen in the genosept cohort, (in which immunocompromised patients were [3] . in the port study, 170 of 1,339 patients were admitted to the icu with an in-hospital mortality rate of 23.3% [24] . the standard censor point for most interventional icu studies is 28 days, although it is recognised that there is a significant attrition rate post icu discharge. it is also well-recognised that in cap patients there is an increased death rate in the months following discharge [34] , and in patients with sepsis there is significant excess mortality for at least five years [35] . in one study, the death rate of icu patients between 28 days and 6 months was 9% in patients with sepsis, similar to the 8% seen in icu patients without sepsis [36] and the 10% found in the present study. this compares to an increase in mortality from 18.2% at 30 days to 24.8% at 90 days in the subgroup of icu patients in the port study [24] and an increase from 17.3% to 34.8% at 12 months in the genims cohort of icu patients [3] . although the microbiological methodology was not standardised, our findings are consistent with previous studies of severe cap. notably, streptococcus pneumoniae accounted for 28% of all cases and no aetiological agent was identified in over a third [37] . within the genosept cohort the rate of streptococcus pneumoniae was higher than previously reported and was mirrored by a decrease in the number of cases where no aetiological agent was identified, suggesting that detection rates may have improved, rather than there being a true increase in all values are significant at a type i error rate of 5% after a bonferroni correction to take account of the multiple testing of 64 variables (a p-value <0.00078 was considered to be statistically significant). results are adjusted for age and sex. all day-1 variables unless specified otherwise. rrt, renal replacement therapy; mv, mechanical ventilation; niv, non-invasive ventilation; sbp, systolic blood pressure; map, mean arterial pressure. incidence. pneumococcal antigen testing in urine and other bodily fluids has become the standard of care in many institutions and has good positive and negative predictive value both in hospitalised cap patients [38] and in those admitted to icu [39] . amongst the 333 patients with confirmed pneumococcal pneumonia in the present study, a total of 429 positive results were obtained. of these 123 (29%) were positive urinary antigen tests and 42 (10%) were based on positive blood serology. further evidence to support this apparent increase in detection rates is provided by a recent study that reported detection rates of 50% for streptococcus pneumoniae, with 16% of cases being diagnosed using antigen testing [21] . in comparison, the bts study from 1992 reported a rate of streptococcus pneumoniae infection of 18%, with positive antigen testing in only 6% of patients [7, 21] . in hospitalised patients with cap, as many as 18 to 29% may involve a viral infection, the virus being the only organism isolated in 10% [40] . failure to respond to standard antimicrobial therapy means that more patients with viral pneumonia are likely to be admitted to icu. certainly patients with co-morbidities have a higher incidence of viral infection. in the present study viral infections were rarely identified. this raises the question as to whether a more aggressive search for viral pathogens should be conducted in all ventilated patients, coupled with more frequent and targeted use of antiviral therapy. multivariate analysis identified four variables (apache ii score, haematocrit, mechanical ventilation and ph) that were independently associated with outcome at both 28 days and 6 months the need for mechanical ventilation was related to a worse outcome at both 28 days and 6 months, consistent with other data showing respiratory failure to be an independent predictor of mortality in many categories of critically ill patients [28, 29] . the persistence of this relationship for up to 6 months reflects the fact that many patients who have received ventilator support will continue to have significant neuromuscular weakness and be at risk for a prolonged period after discharge from the icu [41] . it may be that over-aggressive use of intravenous fluids, reflected in a dilutional reduction in haematocrit worsens lung injury and thus prolongs the need for mechanical ventilation. conservative fluid management has been associated with better outcomes, albeit in the later phases of critical illness [42] . a key element of early goal-directed therapy in patients with sepsis is blood transfusion to maintain the haematocrit, perhaps accounting for the positive association between better outcomes and a higher haematocrit in the present, and other studies [43] . similarly the positive independent relationship between a higher ph on admission and a better outcome may reflect more effective early resuscitation. although there was no association between the admission p:f ratio and outcome, diffuse bilateral changes on the chest radiograph (suggesting a diagnosis of acute lung injury/acute respiratory distress syndrome) independently predicted a worse outcome at 6 months. this is consistent with other studies showing a mortality rate for ards much higher than that seen in our cohort of patients with cap [41] . urine volume, renal failure and the need for renal replacement therapy were associated with worse outcome in the univariate analysis and there was a clear independent association between urine output and mortality at 6 months. acute kidney injury (aki) has been shown to be independently associated with higher icu and in hospital mortality rates [44, 45] . the need for ongoing renal support in those with aki is estimated to be 14%, perhaps explaining the association with outcome at 6 months. other studies have attempted to determine independent risk factors for death from cap. for example, the presence of septic shock has been associated with odds ratios for risk of death ranging from 2 to 141 but inevitably with wide confidence intervals due to the small numbers of patients included in these analyses [5, 6, 15, 16, 22] ; also the lack of a consistent censor point complicates interpretation of these findings. we found an association between septic shock and outcome on univariate analysis but this effect was not seen in multivariate analysis, perhaps reflecting improvements in the acute management of shock. this study has two important limitations. firstly participating centres were at liberty to decide which patients they would enrol; subjects were not, therefore, enrolled consecutively, thereby introducing a potential for selection bias. also there was considerable variation in the number of patients recruited in each country and some centres contributed only small numbers of patients. nevertheless there was a wide range of ages, severity of physiological derangement and co-morbidities, whereas apache ii scores and ventilation rates were similar to previous studies, suggesting that a significant, systematic selection bias is unlikely. secondly, microbiological protocols were not standardised. on the other hand our observations therefore reflect current approaches to microbiological diagnosis in routine clinical practice across europe. the icu mortality rate in this contemporary cohort of patients admitted to icus across europe with severe cap was 19%, rising to 24% at hospital discharge and 27% at 6 months. streptococcus pneumoniae was the commonest cause of cap, but in many cases the infecting organism was not identified. the need for ventilator support, and the presence of diffuse bilateral infiltrates on the chest radiograph, as well as lower haematocrit, urine volume and ph on admission to icu were independent predictors of a worse outcome. prospective study of the aetiology and outcome of pneumonia in the community incidence of community-acquired pneumonia in the population of four municipalities in eastern finland understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (genims) study community-acquired pneumonia: the annual cost to the national health service in the uk severe community-acquired pneumonia. epidemiology and prognostic factors prognostic factors of pneumonia requiring admission to the intensive care unit the british thoracic society research committee and the public healthlaboratory 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to community-acquired pneumonia in patients needing icu admission severe community-acquired pneumonia: factors influencing need of intensive care treatment and prognosis a three-year study of severe community-acquired pneumonia with emphasis on outcome a new diagnostic approach to the patient with severe pneumonia antibiotic prescription for community-acquired pneumonia in the intensive care unit: impact of adherence to infectious diseases society of america guidelines on survival severe community-acquired pneumonia: assessment of microbial aetiology as mortality factor the british thoracic society and the public health laboratory service: community-acquired pneumonia in adults in british hospitals in 1982-1983: a survey of aetiology, mortality, prognostic factors and outcome severe community-acquired pneumonia: use of intensive care services and evaluation of american and british thoracic society diagnostic criteria severe sepsis in community-acquired pneumonia: when does it happen, and do systemic inflammatory response syndrome criteria help predict course? chest australian community-acquired pneumonia study c, grayson ml: smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia sccm/esicm/accp/ats/sis international sepsis definitions conference apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults a new method of classifying prognostic comorbidity in longitudinal studies: development and validation modeling survival data: extending the cox model communityacquired pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the icnarc case mix programme database inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis long-term mortality and quality of life in sepsis: a systematic review quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness community-acquired pneumonia in europe: causative pathogens and resistance patterns evaluation of the immunochromatographic binax now assay for detection of streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in spain evaluation of the binax now streptococcus pneumoniae urinary antigen assay in intensive care patients hospitalized for pneumonia viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation canadian critical care trials group: one-year outcomes in survivors of the acute respiratory distress syndrome comparison of two fluid-management strategies in acute lung injury sepsis in european intensive care units: results of the soap study beginning and ending supportive therapy for the kidney (best kidney) investigators: acute renal failure in critically ill patients: a multinational, multicenter study effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients submit your next manuscript to biomed central and take full advantage of: â�¢ convenient online submission â�¢ thorough peer review â�¢ no space constraints or color figure charges â�¢ immediate publication on acceptance â�¢ inclusion in pubmed, cas, scopus and google scholar â�¢ research which is freely available for redistribution the genosept project was supported by the european critical care research network and the european society of intensive care medicine. we would like to acknowledge all the co-investigators and research nurses who were involved in the project. a list of their names can be found in the additional file 1. the mortality rate from severe cap in patients admitted to icu is 27% at six months streptococcus pneumonia remains the most commonly isolated organism no microbiological diagnosis is found in a third of patients the need for mechanical ventilation is a strong predictor of a poor outcome ph, haematocrit, urine output and diffuse changes on chest radiography all predict a worse outcome authors' contributions apw prepared the database for analysis, prepared the first copy of the manuscript and coordinated all manuscript revisions; gmc performed the primary statistical analysis, helped in the writing of the manuscript and provided the tables and figures; smck assisted in preparation of the database for analysis and helped in writing and reviewing the manuscript; ph helped with the preparation of the database for analysis and helped in writing and reviewing the manuscript; acg helped in the design of the genosept project and in the writing an reviewing of the manuscript; jr helped in the design of the genosept project and in writing and reviewing the manuscript; j-dc helped in the design of the genosept project and in writing and reviewing the manuscript; fs helped in the design of the genosept project and in writing and reviewing the manuscript; csg helped in the design of the genosept project and in writing and reviewing the manuscript; cjh helped in the design of the genosept project and in writing and reviewing the manuscript. all authors read and approved the final manuscript. andrew p walden and geraldine m clarke contributed equally as joint first authors. key: cord-001319-mlkaowqr authors: giamarellos-bourboulis, evangelos j; apostolidou, efterpi; lada, malvina; perdios, ioannis; gatselis, nikolaos k; tsangaris, iraklis; georgitsi, marianna; bristianou, magdalini; kanni, theodora; sereti, kalliopi; kyprianou, miltiades a; kotanidou, anastasia; armaganidis, apostolos title: kinetics of circulating immunoglobulin m in sepsis: relationship with final outcome date: 2013-10-21 journal: crit care doi: 10.1186/cc13073 sha: doc_id: 1319 cord_uid: mlkaowqr introduction: the aim of this study was to investigate the kinetics of immunoglobulin m (igm) during the different stages of sepsis. methods: in this prospective multicenter study, blood sampling for igm measurement was done within the first 24 hours from diagnosis in 332 critically ill patients; in 83 patients this was repeated upon progression to more severe stages. among these 83 patients, 30 patients with severe sepsis progressed into shock and igm was monitored daily for seven consecutive days. peripheral blood mononuclear cells (pbmcs) were isolated from 55 patients and stimulated for igm production. results: serum igm was decreased in septic shock compared to patients with systemic inflammatory response syndrome (sirs) and patients with severe sepsis. paired comparisons at distinct time points of the sepsis course showed that igm was decreased only when patients deteriorated from severe sepsis to septic shock. serial measurements in these patients, beginning from the early start of vasopressors, showed that the distribution of igm over time was significantly greater for survivors than for non-survivors. production of igm by pbmcs was significantly lower at all stages of sepsis compared with healthy controls. conclusions: specific changes of circulating igm occur when patients with severe sepsis progress into septic shock. the distribution of igm is lower among non-survivors. although initially considered a state of hyperactivity of the innate and adaptive immune systems, it is currently understood that severe sepsis and septic shock are characterized by a functional state of immunoparalysis [1] . this involves not only monocytes and macrophages, but also cd4 lymphocytes and b lymphocytes [2] . under normal conditions, cd4 lymphocytes orchestrate b lymphocyte responses for the secretion of the polyvalent immunoglobulin m (igm) antibodies that are of crucial importance for the opsonization and the subsequent rapid clearance of the invading microorganisms [3] . immunoparalysis of sepsis is characterized by defective b-lymphocyte responses toward low immunoglobulin production [2] . to this end, it was expected that the intravenous administration of immunoglobulin preparations enriched in igm would be beneficial for patients with severe sepsis and septic shock. on the contrary, most of the conducted randomized clinical trials (rct) yielded contradictory results [4, 5] , despite one meta-analysis indicating that igm preparations significantly decrease the relative risk of death in both adult and child populations [4] . the existing controversies of conducted rcts may derive from our incomplete understanding of the kinetics of igm over the time course of sepsis. the current study was designed in order to embed into the changes of circulating igm levels of patients upon progression to the more severe stages of sepsis in relation with the production of igm from circulating lymphocytes and with the final outcome. this prospective multicenter study was conducted from january 2010 to december 2010 in 27 departments across greece participating in the hellenic sepsis study group. the participating departments were 15 intensive care units (icus), seven departments of internal medicine, two departments of pulmonary medicine, two departments of surgery and one department of urology. patients with signs of systemic inflammatory response syndrome (sirs) either admitted to the emergency department or hospitalized in the general ward or in the icu were eligible. written informed consent was provided by the patients or by their first-degree relatives for patients unable to consent. inclusion criteria were: (a) age ≥18 years; (b) diagnosis of sirs, sepsis, severe sepsis or septic shock; and (c) sirs due to acute pancreatitis or sepsis due to specific infections. these infections were: community-acquired pneumonia (cap), ventilator-associated pneumonia (vap), acute pyelonephritis (uti), acute intra-abdominal infection (iai) and primary bacteremia (bsi); and (d) first blood sampling within 24 hours from diagnosis. exclusion criteria were (a) infection by the human immunodeficiency virus type 1; (b) neutropenia defined as less than 1,000 neutrophils/mm 3 ; (c) chronic intake of corticosteroids defined as systemic intake of more than 1 mg/kg of equivalent prednisone for more than one month; and (d) other types of immunodeficiency like organ transplantation, hematologic malignancies and intake of chemotherapy. sirs was diagnosed by the presence of at least two of the following [6] : (a) core temperature >38°c or <36°c, (b) p co2 <32 mmhg or more than 20 breaths/min, (c) pulse rate >90/min, and (d) white blood cells >12,000/mm 3 or <4,000/mm 3 or >10% of band forms. sepsis was defined as any microbiologically or clinically documented infection complicated by sirs. patients with sepsis were classified as suffering from uncomplicated sepsis, severe sepsis or septic shock, according to standard definitions [6] . multiple organ dysfunctions syndrome (mods) was defined by the same criteria [6] . acute pancreatitis, cap, vap, uti, iai and bsi were defined according to standard definitions [7] [8] [9] [10] [11] . for each patient a complete diagnostic workup was performed comprising history, thorough physical examination, white blood cell (wbc) count, blood biochemistry, arterial blood gas, blood cultures from peripheral veins and central lines, urine cultures, chest x-ray and chest and abdominal computed tomography if appropriate. if necessary, quantitative cultures of tracheobronchial secretions (tbs) or bronchoalveolar lavage (bal) were performed and evaluated as previously described [9] . survival was recorded for 28 days and at hospital discharge. clinical and demographic data were recorded on a case report form (crf). all crfs were monitored by an independent monitor blinded to the study design. for all enrolled patients and for 35 healthy volunteers 5 ml of blood was sampled within the first 24 hours from diagnosis. from this volume: (a) 2 ml was collected into sterile, pyrogen-and anticoagulant-free tubes (vacutainer, becton dickinson, cockeysville, md, usa) for quantitative measurement of igm; and (b) 3 ml was collected into edta-coated tubes (vacutainer) for the measurement of the absolute counts of b lymphocytes. from 55 patients and 20 healthy volunteers another 8 ml was collected into heparin-coated tubes (vacutainer) and used for the isolation of peripheral blood mononuclear cells (pbmcs). for 83 patients, blood sampling was repeated on the day of worsening of sepsis stage. for 30 patients who progressed into septic shock, blood was sampled daily for seven days starting immediately after the start of vasopressors. tubes were transported by a courier service within the same day to the laboratory of immunology of infectious diseases of the 4 th department of internal medicine at attikon university hospital of athens. tubes were centrifuged and serum was kept frozen at -70°c until assayed. igm was estimated in duplicate by an enzyme-linked immunosorbent assay (e-bioscience inc., san diego, ca, usa) following the manufacturer's instructions; the lower detection limit was 20 ng/ml. all estimations were performed and reported by two technicians who were blinded to clinical information. the central laboratory of the study participates in the uk neqas quality control system for leukocyte immunophenotyping (registration number 40926). in this laboratory, the absolute count of b lymphocytes was measured as described elsewhere [12] . briefly, red blood cells were lysed with ammonium chloride 1.0 mm. white blood cells were washed three times with phosphate-buffered saline (pbs) (ph 7.2) (merck, darmstadt, germany) and subsequently incubated for 15 minutes in the dark with the monoclonal antibody anti-cd19 at the flurochrome fluorescein isothiocyanate (fitc, emission 525 nm, immunotech, marseille, france) using fluorospheres (immunotech) for the determination of absolute counts. one igg isotypic negative control at the fluorocolor fitc was analyzed for every patient. cells were analyzed after running through the epics xl/msl flow cytometer (beckman coulter, inc., miami, fl, usa) with gating for mononuclear cells based on their characteristic forward scatter/side scatter (fs/ss) scattering. the isolation of pbmcs was limited to 55 patients because these samples should come from patients hospitalized at study sites close to the central laboratory. this allowed the time from blood collection until processing to be less than 30 minutes. as such, pbmcs were studied from patients hospitalized at the attikon university hospital that is close to the central laboratory of the study. production of igm was studied according to a procedure described elsewhere [13] . heparinized venous blood was layered over ficoll hypaque (biochrom, berlin, germany) and centrifuged for 20 minutes at 1400 g. separated pbmcs were washed three times with ice-cold pbs (ph: 7.2) (biochrom) and counted in a neubauer chamber. their viability was more than 99% as assessed by trypan blue exclusion of dead cells. they were then diluted in rpmi 1640 enriched with 2 mm of l-glutamine, 10% fetal bovine serum (biochrom), 100 u/ml of penicillin g, 100 μg/ml of gentamicin and 10 mm of pyruvate and suspended into wells of a 96-well plate (greiner, alphen a/d rijn, the netherlands). the final volume per well was 200 μl with a density of 2 ×10 6 cells/ml. pbmcs were incubated in the absence or presence of 5 μg/ml of the lymphocyte agonist phytohemagglutin (pha) of phaseolus vulgaris (pha-l, roche diagnostics gmbh, mannheim, germany) for 24 or 72 hours at 37°c in 5% co 2 atmosphere. at the end of the incubation, the plates were centrifuged. supernatants were kept stored at -70°c until assayed. concentrations of igm were measured at the end of the 72-hour incubation period; those of tumor necrosis factor alpha (tnfα) were measured at the end of the 24-hour incubation period. measurements were done in duplicate and igm was measured as described above. tnfα was measured by an enzyme-linked immunosorbent assay (r&d minneapolis, mi, usa). the lower detection limit was 40 pg/ml. the primary endpoint was the over-time changes of igm serum levels of patients upon progression to septic shock in relation with the final outcome that is survival or 28-day mortality. the secondary study endpoint was the impact of sepsis on production of igm from circulating lymphocytes. demographic characteristics of enrolled patients were provided as percentages for qualitative variables and as means ± standard error of the mean (se) or medians and interquartile ranges for quantitative variables. comparisons between groups were done by the x 2 test for qualitative variables and by anova with post hoc bonferroni corrections for quantitative variables. serum concentrations of igm were expressed as medians and 95% confidence intervals (ci). comparisons between groups were done by the mann-whitney u test with corrections by bonferroni for multiple testing. paired comparisons of serum igm at baseline and upon progression of the same patients to a more severe stage were done by the wilcoxon's rank sum test. for every patient with septic shock, the area under the curve (auc) of igm over time for seven days was measured by the linear trapezoidal rule. comparison between survivors and non-survivors was done by student's t test. concentrations of igm and of tnfα in supernatants of pbmcs were expressed as means ± se. comparisons between groups were done by the kruskal-wallis test with corrections by bonferroni for multiple testing. patients were also divided into 'non-igm' and 'igm-producers' if the concentrations of igm in supernatants of pbmcs were below the limit of detection or not. comparisons were done by the x 2 test. values of p below 0.05 were considered significant. a total of 351 patients were screened and 332 were enrolled ( figure 1 ). the demographic characteristics of enrolled patients in relation with the severity of critical illness are shown in table 1 . as expected, acute physiology and chronic health evaluation ii (apache ii) score, wbc counts, c-reactive protein and mortality were greater in the more severe stages of sepsis. the study end point was the kinetics of serum igm upon progression from severe sepsis to septic shock in relation with final outcome. to reach this end point, a three-step approach was followed ( figure 1 ) (a) circulating igm was compared between critically ill patients with varying severity; (b) circulating igm was measured at baseline and on the first day of worsening; and (c) distribution of igm was compared over time between survivors and nonsurvivors from septic shock. median igm was 44.1 mg/dl in healthy volunteers; 34.9 mg/dl in sirs; 23.0 mg/dl in sepsis; 36.2 mg/dl in severe sepsis; and 21.9 mg/dl in septic shock. statistical analysis showed that serum igm was decreased in septic shock compared to healthy volunteers (p = 0.001), to patients with sirs (p = 0.028) and to patients with severe sepsis (p <0.0001) but not to patients with uncomplicated sepsis (p = 0.754) (figure 2 ). paired comparisons of igm were done for 83 patients at two specific time points: on initial diagnosis and on worsening. these measurements involved: 13 patients initially diagnosed with uncomplicated sepsis who worsened into severe sepsis; 16 patients initially diagnosed with uncomplicated sepsis who worsened into septic shock; 49 patients initially diagnosed with severe sepsis who worsened into septic shock; and five patients initially diagnosed with septic shock who worsened into mods (figure 3 ). from all these paired comparisons, significant changes of circulating igm were found only between severe sepsis and septic shock; igm was significantly decreased upon worsening from severe sepsis into septic shock (p = 0.039). within the enrolled population with septic shock, serum igm did not differ between survivors and nonsurvivors (median igm of survivors 23.1 mg/dl and of non-survivors 20.7 mg/dl, p = 0.442). the time curves of igm were designed for 30 patients with severe sepsis who progressed into septic shock. sampling was started on the day of the start of vasopressors and lasted for seven consecutive days. separate curves were designed for survivors and non-survivors. these curves suggested that circulating igm remained stable and at low levels in non-survivors whereas igm of survivors increased to an early peak and then gradually decreased. as a consequence, the distribution of igm expressed by the auc of serum igm over time was significantly greater for survivors than for non-survivors. this finding was similar both when outcome was assessed after 28 days and at hospital discharge ( figure 4a and 4b). production of igm by pbmcs of 55 patients was also studied. from these patients, 24 had uncomplicated sepsis, 20 severe sepsis and 21 septic shock. respective mean ± sd age was 66.5 ± 18.7, 76.4 ± 9.2 and 60.0 ± 21.4 years; mean ± sd apache ii score was 10.7 ± 5.4, 17.4 ± 4.3 and 23.6 ± 4.8; and mean ± sd white blood cell count was 12,226.4 ± 5,262.0, 16,384.0 ± 11,294.0 and 17,130.9 ± 9,793.7/mm 3 . high production of both igm and tnfα was found by the pbmcs of healthy volunteers after stimulation with the selective lymphocyte agonist pha. production of igm and of tnfα was significantly lower at all stages of sepsis compared with healthy controls (figure 5a and 5b). furthermore, the rate of 'igm producers' was significantly lower among patients with septic shock than among patients at all other sepsis stages ( figure 5c ). the present study is the largest cohort to the best of our knowledge that describes the kinetics of circulating igm in sepsis. analysis indicates that the decrease of igm is a predominant characteristic when a patient with severe sepsis develops septic shock. close monitoring from the start of vasopressors shows that the distribution of igm is greater in survivors than in non-survivors from septic shock. these conclusions are based on the multilevel approach of the current study; at first, comparisons between sirs, sepsis, severe sepsis and septic shock indicated that septic shock is the stage of critical illness with the lower circulating igm; then measurements at distinct time points that is, upon initial diagnosis and upon worsening showed that circulating igm decreases specifically upon progression from severe sepsis to septic shock; and finally, intense monitoring of igm after the start of vasopressors revealed a relationship between lacking distribution of igm and unfavorable prognosis. igm levels in patients with septic shock are reported in two more studies. in the first study [14] , igm was decreased in 21 patients with septic shock. patients were followed up every 48 hours for five days and they were divided into those with hypo igm concentrations and normal igm concentrations. no differences were found between survivors and non-survivors. in the second study [15] , low igm levels were reported in the plasma of 62 patients with septic shock. the igm concentrations reported by the authors of this study were within the range of concentrations reported in our study. however, the authors failed to define any differences in circulating igm between survivors and nonsurvivors [15] . in their study, blood samplings of days 1 and 2, of days 3 and 4 and of days 5 to 7 were reported together which did not allow measurement of the distribution of circulating igm as this was done in our study. igm is a polyvalent immunoglobulin circulating as a pentamer [3] . it opsonizes bacteria and primes phagocytosis by neutrophils; it binds and inactivates endotoxins of gram-negative bacteria and exotoxins of gram-positive cocci; and it also binds and inactivates proinflammatory host mediators like cytokines. its role is underscored by models of experimental sepsis in mice; survival is prolonged after induction of sepsis through cecal ligation and puncture (clp) within the animals that possess the highest potential for igm-primed phagocytosis [16] . recent data coming both from rodents and humans suggest that release of igm is primed by a new subset of b lymphocytes known as ira (innate response activator) b cells. these cells belong to the innate defense system, they contain large cytoplasmic stores of igm antibodies and they are the main effectors of the rapid release of igm. ira b cells are depleted in experimental sepsis and this leads to early death [17] . the evidence coming from experimental animal data may help explain the importance of the ex vivo production of igm from our patient population. all patients produced much lower igm than healthy volunteers; this defect was exaggerated in septic shock. our findings lead to the hypothesis that during severe sepsis lymphocytes are hypofunctional for igm production but high circulating igm compensates for the patient's needs; once septic shock develops circulating igm is fully consumed and lymphocytes are completely anergic for any igm production. two major limitations of the current study should, however, be acknowledged: (a) the lack of explanation why septic shock is a specific condition where circulating igm is depleted. it is most probable that this is related with the consumption of circulating igm during sepsis worsening and with the inability of b lymphocytes for igm production; and (b) the lack of explanation from our findings why circulating igm does not differ between uncomplicated sepsis and septic shock. the present study managed to identify specific changes of the kinetics of circulating igm that are related with final outcome. these occur when patients with severe sepsis progress to septic shock. in these patients, the distribution of igm is lower among non-survivors. these findings may guide the design of future rcts for the management of septic shock. serum levels of igm are significantly decreased in septic shock but not in severe sepsis. dramatic changes of serum igm occur when patients at severe sepsis progress into septic shock. in these cases, the distribution of igm is lower among non-survivors. circulating lymphocytes of patients render anergic for the production of igm. the immune response to severe bacterial infections: consequences for therapy hotchkiss rs: immunosuppression in patients who die of sepsis and multiple organ failure igm in microbial infections: taken for granted? use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis sccm/esicm/accp/ats/sis international sepsis definitions conference acute pancreatitis procalcitonin guidance of antibiotic therapy in community-acquired pneumonia. a randomized trial international conference for the development of consensus on the diagnosis and treatment of ventilator-associated pneumonia fever in the clinical diagnosis of acute pyelonephritis the international sepsis forum consensus conference definitions of infections in the intensive care unit early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection grouping of patients with common variable immunodeficiency based on immunoglobulin biosynthesis: comparison with a classification system on cd4-naïve cells γ-globulin levels in patients with community-acquired septic shock assessment of plasmatic immunoglobulin g, a and m levels in septic shock patients presence of pre-existing antibodies mediate survival in sepsis innate response activator b cells protect against microbial sepsis submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution the study was funded (a) in part by the hellenic institute for the study of sepsis; and (b) in part by an unrestricted educational grant by biotest ag, dreieich, germany. abbreviations apache ii: acute physiology and chronic health evaluation ii; ards: acute respiratory distress syndrome; bsi: primary bacteremia; cap: communityacquired pneumonia; iai: intra-abdominal infection; igm: immunoglobulin m; ira: innate response activator; mods: multiple organ dysfunction syndrome; pbmc: peripheral blood mononuclear cell; pha: phytohemagglutin; rct: randomized controlled trial; sirs: systemic inflammatory response syndrome; tnfα: tumor necrosis factor alpha; uti: acute pyelonephritis; vap: ventilator-associated pneumonia; wbc: white blood cell. the authors declare that they have no competing interests related to this submission. key: cord-259747-sl9q63oc authors: remmelink, myriam; de mendonça, ricardo; d’haene, nicky; de clercq, sarah; verocq, camille; lebrun, laetitia; lavis, philomène; racu, marie-lucie; trépant, anne-laure; maris, calliope; rorive, sandrine; goffard, jean-christophe; de witte, olivier; peluso, lorenzo; vincent, jean-louis; decaestecker, christine; taccone, fabio silvio; salmon, isabelle title: unspecific post-mortem findings despite multiorgan viral spread in covid-19 patients date: 2020-08-12 journal: crit care doi: 10.1186/s13054-020-03218-5 sha: doc_id: 259747 cord_uid: sl9q63oc background: post-mortem studies can provide important information for understanding new diseases and small autopsy case series have already reported different findings in covid-19 patients. methods: we evaluated whether some specific post-mortem features are observed in these patients and if these changes are related to the presence of the virus in different organs. complete macroscopic and microscopic autopsies were performed on different organs in 17 covid-19 non-survivors. presence of sars-cov-2 was evaluated with immunohistochemistry (ihc) in lung samples and with real-time reverse-transcription polymerase chain reaction (rt-pcr) test in the lung and other organs. results: pulmonary findings revealed early-stage diffuse alveolar damage (dad) in 15 out of 17 patients and microthrombi in small lung arteries in 11 patients. late-stage dad, atypical pneumocytes, and/or acute pneumonia were also observed. four lung infarcts, two acute myocardial infarctions, and one ischemic enteritis were observed. there was no evidence of myocarditis, hepatitis, or encephalitis. kidney evaluation revealed the presence of hemosiderin in tubules or pigmented casts in most patients. spongiosis and vascular congestion were the most frequently encountered brain lesions. no specific sars-cov-2 lesions were observed in any organ. ihc revealed positive cells with a heterogeneous distribution in the lungs of 11 of the 17 (65%) patients; rt-pcr yielded a wide distribution of sars-cov-2 in different tissues, with 8 patients showing viral presence in all tested organs (i.e., lung, heart, spleen, liver, colon, kidney, and brain). conclusions: in conclusion, autopsies revealed a great heterogeneity of covid-19-associated organ injury and the remarkable absence of any specific viral lesions, even when rt-pcr identified the presence of the virus in many organs. coronaviruses, including severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov), cause severe acute respiratory failure, which is associated with high mortality rates [1] . the novel sars-cov-2 strain exhibits phylogenetic similarities to sars-cov and causes coronavirus disease 2019 (covid19) , which has resulted in more than 540,000 deaths worldwide so far. as the pandemic has progressed, the pathophysiology of this viral infection has become clearer; in particular, it has been shown that sars-cov-2 can directly alter cell function by a link to the angiotensin converting enzyme 2 (ace2) receptor, which is almost ubiquitous in the human body [2] . nevertheless, the mechanisms behind the high mortality and severe organ dysfunction associated with covid-19 remain poorly understood. controversies exist regarding the occurrence of fatal complications, such as pulmonary embolism or diffuse endothelial injury [3, 4] , as well as on the roles of direct viral cellular injury or concomitant comorbidities in the fatality of this disease [5] . in this setting, autopsy is of great importance to help physicians understand the biological characteristics and the pathogenesis of covid-19. most of the previously reported post-mortem findings focused on lung morphology and few data are available on complete post-mortem analyses of other organs [6, 7] . the aim of this study was therefore to investigate the presence of specific features of viral injury as well as the distribution of the virus in different organs of patients who died from covid-19. in this post-mortem study, we included the first 17 adult patients (> 18 years) who died in our hospital (either in a covid-19 unit or an intensive care unit) from march 13, 2020, with confirmed sars-cov-2 infection (i.e., positive rt-pcr assay on nasopharyngeal swab and/or bronchoalveolar lavage specimen). exclusion criteria were lack of family consent and a delay of more than 5 days after death before post-mortem examination. the study protocol was approved by the local ethics committee (p2020/218). we collected demographics, comorbidities, relevant clinical data, including duration between symptom onset or hospitalization and death, the results of chest computed tomography scan, and, if available, microbiological tests and medical treatments (e.g., hydroxychloroquine, antivirals or antibiotics, and use of organ support). acute respiratory distress syndrome (ards) and acute kidney injury (aki) were defined according to standard definitions [8, 9] . the belgian public health institute (sciensano) guidelines were integrated into our post-mortem procedure [10] . the cadavers were kept in the refrigerator at 4°c and autopsies were performed 72 to 96 h after death to ensure the safety of the autopsy team. personal protective equipment consisted of two superposed disposable latex gloves, plastic sleeves, ffp3 mask, scrub hat, clear face visor, surgical gown plus plastic apron, and rubber boots. in the post-mortem room, dirty and clean circulations were used in the airlocks to allow decontamination. all analyses were performed at normal pressure. using standard surgical pathology processing, complete sets of tissue samples were collected for diagnosis and biobanking. the material was biobanked by biobanque hôpital erasme-ulb (be_bera1), cub hôpital erasme; bbmri-eric. the banked material consists of 6 samples per organ, including the trachea, thyroid, lymph nodes, heart, spleen, bone marrow, kidney, bladder, liver, stomach, colon, and brain. for the lungs, we collected six samples per lobe (i.e., a total of 30 samples), except for two patients who had undergone lobectomy for cancer and from whom only 18 samples were taken. for safety reasons, complete brain removal was not allowed, but, with the help of a neurosurgeon, in 11 cases, we used a new, safe procedure with drills and protective devices to avoid air dispersion, to obtain between 12 and 51 samples from different brain regions, as detailed in the additional file 1 (additional material). formalinfixed paraffin-embedded (ffpe) tissues underwent standard processing to provide hematoxylin and eosin (h&e)-stained sections. special stains and immunohistochemistry (ihc) were used for lung (masson's trichrome, periodic acid-schiff [pas], gomori-grocott, anti-cmv ihc, anti-hsv ihc, anti-pneumocystis j ihc) and kidney (pas, masson's trichrome, jones methenamine silver) samples. morphological analysis was performed on h&e stained glass slides using the secundos digital platform (tribvn health care, chatillon, france) for digital diagnosis, after the acquisition of whole slide digital scans (× 40 magnification) using a nanozoomer 2.0 ht slide scanner (hamamatsu, hamamatsu city, japan). since no antibody against sars-cov-2 has been validated for ihc on ffpe tissues, we selected an anti-sarsnucleocapsid protein antibody. standard ihc was applied as previously described to 4-μm-thick post-mortem lung sections (one sample for each lung lobe per patient) to display sars-nucleocapsid protein (invitrogen, pa1-41098, dilution 1:50) on dako omnis (agilent technologies, santa clara, ca, usa) using the envision flex detection system according to the manufacturer's protocol [11] . the sections were counterstained with hematoxylin. negative tissue controls were obtained from patients who had an autopsy before the covid-19 pandemic. semi-quantitative ihc evaluation was performed by two senior pathologists (nd, mr) as follows: negative (−); between one and five positive cells per whole slide (scattered cells, +); more than five cells per whole slide but no foci (isolated cells, ++); and with foci (more than 10 cells in one × 20 field, +++). total nucleic acid was extracted from ffpe tissues using the maxwell rsc dna ffpe kit (reference: as1450. promega corporation, madison, wi, usa) and the promega maxwell extractor, following the protocol described by the manufacturer. one-step rt-pcr assays specific for the amplification of sars-cov-2 e envelope protein gene were adapted from a published protocol [12] . briefly, 4 μl of rna (100 ng) was amplified in 20 μl reaction mixture containing 5 μl of taqman fast virus 1-step master mix (life technologies), 0.4 μm of each forward (acaggtacgttaatagttaatagc gt) and reverse (atattgcagcagtacgcacaca) primers and 0.2 μm of probe (fam-acactagcca tccttactgcgcttcg-bbq). the amplification condition was 50°c for 10 min for reverse transcription, followed by 95°c for 20 s and then 45 cycles of 95°c for 3 s and 58°c for 30 s. a clinical sample highly positive for sars-cov-2 was diluted 1:1000 and used as a positive control in each analysis. a clinical sample obtained from a patient who was autopsied before the covid-19 pandemic was used as a negative control. the quality of the rna from the samples showing negative results was assessed by amplification of the human met rna according to a validated iso:15189 accredited method used as a routine diagnostic method in our laboratory. data are reported as counts (percentage) or medians [interquartile ranges (iqrs)]. all data were analyzed using graphpad prism version 8.4.2 (graphpad software, san diego, ca, usa). the main characteristics of the study cohort (12 males out of 17; median age 72 [62-77] years) are given in table 1 . the time period between the onset of symptoms and death ranged from 2 to 40 days (median, 14 days) and between admission and death from 0 to 33 days (median, 10 days). all except two patients had at least one comorbidity, including hypertension (n = 10), diabetes (n = 9), cerebrovascular disease (n = 4), coronary artery disease (n = 4), and solid cancer (n = 4). none of the patients had tested positive on admission for the respiratory syncytial virus or influenza a and b viruses. eleven of the patients were treated with mechanical ventilation. eleven patients died in the icu and 6 on the medical ward; the main causes of death were respiratory failure (n = 9) and multiple organ failure (n = 7). laboratory data are reported in additional file 2 (table s1 ). one patient had had a left pneumonectomy and one patient a right bilobectomy. the lungs were typically heavy and the lung parenchyma had a diffuse firm consistency with red/tan and patchy dark/red areas of hemorrhage. thrombi were found in the large pulmonary arteries in 2 patients and lung infarction in 4 patients. pleural adhesions associated with pleural effusions were observed in 4 cases. we observed cardiomegaly in 14 and hepatomegaly in 5 patients. the kidneys were often enlarged, with a pale cortex and petechial aspect but no hemorrhage or infarct. the gut had advanced post-mortem autolysis with no evidence of specific lesions, except for one patient who had ischemic enteritis. in the 11 patients for whom brain samples were available, one had had a recently drained subdural hematoma and another a cerebral hemorrhage. as shown in figs. 1 and 2 and additional file 3 (table s2) , the main pulmonary findings included early-stage diffuse alveolar damage (dad), which consisted of interstitial and intra-alveolar edema, with variable amounts of hemorrhage and fibrin deposition, hyaline membranes, minimal interstitial mononuclear inflammatory infiltrate, and type ii pneumocyte hyperplasia. microthrombi were noted in the small pulmonary arteries in 11 patients. ten of the 17 patients also had advanced dad lesions (i.e., fibroblastic proliferation within the interstitium and in the alveolar spaces); 8 patients had evidence of acute pneumonia or bronchopneumonia, 4 had atypical pneumocytes, and three had syncytial multinucleated giant cells. we observed no viral inclusions or squamous metaplasia. all the patients who survived more than 3 weeks (n = 5) had late dad lesions. there was no relationship between the delay from onset of symptoms to death or from hospitalization to death and the presence of other histological lesions, including bronchopneumonia, pneumonia, microthrombi, ischemic lesions, pulmonary emboli, or pulmonary infarct. in 4 of the 6 patients who had not received mechanical ventilation, the delay between hospitalization and death was less than 5 days; in this group, only 1 case had microthrombi. the other 2 patients had longer fifteen patients had signs of chronic ischemic cardiomyopathy of different severities and 2 patients had signs of acute myocardial infarction; there was no evidence of contraction bands or myocarditis. histological evaluation of the kidneys was limited because of moderate to severe post-mortem autolysis; occasional hemosiderin granules were observed in the tubular epithelium in 9 patients and pigmented casts in 12. in the medulla, edematous expansion of the interstitial space without significant inflammation was observed in 4 patients. chronic renal lesions (i.e., nodular mesangial expansion and arteriolar hyalinosis, glomerulosclerosis, or chronic pyelonephritis) were also observed; no microthrombi were identified, but one patient had a thrombus in an interlobar artery. liver examination revealed congestive hepatopathy and steatosis, but no patchy necrosis, hepatitis, or lobular lymphocytic infiltrate. the histological changes in the abdominal organs including the esophagus, stomach, and colon are reported in additional file 3 (table s2) ; most of the findings were related to chronic underlying diseases, except for one case of ischemic enteritis. brain samples showed cerebral hemorrhage or hemorrhagic suffusion (n = 8), focal ischemic necrosis (n = 3), edema and/or vascular congestion (n = 5), and diffuse or focal spongiosis (n = 10). we found no evidence of viral encephalitis or vasculitis, isolated neuronal necrosis, or perivascular lymphocytic infiltration. sars-cov-2 was identified by ihc in the lungs of 11 of the 17 patients (fig. 3) . however, there was large variability in the distribution of sars-cov-2-positive cells in the lung parenchyma. sars-cov-2 rna was detected in at least one organ from every patient (fig. 4) . in the lung, rt-pcr was positive in 16 patients, with threshold cycle (ct) values varying from 16.02 to 33.03. viral rna was also detected in the heart (n = 14), the liver (n = 14), the bowel (n = 14), the spleen (n = 11), and the kidney (n = 10), as well as in 9 of the 11 cerebral samples. ct values for non-pulmonary organs ranged from 28.67 to 35.11. eight patients had positive rt-pcr in all tested organs. this post-mortem study showed several histopathological abnormalities in covid-19 non-survivors; however, none of the findings was specific for direct viral injury, even though sars-cov-2 was detected in all examined organs using rt-pcr. we decided to perform complete autopsies rather than other techniques such as post-mortem core biopsies, so as to obtain a better overview of all organs, especially the lungs (we collected 6 samples from each lobe). this approach enabled us to the diagnosis of sars-cov-2-related organ injury is challenging; post-mortem histological findings were heterogeneous and often associated with chronic underlying diseases. in a previous autopsy study in , the authors reported that dad associated with viral pneumonia was almost impossible to distinguish from that caused by bacterial pneumonia. no obvious intranuclear or intracytoplasmic viral inclusions were identified in another report [6] . desquamation of pneumocytes and hyaline membrane formation are frequently described in ards of many different causes, especially in early-phase ards [13] . the presence of multinucleated cells with nuclear atypia is used to diagnose herpes virus infection in daily practice. as in previous reports [6, 14] , we also observed the presence of multinucleated cells within lung alveoli in three patients; however, the significance of multinucleated cells is unclear and may not be specific of sars-cov-2 infection [15] . finally, some of the microscopic features of these patients are compatible with organ changes secondary to shock or systemic inflammation and no histological finding could be specifically ascribed to sars-cov-2. in the absence of typical post-mortem viral features, our results show that rt-pcr is feasible on ffpe blocks and could be used in post-mortem analyses to identify the presence of sars-cov-2 in multiple organs and to understand the spread of the virus within the human body. the discordant rt-pcr and ihc results for detection of sars-cov2 in the lungs may be explained by the different sensitivity of these assays, which was higher for the rt-pcr, whereas low-level viral replication might not be detected by ihc. moreover, ihc was based on the only available antibodies, which are targeted against sars-cov. new antibodies against sars-cov-2 need to be developed to improve the accuracy of ihc in the analysis of tissue samples from suspected or confirmed covid-19 patients. most of the previous post-mortem studies in covid-19 patients were conducted using needle biopsies and were therefore rather limited in terms of sampling; our complete autopsy analysis identified considerable heterogeneity of sars-cov-2 spread through the human body and provides a more accurate description of macroscopic and microscopic organ alterations. as for previous coronavirus diseases [16, 17] , the lungs are the most affected organs in covid-19. however, dad findings were highly heterogeneous, including both early-onset and additional late lesions. this finding could be explained by the heterogeneity of the pulmonary injury, including compliant lungs in the early phase and a more dense and non-recruitable lung in the late phase [18] . as some patients died outside the icu without receiving mechanical ventilation, we could not estimate lung compliance before death. the heterogeneity could also reflect different treatments (e.g., fluid administration or corticosteroids) or different complications; as an example, half of the patients had concomitant acute pneumonia and it is difficult to conclude whether the dad reflected the natural time-course of the viral disease or was secondary to superimposed complications, such as nosocomial infections. in a recent report, needle post-mortem biopsies suggested that covid-19 is not associated with dad but rather with an acute fibrinous and organizing pneumonia (afop), consequently requiring corticoid treatment [19] . a diagnosis of afop is based on the absence of hyaline membranes and the presence of alveolar fibrin balls; however, hyaline membranes are heterogeneously distributed in the lung parenchyma with dad and complete lung analysis, not just biopsies, are necessary to exclude their presence. moreover, afop may be a fibrinous variant of dad [20] . the limitation of lung biopsy was also shown in another study, in which only 50% of lung samples were positive for sars-cov-2 using rt-pcr [21] , when compared to almost 100% in our series. in addition, we did not find specific "endothelitis" as previously reported in a small case series [4] . considering the heterogeneity of postmortem covid-19 associated lesions, molecular and ihc assessments are mandatory in the histological analysis of covid-19 tissue samples. patients with covid-19 often have altered coagulation and a prothrombotic status, with the possible development of acute pulmonary embolism (pe) [22] . in our study, three patients had pe, already diagnosed before death. four patients had pulmonary infarction. in a previous study, acute pe was considered as the main cause of death in four patients [3] ; however, the inclusion of patients who died before hospital admission and the lack of specific thromboprophylaxis during the hospital stay may account for the differences in the severity of pe when compared to our study. although we frequently observed the presence of microthrombi in the lung parenchyma, this feature is also reported in other forms of ards, regardless of etiology [13, 23] . as such, whether diffuse pulmonary thrombosis is a main contributor of the fatal course of severe hypoxemia in covid-19 patients remains to be further studied. in a systematic review of pathological findings in covid-19, polak et al. [24] identified a timeline in the histopathological findings in the lung, with epithelial (dad, denudation and reactive pneumocytes atypia) and vascular (microvascular damage, thrombi, intra-alveolar fibrin deposits) changes present at all stages of the disease, but fibrotic changes (interstitial fibrous changes) only appearing about 3 weeks after the onset of symptoms. few patients had fibrosis at early stages, and in these cases, it was likely because of pre-existing lung disease. our results are consistent with those of polak et al. [24] except for the lack of late fibrotic changes, which may be related to the use of anti-inflammatory drugs at high doses for nearly all our patients (16/17). we did not observe specific viral organ injury, such as myocarditis, hepatitis, or encephalitis. the cases of "acute cardiac injury" reported in covid-19 clinical studies [25] do not necessarily translate into myocarditis or acute myocardial ischemia (only two had acute myocardial ischemia), similar to data reported in septic patients (i.e., elevated troponin without overt cardiac ischemia) [26] . however, using rt-pcr, we found the virus in almost all the examined organs; this suggests that the virus can bind to most cells, probably via the ace2 receptor, which is ubiquitous, but may not directly cause organ injury. as extra-pulmonary direct viral injury (e.g., encephalitis, hepatitis, or myocarditis) has only been reported in very few cases, we suggest that sars-cov-2 infection may be just the trigger for an overwhelming host response, which could secondarily result in covid-19-associated organ dysfunction. as rt-pcr might just detect residual viral genome, it remains unclear whether this represents active viral replication into the tissues or previous cellular infection, without clinically relevant significance [27] . this study has several limitations: (i) we only included patients who had had a positive rt-pcr on nasopharyngeal swab and/or broncho-alveolar lavage. to ensure that only true positive cases were enrolled, we decided not to include three patients who had had thoracic ctscan findings suggestive of covid-19 but had negative rt-pcr results. this limitation in our study reflects the difficulty of diagnosing covid-19 on a clinical basis; (ii) the sample size was relatively small, and autopsies were only carried out from 72 to 96 h after death. this delay did not allow us to properly analyze the gastrointestinal tract and kidneys, which showed signs of autolysis; in particular, acute tubular injury in the proximal tubules was indistinguishable from autolysis; (iii) we could not determine the time-course and/or sequence of organ spread of the virus and no specific hypothesis regarding how sars-cov-2 spreads (e.g., hematogenously) could be identified; and (iv) the time to death differed from patient to patient as did the course of the disease and treatments received, which limits a precise clinicalpathological correlation of histological findings related to covid-19. finally, we did not evaluate specific mechanisms involved in the pathogenesis of organ injury. these results underline the heterogeneity of organ injuries during covid-19 disease and the absence of specific sars-cov-2 lesions. using rt-pcr, sars-cov-2 could be detected in all organs, even those without evident microscopic lesions. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03218-5. additional file 1. critical care-autopsy-covid. additional material. procedure to obtain brain samples. additional file 2: critical care-autopsy-covid. additional table s1 . laboratory findings on the day of admission. additional file 3: critical care-autopsy-covid. additional table s2 . detailed histological findings in all patients. clinical characteristics of coronavirus disease 2019 in china sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor autopsy findings and venous thromboembolism in patients with covid-19: a prospective cohort study. ann intern med. 2020. epub ahead of print endothelial cell infection and endotheliitis in covid-19 clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. bmj. 2020. epub ahead of print pathological findings of covid-19 associated with acute respiratory distress syndrome covid-19 autopsies acute respiratory distress syndrome: the berlin definition guideline work group. diagnosis, evaluation, and management of acute kidney injury: a kdigo summary (part 1) procédure pour les hôpitaux: prise en charge d'un patient possible ou confirmé covid-19 design and validation of a gene-targeted, nextgeneration sequencing panel for routine diagnosis in gliomas detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr ards: a clinicopathological confrontation post-mortem examination of covid19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction. histopathology. 2020. epub ahead of print lung pathology of severe acute respiratory syndrome (sars): a study of 8 autopsy cases from singapore lung pathology of fatal severe acute respiratory syndrome pulmonary pathology of severe acute respiratory syndrome in toronto covid-19 pneumonia: ards or not ? time to consider histologic pattern of lung injury to treat critically ill patients with covid-19 infection pathophysiology of acute fibrinous and organizing pneumonia -clinical and morphological spectra clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china. jama. 2020. epub ahead of print high incidence of venous thromboembolic events in anticoagulated severe covid-19 patients acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis a systematic review of pathological findings in covid-19: a pathophysiological timeline and possible mechanisms of disease progression association of cardiac injury with mortality in hospitalized patients with covid-19 in wuhan, china. jama cardiol. 2020. epub ahead of print structural changes of the heart during severe sepsis or septic shock virological assessment of hospitalized patients with covid-2019 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank nathalie lijsen, christophe valleys, georges lacroix, barbara alexiou, dominique penninck, nicole haye, and audrey verrellen for technical and logistic supports; prof frédéric schuind and dr. djamel-eddine yahia-cherif for neurosurgical procedure; egor zindy (diapath, ulb) for proofreading the paper; and dr. marie-paule van craynest for trainees' supervision.authors' contributions is had the idea for and designed the study and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. is, ft, jlv, and cd drafted the paper. mr, cv, ll, pl, mlr, cm, alt, jcg, lp, rdm, sd, sr, nd, lp, and od collected the data. mr, nd, and rdm did the analysis, and all authors critically revised the manuscript for important intellectual content and gave final approval for the version to be published. all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. this study received financial support from fonds y. boël (brussels, belgium), fonds erasme pour la recherche médicale (brussels, belgium), and "appel à projet spécial covid-19 -ulb" (brussels, belgium). the cmmi is supported by the european regional development fund and the walloon region of belgium (wallonia-biomed; grant no. 411132-957270; project "cmmi-ulb" support the center for microscopy and molecular imaging and its diapath department). cd is a senior research associate with the f.n.r.s. (belgian national fund for scientific research). 3 immunodeficiency treatment unit, erasme hospital, université libre de bruxelles (ulb), route de lennik 808, 1070 brussels, belgium. 4 the data that support the findings of this study are available from the corresponding author on reasonable request. participant data without names and identifiers will be made available after approval from the corresponding author and local ethics committee. the research team will provide an email address for communication once the data are approved to be shared with others. the proposal with a detailed description of study objectives and statistical analysis plan will be needed for the evaluation of the reasonability to request for our data. additional materials may also be required during the process. the study protocol was approved by the local ethics committee (erasme hospital p2020/218). the ethical committee has waived the need for written informed consent. the authors declare that they have no competing interests. key: cord-048448-kfwbqp4p authors: sandrock, christian; kelly, terra title: clinical review: update of avian influenza a infections in humans date: 2007-03-22 journal: crit care doi: 10.1186/cc5675 sha: doc_id: 48448 cord_uid: kfwbqp4p influenza a viruses have a wide host range for infection, from wild waterfowl to poultry to humans. recently, the cross-species transmission of avian influenza a, particularly subtype h5n1, has highlighted the importance of the non-human subtypes and their incidence in the human population has increased over the past decade. during cross-species transmission, human disease can range from the asymptomatic to mild conjunctivitis to fulminant pneumonia and death. with these cases, however, the risk for genetic change and development of a novel virus increases, heightening the need for public health and hospital measures. this review discusses the epidemiology, host range, human disease, outcome, treatment, and prevention of cross-transmission of avian influenza a into humans. human influenza pandemics over the last 100 years have been caused by h1, h2, and h3 subtypes of influenza a viruses. more recently, avian influenza virus subtypes (that is, h5, h7) have been found to directly infect humans from their avian hosts. the recent emergence, host expansion, and spread of a highly pathogenic avian influenza (hpai) h5n1 subtype in asia have heightened concerns globally, both in regards to mortality from hpai h5n1 infection in humans and the potential of a new pandemic. this paper will review the current human infections with avian influenza and their public health and medical implications. influenza a, b and c are the most important genera of the orthomyxoviridae family, casusing both pandemic and seasonal disease in humans. influenza a viruses are enveloped, single-stranded rna viruses with a segmented genome (table 1 ) [1] . they are classified into subtypes on the basis of the antigenic properties of the hemagglutinin (ha) and neuraminidase (na) glycoproteins expressed on the surface of the virus [1, 2] . influenza a viruses are characterized by their pathogenicity, with highly pathogenic avian influenza (hpai) causing severe disease or death in domestic poultry [3] . molecular changes in the rna genome occur through two main mechanisms: point mutation (antigenic drift) and rna segment reassortment (antigenic shift) [4, 5] . point mutations cause minor changes in the antigenic character of viruses and are the primary reason a vaccination for influenza a is given yearly. reassortment occurs when a host cell is infected with two or more influenza a viruses, leading to the creation of a novel subtype. the influenza subtypes of the 1957 (h2n2) and 1968 (h3n2) pandemics occurred through reassortment, while the origins of the 1918 (h1n1) pandemic are unclear. the ha glycoprotein mediates attachment and entry of the virus by binding to sialic acid receptors on the cell surface. the binding affinity of the ha to the host sialic acid allows for the host specificity of influenza a [6, 7] . avian influenza subtypes prefer to bind to sialic acid linked to galactose by α-2,3 linkages, which are found in avian intestinal and respiratory epithelium ( table 2 ) [8] . human virus subtypes bind to α-2,6 linkages found in human respiratory epithelium [8, 9] . swine contain both α-2,3 and α-2,6 linkages in their respiratory epithelium, allowing for easy co-infection with both human and avian subtypes (thus acting as a 'mixing vessel' for new strains) [10] . humans have been found to contain both α-2,3 and α-2,6 linkages in their lower respiratory tract and conjunctivae, which allows for human infections by avian subtypes [9, 11, 12] . the ha glycoprotein is the main target for immunity by neutralizing antibodies. the na glycoprotein allows the spread of the virus by cleaving the glycosidic linkages to sialic acid on host cells and the surface of the virus. the virus is then spread in secretions or other bodily fluids. the na glycoprotein is not the major target site for neutralization of the virus by antibodies. influenza a viruses infect a wide range of hosts, including many avian species, and various mammalian species, such as swine, ferrets, felids, mink, whales, horses, seals, dogs, civets, and humans [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] . wild birds (ducks, geese, swans, and shorebirds) are important natural reservoirs of these viruses, and all of the known 16 ha and 9 na subtypes have been found in these birds [32] [33] [34] [35] . in most cases, these subtypes are found within the gastrointestinal tract of the birds, are shed in their feces, and rarely cause disease [32] . since 2002, however, hpai h5n1 viruses originating in asia have been reported from approximately 960 wild bird species, causing disease in some instances and asymptomatic shedding in others [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] . the virus has now spread across asia, europe, the middle east, and some african countries. additional species, such as tigers, leopards, cats, stone martens, and humans have also become infected with hpai h5n1 [49] . this spread of h5n1 into a wide range of animal and avian species may enhance the spread of the virus into the human population as it interacts with animals in a number of ways (increased land use, markets, consumption) [44] . thus, the potential contact, transmission, and mutability of hpai h5n1 worldwide will increase as the number of species and their interactions increase, complicating prevention, surveillance and treatment possibilities. the incidence of avian influenza infections in humans has increased over the past decade (table 3) . initially, cases of avian influenza (h7n7) in humans occurred in association with poultry outbreaks, manifesting as self-limiting conjunctivitis [30, [50] [51] [52] [53] . then, in 1997, a large scale hpai h5n1 outbreak occurred among poultry in hong kong, with 18 documented human cases [29, 31, 54, 55] . two subsequent poultry outbreaks in hong kong in 1999 and 2003 with hpai h5n1 occurred without human cases until 2003 when two members of a family in hong kong contracted hpai h5n1 [56] . in december of 2003, hpai h5n1 surfaced in poultry in korea and china, and from 2003 to 2006 the outbreak stretched worldwide in the largest outbreak in poultry history. human cases of hpai h5n1 followed the poultry outbreak, with a total of 256 cases and 151 fatalities thus far [57] . other limited outbreaks have occurred, causing variable human disease (table 3 ) [52, 58] . however, hpai h5n1 remains the largest and most significant poultry and human avian influenza outbreak. epidemiological investigations of human cases of avian influenza show that the virus was acquired by direct contact with infected birds [29] [30] [31] [50] [51] [52] [53] [54] [55] [56] . influenza a is transmitted through the fecal-oral and respiratory routes among wild birds and poultry [32] . human interaction with these infected secretions and birds was the major mode of transmission, with contact including consumption of undercooked or raw poultry products, handling of sick or dead birds without protection, or food processing at bird cleaning sites. all birds were domesticated (chicken, duck, goose) and no transmission from birds in the wild (migrating) or contaminated waterways has been documented. in a few cases, limited human to human transmission has been reported among health care workers and family members (table 4 ) [59] [60] [61] [62] [63] . in each of these cases, no personal protective equipment was used, which is the major factor in transmission between humans [60] . the clinical manifestations of avian influenza in humans has ranged from mild conjunctivitis to severe pneumonia with multi-organ system failure ( [53] . however, with hpai in hong kong in 1997 and in southeast asia currently, pneumonia progressing to multiorgan failure, acute respiratory distress syndrome (ards), and death are the predominant findings [17, 55, [65] [66] [67] [68] . rye syndrome, pulmonary hemorrhage, and predominant nausea, vomiting, and diarrhea complicate these cases [68] . laboratory findings include both thrombocytopenia and lymphopenia [65, 66] . chest radiographic findings include interstitial infiltrates, lobar consolidation, and air bronchograms. the clinical course of patients with hpai h5n1 is rapid, with 68% percent of patients developing ards and multiorgan failure within 6 days of disease onset [69] . the case fatality rate ranges form 67% to 80%, depending on the case series [17, 55, 65, 66] . once the patients reached the critical care unit, however, the mortality rate was 90% [69] . the average time of death from disease onset was nine to ten days. avian influenza a infections in humans differ from seasonal influenza in several ways. the presence of conjunctivitis is available online http://ccforum.com/content/11/2/209 number of fatalities (percent) 0 (0) 6 (33) 0 (0) 1 (1) 0 (0) 151 (59) h, hemagglutinin; ili, influenza like illness; n, neuroaminidase. more common with avian influenza a infections than with seasonal influenza. gastrointestinal symptoms, as seen with hpai h5n1, and reports of primary influenza pneumonia and development of ards are also more common with avian influenza a infections [65, 67, 69] . finally, the rapid progression to multi-organ failure and eventually death occurs at a much higher rate with avian influenza a infections [69] . post-mortem studies have illustrated findings consistent with an overwhelming systemic inflammatory response syndrome, including diffuse alveolar damage, acute tubular necrosis and atrophy, disseminated intravascular coagulation, and multiorgan damage [70, 71] . interestingly, the virus has been isolated from the lungs, intestine, spleen, and brain, suggesting viremia, but active replication of the virus has been limited to the lungs [71] . this overwhelming inflammatory response, with acute lung injury and ards as the predominant features, coincides with the findings of preferential binding of the avian influenza a viruses to α-2,3 linkages in type ii pneumocytes of the lower respiratory tract of humans and a vigorous cytokine response, including increased interleukin-6, interleukin-10, and interferon beta release [11, 12, 70, 71] . the clinical diagnosis of avian influenza infection in humans is difficult and relies on the epidemiological link to endemic areas, contact with sick or dead poultry, or contact with a confirmed case of avian influenza (table 6 ). since many infectious diseases present with similar symptoms, the only feature significant to the clinician may be contact in an endemic area, through travel or infected poultry, and the clinician should always elicit a detailed patient history. the definitive diagnosis is made from isolation of the virus in culture from clinical specimens. this method not only provides the definitive diagnosis, but the viral isolate is now available for further testing, including pathogenicity, antiviral resistance, and dna sequencing and analysis. alternatively, antibody testing can be performed, with a standard four-fold titer increase to the specific subtype of avian influenza virus. neutralizing antibody titer assays for h5, h7 and h9 are performed by the micorneutralization technique [72] . western blot analysis with recombinant h5 is the confirmatory test for any positive microneutralization assay [59, 60, 72] . more recently, rapid diagnosis can be performed with reverse transcription-pcr on clinical samples with primers specific for the viral subtype [73] [74] [75] . this test should be performed only on patients meeting the case definition of possible avian influenza a infection. any suspected case of avian influenza in a human should be investigated by the public health officials in the province or country of origin [39, 76] . additionally, governmental labs are often equipped with the appropriate biolevel safety 3 laboratories, primer libraries, and associated expertise to confirm the diagnosis quickly and efficiently. any clinical specimens should be submitted with the assistance of the public health experts. treatment of avian influenza infections in humans includes antiviral therapy and supportive care. controlled clinical trials on the efficacy of antivirals (na inhibitors), supportive therapy, or adjuvant care have never been performed, so current recommendations stem from the experiences of past avian influenza outbreaks and animal models. the adamantanes (rimantadine and amantadine) and na inhibitors (oseltamivir and zanamivir) are the antivirals used for treatment and prophylaxis of influenza infections in humans. in avian influenza virus infections, adamantanes have no role due to widespread resistance through a m2 protein alteration. in addition, over 90% of isolates of h1 and h3 human subtypes during seasonal influenza have had resistance to the adamantanes [77] . their role has now been limited to prophylaxis in the community when the circulation strain is know to be susceptible to the adamantanes [78] [79] [80] . na inhibitors (oseltamivir and zanamivir) have been studied for both treatment and prophylaxis with the human influenza a subtypes h1, h2, and h3 as well as influenza b (table 7 ) [80] [81] [82] . in animal models with hpai h5n1, their efficacy has been well documented, with improved survival rates seen after infection [83] [84] [85] . oseltamivir has been used in avian influenza outbreaks involving h7n7 and hpai h5n1, and therapy with oseltamivir has been shown to decrease the viral load in nasal secretions in patients infected with hpai h5n1 [11, 86, 87] . resistance to oseltamivir has been documented in a hpai h5n1 subtype in a vietnamese girl treated with 75 mg daily for 4 days as post-exposure prophylaxis [68] . the na glycoprotein had a histidine to tyrosine substitution at position 274, conveying a markedly higher ic50 for oseltamivir [68, 88] . in one study, the viral count of hpai h5n1 in nasal secretions did not decrease with the administration of oseltamivir when the h5n1 isolate carried this resistance mutation [68] . however, resistance produced by this change may be overcome with higher doses of oseltamivir in vitro, and this change has not been documented to confer resistance to zanamivir [88] . the timing of treatment with na inhibitors is paramount, as early therapy is directly related to improved survival [66, [83] [84] [85] . the greatest level of protection was seen if the na inhibitors were started within 48 hours of infection, and protection rapidly dropped after 60 hours [78, 79] . these initial studies, however, were performed with seasonal human influenza a and b, where the period of viral shedding is approximately 48 to 72 hours. in hpai h5n1 cases from southeast asia, survival appeared to be improved in patients who received oseltamavir earlier (4.5 days versus 9 days after onset of symptoms) [66] . both of these time periods are much longer than documented in animal models, so the window of optimal therapy is still unknown, particularly if viral shedding exceeds the average 48 to 72 hour period seen in seasonal influenza a and b infections. combination therapy with influenza a viruses has not been studied [84] . ribaviron by inhalation has been evaluated in vitro with some avian influenza a subtypes and has been found to reduce mortality from influenza b in a mouse model [89] . further animal model studies are indicated to determine if there is a role for ribaviron or combination therapy with avian influenza a viruses. supportive care with intravenous rehydration, mechanical ventilation, vasopressor therapy, and renal replacement therapy are required if multiorgan failure and ards are a feature of disease [69, 90] . due to the progression of pneumonia to ards, non-invasive ventilation is not recommended, and early intubation may be beneficial before overt respiratory failure ensues. corticosteroids have been used in some patients with hpai h5n1, but no definitive role for steroids has been determined. other immunomodulatory therapy has not been reported [91] . human vaccination for avian influenza viruses has not been widely used, although multiple vaccination trials are underway. prior avian vaccines in humans have been poorly immunogenic and thus have limited use. an inactivated h5n3 has been tested and was tolerated but with limited immunogenicity [91, 92] . other h5 vaccines have resulted in the development of neutralizing antibodies, but to a limited degree [93, 94] . recently, a large randomized trial looked at an h5n1 attenuated vaccine from the vietnam strain [95] . only a modest immune response was seen, with microneutralization antibodies being developed at 12 times the dose used in the seasonal influenza vaccine. the side effects were minimal. a number of other industry trials with adjuvant vaccines are currently ongoing. although promising, human vaccination against avian influenza viruses is still under development. underscoring this development is the uncertainty of a pandemic strain, which may have vastly different antigenic properties from any developed h5 vaccine. health care infection control is a crucial component in the management of avian influenza infection or a new pandemic strain. experience from the severe ards outbreak in 2002 has illustrated that appropriate infection control measures are paramount to reduce spread to health care workers and, possibly, the community [96] [97] [98] . therefore, the world health organization (who) and centers for disease control and prevention (cdc) recommend contact and airborne precautions for any initial suspected case of avian influenza in a human [99] . in late october 2006, the cdc released updated interim guidance on the use of masks and respirators in the health care setting (table 8 ) [99] . in certain high risk procedures, additional protection may be considered given the likelihood of generating aerosol particles that may enhance transmission (table 9 ) [99] . respiratory protection should be worn along with an impermeable gown, face shield, and gloves. initial cases should be placed in a negative pressure isolation room with 6 to 12 air changes per hour. hand hygiene with antibacterial soap or alcohol based washless gel should be standard, with appropriate basins at each patient room. seasonal vaccination of all health care workers should be preformed and further emphasized in order to reduce the likelihood of co-infection with two stains of influenza. visitors and family members should be strictly monitored and their access to the patient limited to reduce the likelihood of spread. finally, antiviral chemoprophylaxis should be available to any health care workers exposed to an infected individual. any symptomatic worker should be taken off duty and workplace surveillance should occur. with these aggressive measures, risk to health care workers, patients, and family members will be reduced. avian influenza viruses have occurred with increased incidence within the human population, reflecting the delicate and tangled interaction between wildlife, domesticated animals, and humans. disease in humans can be limited to conjunctivitis or an influenza-like illness, but hpai h5n1 causes mainly severe pneumonia, respiratory failure, and death. most cases have occurred through direct transmission from infected poultry or waterfowl, with only a few limited cases of human to human transmission. treatment has been successful with the na inhibitors if started early, and vaccine development is underway with a more immunogenic attenuated h5n1 virus preparation. infection control measures are the mainstay for prevention and disease reduction. avian influenza viruses may constitute part of the next pandemic, so appropriate knowledge, prevention, and treatment will reduce the likelihood of this occurrence. table 9 high risk aerosol procedures in avian influenza non-invasive mechanical ventilation bronchoscopy humidified oxygen delivery non-rebreather mask without expiratory filter this article is part of a thematic series on disaster management edited by j christopher farmer. other articles in this series can be found online at http://ccforum.com/articles/ theme-series.asp?series=cc_disaster world health organization expert committee: a revision of the system of nomenclature for influenza viruses: a who memorandum characterization of a novel influenza a virus hemagglutinin subtype (h16) obtained from black-headed gulls highly pathogenic avian influenza: manual of diagnostic tests and vaccines for terrestrial animals molecular mechanism of acquisition of virulence in influenza virus in nature epidemiologic implications of changes in the influenza virus genome differences between influenza virus receptors on target cells of duck and chicken and receptor specificity of the 1997 h5n1 chicken and human influenza viruses from hong kong molecular basis for the generation in pigs of influenza a viruses with pandemic potential influenza virus strains selectively recognize sialyloligosaccharides on human respiratory epithelium: the role of the host cell in selection of hemagglutinin receptor specificity human and avian influenza (ai) viruses target different cell types in cultures of human airway epithelium the surface glycoproteins of h5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties avian flu: influenza virus receptors in the human airway h5n1 virus attachment to lower respiratory tract evidence for the natural transmission of influenza a virus from wild ducks to swine and its potential importance for man genetic relatedness of hemagglutinins of the h1 subtype of influenza a viruses isolated from swine and birds replication of avian influenza a viruses in mammals influenza a virus (h5n1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts avian influenza h5n1 in tigers and leopards avian influenza a virus causing an outbreak of contagious interstitial pneumonia in mink an avian influenza a virus killing a mammalian species -the mink characterization of two influenza a viruses from a pilot whale seroepidemiological and molecular evidence for the presence of two h3n8 equine influenza viruses in china in 1993-94 characterization of a new avian-like influenza a virus from horses in china the appearance of h3 influenza viruses in seals are seals frequently infected with avian influenza viruses? characterization of an influenza a virus from seals transmission of equine influenza virus to dogs avian influenza h5n1 in viverrids: implications for wildlife health and conservation characterization of an avian influenza a virus isolated from a human -is an intermediate host necessary for the emergence of pandemic influenza viruses human influenza a h5n1 virus related to a highly pathogenic avian influenza virus avian influenza a virus (h7n7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome characterization of an avian influenza a (h5n1) virus isolated from a child with a fatal respiratory illness evolution and ecology of influenza a viruses antigenic and genetic characterization of a novel hemagglutinin subtype of influenza a viruses from gulls molecular characterization of a new hemagglutinin, subtype h14, of influenza a virus characterization of a novel influenza hemagglutinin, h15: criteria for determination of influenza a subtypes investigation of outbreaks of highly pathogenic h5n1 avian influenza in waterfowl and wild birds in hong kong in late highly pathogenic h5n1 influenza virus infection in migratory birds reemerging h5n1 viruses in hong kong in 2002 are highly pathogenic to ducks genesis of a highly pathogenic and potentially pandemic h5n1 virus in eastern asia new genotype of avian influenza h5n1 viruses isolated from tree sparrows in china characterization of h5n1 influenza a viruses isolated during the 2003-2004 influenza outbreaks in japan. virol highly pathogenic h5n1 influenza virus in smuggled thai eagles establishment of multiple sublineages of h5n1 influenza virus in asia: implications for pandemic control role of domestic ducks in the propagation and biological evolution of highly pathogenic h5n1 influenza viruses in asia intestinal influenza: replication and characterization of influenza viruses in ducks perpetuation of influenza a viruses in alaskan waterfowl reservoirs factors in the emergence of infectious diseases mallards and highly pathogenic avian influenza ancestral viruses host range and emerging and reemerging pathogens conjunctivitis in human beings caused by influenza a virus of seals avian influenza virus isolated from a woman with conjunctivitis human infection with influenza h9n2 transmission of h7n7 avian influenza a virus to human beings during a large outbreak in commercial poultry farms in the netherlands clinical features and rapid viral diagnosis of human disease associated with avian influenza a h5n1 virus outbreak of avian influenza a (h5n1) virus infection in hong kong in 1997 re-emergence of fatal human influenza a subtype h5n1 disease world health organization: cumulative number of confirmed human cases of avian influenza a/(h5n1) reported to who human illness from avian influenza h7n3, british columbia antibody response in individuals infected with avian influenza a (h5n1) viruses and detection of anti-h5 antibody among household and social contacts risk of influenza a (h5n1) infection among health care workers exposed to patients with influenza a (h5n1), hong kong probable person-to-person transmission of avian influenza a (h5n1) world health organization international avian influenza investigation team, vietnam: lack of h5n1 avian influenza transmission to hospital employees avian influenza h5n1 and healthcare workers avian influenza, human (09): indonesia avian influenza a (h5n1) in 10 patients in vietnam human disease from influenza a (h5n1) the writing committee of the world health organization (who): consultation on human influenza a/h5. avian influenza a (h5n1) infection in humans fatal avian influenza a (h5n1) in a child presenting with diarrhea followed by coma avian influenza (h5n1): implications for intensive care induction of proinflammatory cytokines in human macrophages by influenza a (h5n1) viruses: a mechanism for the unusual severity of human disease? pathology of fatal human infection associated with avian influenza a h5n1 virus risk of influenza a (h5n1) infection among poultry workers development of a realtime reverse transcriptase pcr assay for type a influenza virus and the avian h5 and h7 hemagglutinin subtypes application of real-time rt-pcr for the quantitation and competitive replication study of h5 and h7 subtype avian influenza virus single-step multiplex reverse transcription-polymerase chain reaction (rt-pcr) for influenza a virus subtype h5n1 detection the world health organization global influenza program surveillance network: evolution of h5n1 avian influenza viruses in asia emergence of drug-resistant influenza virus: population dynamical considerations antiviral agents. clinical virology antiviral agents active against influenza a viruses neuroaminidase inhibitors for preventing and treating influenza in healthy adults pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers the pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (ro 64-0796/gs4104) in healthy adult and elderly volunteers the neuraminidase inhibitor gs4104 (oseltamivir phosphate) is efficacious against a/hong kong/156/97 (h5n1) and a/hong kong/1074/99 (h9n2) influenza viruses neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in mdck cells efficacy of zanamivir against avian influenza a viruses that possess genes encoding h5n1 internal proteins and are pathogenic in mammals resistant influenza a viruses in children treated with oseltamivir: descriptive study oseltamivir resistance during treatment of influenza a (h5n1) infection avian flu: isolation of drug-resistant h5n1 virus in vitro and in vivo influenza virus inhibitory effects of viramidine medical treatment of viral pneumonia including sars in immunocompetent adult safety and antigenicity of non-adjuvanted and f59-adjuvanted influenza a/duck/singapore/97 (h5n3) vaccine: a randomized trial of two potential vaccines against h5n1 influenza cross-reactivity to highly pathogenic avian influenza h5n1 viruses after vaccination with nonadjuvanted and mf59-adjuvanted influenza a/duck/singapore/97 (h5n3) vaccine: a potential priming strategy safety and immunogenicity of a recombinant hemagglutinin vaccine for h5 influenza in humans efficacy of h5 influenza vaccines produced by reverse genetics in a lethal mouse model saftey and immunogenicity of an inactivated subviron influenza a (h5n1) vaccine world health organization: summary of probable sars cases with onset of illness from 1 evidence of airborne transmission of the severe acute respiratory syndrome virus toronto sars critical care group: critically ill patients with severe acute respiratory distress syndrome interim guidance on the planning for the use of surgical masks and respirators in health care settings during an influenza pandemic the authors declare that they have no competing interests. key: cord-001473-aki28lhp authors: chen, qi xing; song, sheng wen; chen, qing hua; zeng, cong li; zheng, xia; wang, jun lu; fang, xiang ming title: silencing airway epithelial cell-derived hepcidin exacerbates sepsis-induced acute lung injury date: 2014-08-06 journal: crit care doi: 10.1186/s13054-014-0470-8 sha: doc_id: 1473 cord_uid: aki28lhp introduction: the production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. however, nothing is known about its function in lung infections and inflammatory diseases. we therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury. methods: acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (clp) surgery. adenovirus-mediated short hairpin rna specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. the adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. lung injury and the seven-day survival rate were assessed. the levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated. results: the hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. the knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in ad-shhepc1-treated mice versus 12.5% in ad-shneg-treated mice, p <0.05). the knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice. conclusions: airway epithelial cell-derived hepcidin plays an important role in clp-induced acute lung injury. the severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages. acute lung injury (ali) and its severe form, acute respiratory distress syndrome (ards), are common clinical disorders and present substantial health problems worldwide [1] [2] [3] . the incidence of ali has been reported to be 190,000 cases per year in the united states, and sepsis is one of the most commonly encountered conditions underlying the development of ali [1, 4] . through advances in supportive care, the mortality rate for patients with ali/ards has decreased over time but still remains high [5, 6] . therefore, elucidating the pathogenesis of ali/ards is necessary and may help with the development of novel therapeutic targets for ali/ards. the lung is exposed to a large number of potentially pathogenic microorganisms that are inhaled. to protect this vital organ against infection and inflammation, many defense mechanisms have been evolved in the lung to prevent the development of pulmonary infections. the secretion of endogenous cationic antimicrobial peptides by epithelial cells onto the airway surface represents an important component of immune defense in the lung [7] [8] [9] . recent studies have demonstrated the importance of these antimicrobial peptides, such as defensins and cathelicidin, in the pulmonary immune system and in pulmonary diseases [10] [11] [12] . hepcidin is a β-defensin-like antimicrobial peptide that is mainly produced by the liver. hepcidin not only shows antimicrobial activity against gram-positive bacteria, gram-negative bacteria and yeasts, but also functions as a principal iron regulatory hormone [13] [14] [15] . hepcidin binds to the iron export protein ferroportin and induces its internalization and degradation, which leads to decreased cellular iron export and increased intracellular iron retention [16, 17] . because iron is an essential nutrient for all organisms, hepcidin also restricts the iron available to invading microbes, thereby enhancing the host defense against pathogens [17] [18] [19] . furthermore, hepcidin can modulate the lipopolysaccharide (lps)-induced acute inflammatory response via the suppression of cytokine expression [20, 21] . the multiple functions of hepcidin suggest its importance in the host immune response to infection and inflammation. recent studies have reported that in addition to being produced mainly by hepatocytes, hepcidin is also expressed by other cells, such as airway epithelial cells (aecs) [22] . however, the role of aecderived hepcidin in pulmonary immune defense against infection and inflammation remains unknown. in the present study, we generated a mouse model of aec-derived hepcidin knockdown and investigated the impact of interfering with aec-derived hepcidin on the pathophysiology of sepsis-induced ali. we also explored the possible mechanisms involved. adenovirus-mediated short hairpin rna (shrna) as the mouse hepcidin gene hepc1 performs similar biological actions as human hepcidin [23, 24] , we investigated hepc1 in the present study. small interfering rna specific to the mouse hepc1 (acagaugagacagacuacadt dt) was described previously [25] , and we used this template to design the corresponding shrna (accgac agatgagacagactacattcatgagatgtagtct gtctcatctgtcttttt) with minor modifications (invitrogen, shanghai, china). an adenovirus that expresses the hepc1 shrna or a nonspecific control oligonucleotide (gcctaaggttaagtcgccctcgcgaac gaaggcgagggcgacttaaccttaggtt) was prepared. briefly, the double-strand shrna oligo was cloned into pentr/u6 vector using the block-it u6 rnai entry vector kit (life technologies, grand island, ny, usa). the expression clone was then generated by recombination of pentr/u6 entry construct and pad/block-it-dest vector using block-it adenoviral rnai expression system (life technologies) according to the manufacturer's instructions. after digested by endonuclease paci (new england biolabs, ipswich, ma, usa), the recombinant adenoviral plasmid was transfected into 293a cells. the harvested adenovirus was concentrated and purified by cscl gradient centrifugation. viral titer was determined using adeno-x rapid titer kit (clontech, mountain view, ca, usa). the recombinant virus and control virus were named ad-shhepc1 and ad-shneg, respectively. to generate a mouse model of aec-derived hepcidin knockdown, ad-shhepc1 or ad-shneg (approximately 2.2 × 10 11 viral particles) was intratracheally injected into the mice after anesthesia with chloral hydrate (400 mg/kg, intraperitoneally (i.p.)). to improve the knockdown efficiency, a second administration of the adenovirus was performed 72 hours later. twelve days after the first injection, the mice were ready used in the experiments. ali was induced by polymicrobial sepsis with cecal ligation and puncture (clp) surgery as described previously [26] . briefly, after the abdominal wall was prepared with a 10% povidone-iodine solution, a 1-cm midline abdominal incision was made. the cecum was then exposed, isolated, and ligated with a 4-0 silk ligature just distal to the ileocecal valve to avoid intestinal obstruction. the puncture was performed twice with a 22-gauge needle. then, the cecum was repositioned, and the incision was closed with a 4-0 sterile suture. sham-operated mice were underwent the same procedure but without ligation and needle perforation of the cecum. at the end of the operation, the mice were resuscitated immediately by the subcutaneous administration of saline (1 ml/mouse) and allowed free access to food and water after awakening. in the experiment to evaluate the survival rate, the mice were monitored for survival every six to twelve hours until seven days post-clp. twenty-four hours after clp, the mice were sacrificed via cervical dislocation. the chest cavity was opened via a midline incision. to perform the bronchoalveolar lavage, the lung was lavaged with 0.5 ml of chilled phosphate-buffered saline three times. in all cases, more than 90% of the total lavage volume was recovered. a 0.5-ml aliquot of balf was used for the total cell counts and bacteriologic culture. the remaining balf was centrifuged at 1000 g for five minutes, and the cell-free supernatant was stored at -80°c for further analysis. the total cell count in the balf was determined using a hemocytometer. the balf was serially diluted in phosphate-buffered saline and inoculated on luria broth agar plates. after incubation at 37°c for 16 hours, visible colonies were counted and calculated as colony-forming units/ml of balf. the total protein in the cell-free supernatant of the balf was determined by using the bca protein assay kit (pierce, rockford, il, usa). the interleukin (il)-6 level in the balf was determined using an enzyme-linked immunosorbent assay kit according to the manufacturer's instructions (abcam, san francisco, ca, usa). in separate groups the lung was excised, weighed, and then placed in an oven at 60°c for 72 hours to achieve the dry weight. the ratio of lung wet weight to dry weight was then calculated. the lung tissues from the mice were fixed in buffered 4% paraformaldehyde solution (ph = 7.4) for 24 hours, embedded in paraffin, and sectioned at a thickness of 4 μm. the histological examination was conducted in a blinded fashion after staining with hematoxylin and eosin. for rna extraction, alveolar macrophages were isolated by adhering bronchoalveolar lavage cells to plastic for one hour at 37°c in 5% co 2 [27] . total rna of the lung and liver tissues as well as the alveolar macrophages was extracted using the trizol™ reagent. reverse transcription was performed using 1 μg of total rna with the reverse transcription system (promega, madison, wi, usa). the transcriptional level of hepcidin was quantified by real-time pcr using a standard sybr™ green pcr protocol on a cfx96 real-time pcr detection system (bio-rad laboratories inc., hercules, ca, usa). the housekeeping gene β-actin served as an internal control, and the relative expression level of hepcidin was calculated using the 2 −δδct method. immunohistochemical staining was performed following standard procedures. the formalin-fixed paraffin-embedded tissues were sliced into 4-μm-thick sections, deparaffinized, and rehydrated. for the hepcidin measurement in the alveolar macrophages, the cells were isolated by adhering bronchoalveolar lavage cells to coverslips at 37°c in 5% co 2. then, the cells were fixed with 95% ethanol for 15 minutes. antigen retrieval was performed in 10 mmol/ l citric acid buffer (ph 6.0) for 10 minutes using a 750-w microwave. endogenous peroxidase activity was blocked with 3% hydrogen peroxide in methanol for 15 minutes. after incubation with rabbit anti-mouse hepcidin antibody (1:400 dilution; abcam) overnight at 4°c, the sections were washed in phosphate-buffered saline and incubated with a polymer horseradish peroxidase-conjugated secondary antibody (zsgb-bio, beijing, china) for one hour. the sections were further incubated with dako liquid dab large-volume substrate-chromogen system (dako, glostrup, denmark) and counterstained with hematoxylin. negative controls were included in all assays by replacing the rabbit anti-mouse hepcidin antibody with nonimmune rabbit antiserum. the immunostaining was evaluated using an olympus bx-50 light microscope (olympus, tokyo, japan). the stain density was analyzed using the image pro-plus 6.0 analysis system (media cybernetics inc., silver spring, md, usa), and the level of hepcidin was measured as the integral optical density. the protein concentrations in the lung homogenate or lysate of alveolar macrophages were detected using a bca protein assay kit (pierce). the proteins (20 μg) were denatured by heating at 70°c for 10 minutes in 4 × nupage lds sample buffer (life technologies) and separated by nupage bis-tris gel electrophoresis (life technologies). then, the proteins were blotted onto polyvinylidene fluoride membrane (millipore, billerica, ma, usa). the membranes were blocked with 5% nonfat milk in tris-buffered saline with 0.05% tween-20 and incubated overnight with goat anti-ferroportin antibody (santa cruz biotechnology, dallas, tx, usa). the membranes were then washed with tris-buffered saline with 0.05% tween-20 three times for five to ten minutes each. after incubation with the related horseradish peroxidaseconjugated secondary antibody (jackson immunoresearch laboratories, inc., west grove, pa, usa), the membranes were visualized with the supersignal west pico chemiluminescent substrate (pierce). the signals were quantified using the image j software by wayne rasband (national institute of health, bethesda, maryland, md, usa). β-actin served as a protein control. the iron content in alveolar macrophages and spleen was determined by prussian blue staining using a commercially available kit according to the manufacturer's instructions (shanghai yuanye bio-technology co., shanghai, china). the stain density in the spleen was analyzed using the image pro-plus 6.0 analysis system as described above. for the iron measurement in the alveolar macrophages, the cells were isolated by adhering bronchoalveolar lavage cells to coverslips at 37°c in 5% co 2. then, the cells were fixed with 95% ethanol for 15 minutes. the cells were considered positive with the presence of bluecolored granules within intact alveolar macrophages under a microscope. at least 200 random macrophages were counted, and the results are presented in terms of the percentage of positive cells. the serum iron concentration was measured using atomic absorption spectroscopy [28] . to investigate the phagocytosis function of alveolar macrophage, alveolar macrophages were isolated as described above. the cells were then incubated with fluorescent escherichia coli (life technologies) for two hours. fluorescence from the extracellular bacteria was quenched with 0.4% trypan blue. after three washes with phosphatebuffered saline, the fluorescence was observed under a fluorescence microscope (olympus). the phagocytic index was quantified as number of fluorescent e.coli internalized by one macrophage cell counted in 10 random fields. the data are expressed as the mean ± standard deviation (sd) or median with range where applicable. the differences between the two groups were analyzed by the t test or mann-whitney u test. the survival curves were analyzed by the kaplan-meier log-rank test. the statistical analyses were performed using graphpad prism software 5.0 (graphpad software inc., la jolla, ca, usa) and spss 16.0 for windows (spss inc., chicago, il, usa). a twotailed p value of less than 0.05 was considered to be statistically significant. hepcidin expression is modulated in response to infectious and inflammatory stimuli [14, 17] . we first investigated whether the hepcidin expression level in the lung tissue changed during polymicrobial sepsis. twenty-four hours after clp surgery, the hepcidin level was significantly increased in the lung tissue, especially in the aecs (figure 1 ). this finding indicates that hepcidin derived from aecs may play an important role in sepsis-induced ali. to confirm the role of hepcidin in ali, ad-shhepc1 or ad-shneg was administered to the mice via intratracheal instillation. twelve days after administration of the adenovirus-mediated shrna, the mice were subjected to an ali model, and the hepcidin level in lung and liver were assessed at 24 hours after induction of ali. as shown in figure 2a and 2b, both the mrna and protein levels of hepcidin in aecs was significantly reduced, whereas the hepcidin expression in alveolar macrophages ( figure 2c and 2d) and hepatocytes ( figure 2e and 2f) was not affected. these results demonstrated that in the current study the intratracheal administration of ad-shhepc1 only silenced the hepcidin gene transcription in aecs, which was in accordance with previous studies that adenovirus-mediated intratracheal gene delivery specifically inhibited targeted gene expression in lung epithelial cells but not in alveolar macrophages and other organs [29, 30] . the lung injury was evaluated both in wild-type mice and adenovirus-treated mice at 24 hours after challenge with clp or a sham operation. histological characteristics of lung injury, including diffuse alveolar damage, infiltration of numerous leukocytes and interstitial edema, were observed both in the wild-type mice and ad-shnegtreated mice after clp challenge. knockdown of hepcidin in aecs led to more severe lung damage in the ad-shhepc1-treated mice after clp challenge ( figure 3a ). lung wet/dry weight ratios from the experimental mice further confirmed the histological findings ( figure 3b ). the balf analysis showed that the hepcidin knockdown mice had significantly higher cell counts and protein concentrations ( figure 3c and 3d ). of note, pulmonary bacterial colonization was much more severe in the ad-shhepc1-treated mice ( figure 3e ). however, the balf il-6 level in the hepcidin knockdown mice was not significantly different from that in the control mice ( figure 3f) . moreover, the influence of disruption of the hepcidin gene in aecs on the outcome of ali was further studied. clp challenge caused a seven-day mortality of 18.75% in the wild-type mice, comparable to a mortality of 12.5% in the ad-shneg-treated mice. however, knockdown of hepcidin in aecs significantly increased the seven-day mortality after clp surgery (53.33% versus ad-shneg-treated mice, p <0.05; figure 3g ). hepcidin regulates iron metabolism by binding to ferroportin and causing its internalization and degradation. we therefore investigated the ferroportin levels in both whole lung tissue and alveolar macrophages. as expected, the ferroportin in the control mice was almost totally degraded, whereas a higher ferroportin level was observed in the hepcidin knockdown mice ( figure 4a and 4b) . we further asked whether hepcidin gene modification in aecs had an impact on local and systemic iron metabolism. of note, the knockdown of hepcidin in aecs resulted in less iron retention in the alveolar macrophages ( figure 5a ), whereas the iron contents in the spleen macrophages and serum iron concentration between the two groups showed no significant differences ( figure 5b and 5c) . moreover, to link the intracellular iron content to the function of alveolar macrophages, we assessed the phagocytosis of alveolar macrophages, and found that the alveolar macrophages from ad-shhepc1-treated mice showed less phagocytic ability than those from the control animals ( figure 5d ). in the current study, we found that the pulmonary hepcidin level was upregulated during polymicrobial sepsis. the knockdown of hepcidin in aecs aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality. these pathophysiologic changes are at least partially related to the altered intracellular iron level and function of alveolar macrophages in the hepcidin knockdown mice. hepcidin is produced predominantly by hepatocytes. its hepatic expression can be upregulated by iron overload and inflammation and suppressed by hypoxia and anemia [14, 17] . a recent study reported that hepcidin is expressed in aecs in response to interferon-γ [22] . in the current study, an increased hepcidin level in aecs was observed during polymicrobial sepsis. because the lung is the first vital organ that is adversely affected at the onset of sepsis [31] , the elevated expression of hepcidin may protect the mice against lung injury. to support this hypothesis, knockdown of hepcidin in aecs exacerbated sepsisinduced lung injury (figure 3 ). considering that disruption of hepcidin has a deleterious effect, a low severity of clp model was used in the current study. since the underlying pathophysiology of sepsis is based on the severity grade of the clp model, the increase in lung injury parameter such as wet/dry weight ratio was minuscule but significantly different. hepcidin is a master regulator of iron metabolism via its interaction with ferroportin. hepcidin can trigger ferroportin polyubiquitination and induce ferroportin endocytosis [32, 33] . in the lung, aecs express high levels of hepcidin and are the main source of local hepcidin production. alveolar macrophages express ferroportin and are therefore target cells for hepcidin [22] . in the present study, knockdown of hepcidin in aecs impacted its interaction with ferroportin, and prevented degradation of the ferroportin protein in both alveolar macrophages and the figure 1 the expression of hepcidin in airway epithelial cells (aec) was upregulated after cecal ligation and puncture (clp) surgery. hepcidin expression was examined by immunohistochemistry. a representative image is presented (magnification: ×400) and quantified data are shown. n = 6 mice/group. *p <0.005. lung, which consequently caused intracellular iron export into the pulmonary microenvironment. the elevated iron in the lung can be used not only for invading pathogen growth and replication, resulting in more virulent and persistent infections [18] , but also to generate reactive oxygen species, leading to cell damage and lung injury [34, 35] . on the other hand, a recent study showed that iron status could impact cytoskeleton rearrangement, which is important for the phagocytic process in macrophages [36] . indeed, the alveolar macrophages from ad-shhepc1-treated mice showed less phagocytosis ability than those from the control animals. since liver is the major source of systemic hepcidin, in the current study liver hepcidin levels were not affected and circulating iron concentrations were comparable between the ad-shneg-and ad-shhepc1-treated mice. therefore, the function of circulating leukocytes should not be influenced. although the inciting injury (clp) is remote, when the bacteria circulating in the blood stream invaded the lung after clp, the decreased phagocytosis function of the alveolar macrophages from the ad-shhepc1-treated mice could result in bacterial accumulation in the lung. in addition, as hepcidin exhibits broad spectrum antimicrobial properties [37] , the knockdown of hepcidin may contribute to more severe pulmonary infections and lung injuries. using primary human aecs and alveolar macrophages, frazier et al. reported that the treatment with exogenous hepcidin did not affect ferroportin expression in the aecs and did not alter iron accumulation in both aecs and alveolar macrophages [22] . the contradictory findings between the current study and frazier's study may result from the difference between the in vivo model and ex vivo model used and the nature of hepcidin peptide. moreover, limited by the sensitivity of the prussian blue staining method, the iron content in the aecs was undetectable in this study. because the role of aecs in pulmonary iron metabolism is much less than that of alveolar macrophages [22] , the iron status in aecs may not play a major role in the pathophysiology of lung injury. the production of cytokines and other inflammatory mediators at the site of injury is a feature of the pathogenesis of ali, with il-6 being one of the hallmarks [38] . however, the balf il-6 level in the aec-specific hepcidin knockdown mice was not significantly different from that in the control mice. previous studies found that low intracellular iron in macrophages could impair the translation of specific inflammatory cytokine transcripts, such as il-6 [39, 40] . because alveolar macrophages are a major source of il-6 production during lung injury, the decreased iron content in alveolar macrophages may compromise the local inflammatory response in the aec-specific hepcidin knockdown mice. the acute respiratory 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positive and negative regulators hepcidin in human iron disorders: therapeutic implications hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice hepcidin and the iron-infection axis iron in innate immunity: starve the invaders two to tango: regulation of mammalian iron metabolism hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice hepcidin protects against lipopolysaccharide-induced liver injury in a mouse model of obstructive jaundice hepcidin expression in human airway epithelial cells is regulated by interferon-γ functional differences between hepcidin 1 and 2 in transgenic mice targeted disruption of the hepcidin 1 gene results in severe hemochromatosis antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia triggering receptor expressed on myeloid cells-2 protects against polymicrobial sepsis by enhancing bacterial clearance hussell t: a critical function for cd200 in lung immune homeostasis and the severity of influenza infection hepatic iron concentration does not predict response to standard and pegylated-ifn/ribavirin therapy in patients with chronic hepatitis c attenuation of igg immune complex-induced acute lung injury by silencing c5ar in lung epithelial cells in vivo gene silencing (with sirna) of pulmonary expression of mip-2 versus kc results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of nf-kappab hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination the iron cycle and oxidative stress in the lung efficacy and toxicity of intravenous iron in a mouse model of critical care anemia murine macrophages response to iron leap-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury selective modulation of tlr4-activated inflammatory responses by altered iron homeostasis in mice attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution this work was supported by the national science fund for distinguished young scholars (no. 30825037), a key program (no. 81130036) and program (no. 81101445) from the national natural science foundation of china, zhejiang provincial program for the cultivation of high-level innovative health talents, and zhejiang provincial natural science foundation of china (y2080253). the funding agencies did not have any role in design, collection, analysis, and interpretation of data, as well as in the writing of the manuscript and in the decision to submit it for publication. the current study explored the role of aec-derived hepcidin in polymicrobial sepsis-induced ali, which is at least partially related to the altered intracellular iron level and function of alveolar macrophages. these observations provide new insight into the pathogenesis of ali/ards and might have therapeutic implications for ali/ards. knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality. knockdown of hepcidin in airway epithelial cells led to reduced ferroportin degradation in lung and a low intracellular iron content in alveolar macrophages.these findings provide new insight into the pathogenesis of ali/ards and might have therapeutic implications for ali/ards. the authors declare that they have no competing interests.authors' contributions qxc contributed to the study design, data analysis and drafting of the manuscript. sws carried out the animal studies, analyzed the data and drafted the manuscript. qhc participated in the animal studies and performed the quantitative pcr experiment. clz carried out the immunoblot and phagocytosis assays. xz participated in the iron determination and balf analysis. jlw contributed to the study design and coordination, and helped to draft the manuscript. xmf conceived of the study and critically revised the manuscript for important intellectual content. all authors read and approved the final manuscript. key: cord-005503-hm8tvkt3 authors: rasulo, frank a.; togni, tommaso; romagnoli, stefano title: essential noninvasive multimodality neuromonitoring for the critically ill patient date: 2020-03-24 journal: crit care doi: 10.1186/s13054-020-2781-2 sha: doc_id: 5503 cord_uid: hm8tvkt3 this article is one of ten reviews selected from the annual update in intensive care and emergency medicine 2020. other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. further information about the annual update in intensive care and emergency medicine is available from http://www.springer.com/series/8901. technology has made huge progress within the field of medicine, where newer and more sophisticated devices have been created to assist clinicians in daily practice. many of these instruments have become either less invasive or noninvasive. such is the case for neuromonitoring, where it is now possible to apply multimodality noninvasive monitoring to derive a great deal of information necessary for both therapeutic and prognostic purposes. multimodal evaluation becomes paramount when dealing with brain injury, whether it be traumatic or nontraumatic. such is the case for monitoring of brain stem reflexes, cerebral hemodynamics, and brain function. brain stem reflexes can be evaluated through a clinical neurological exam. however, this is not always possible, due to drugs or impossibility of evoking the reflexes for inaccessible areas of the scalp or head. yet, there are reflexes that require a more precise evaluation in order to be useful. such is the case for the automated pupillary response to light, which can be done with extraordinary accuracy using pupillometry devices. cerebral hemodynamics, most commonly represented by cerebral blood flow (cbf), intracranial pressure (icp), and cerebral perfusion pressure (cpp), can now be evaluated with a good level of reliability using brain ultrasound. cerebral function can be evaluated using electrophysiological monitoring, which has become easily applicable also by neurointensivists, in part due to the development of more user-friendly devices. these three components represent the concept of essential noninvasive multimodality neuromonitoring, which we describe in this chapter. one of the most important parameters to evaluate when performing a clinical neurological examination of the brain stem reflexes is the pupillary light reflex. the pupil constricts when the light signal is carried to the tectal plate in the midbrain, then to the edinger-westphal nucleus, and then to the eye where it causes the motor fibers to contract, visualized clinically by pupil constriction. the pupillary light reflex, along with size and size differences between pupils (anisocoria), provides information regarding the functional status of both the optic and the oculomotor nerves. until recently, evaluation of the pupils was performed through simple observation of the pupil's reaction to light evoked by flashlights. similarly, the pupil's diameter and anisocoria were assessed by an approximate estimation. however, manual examination of the pupillary light reflex is subject to large inter-examiner discrepancies, as high as 40%, particularly when miosis is present. the discrepancy may be further increased in the presence of other confounding factors such as alcohol, drugs, or hypothermia [1] . couret et al. observed an error rate of 20% and a 50% failure rate in the detection of anisocoria even for pupils of an intermediate size (2-4 mm) [2] . larson et al. demonstrated that there was a complete failure in detecting the pupillary light reflex when manual examination was performed when the reflex amplitude was <0.3 mm [3] . the examiner would score the initial diameter of the pupil, followed by light stimulation. reactivity was described as present or absent, or briskly reactive versus sluggishly reactive. recently, automated infrared pupillometry has been introduced into clinical practice, quickly gaining popularity due to its quantitative precision, low cost, noninvasiveness, bedside applicability, and easy-to-use technology, contributing to a modern precision-oriented approach to medicine. with the event of this new technology, it is now possible to add important prognostic and diagnostic information to clinical practice when dealing with the patient with brain injury of various origins. a few devices are available on the market and are composed of an infrared light-emitting diode, a digital camera that captures the outer border of the iris and senses the reflected infrared light, a data processor, and a screen display showing measured variables in response to the light stimulation, in both a numerical and a graphical format (fig. 1 ). the measured variables are size, asymmetry, constriction change to light stimulation, latency, and constriction and dilation velocity. the average reported values are shown in table 1 . clinicians have been checking the pupils of patients with suspected or known brain injury or impaired consciousness for over 100 years. the use of the automated pupillary light reflex has been applied in various forms of brain injury for both prognostic and diagnostic reasons. its use as a prognostic tool has been mostly studied in the comatose post-cardiac arrest patient. rossetti et al. showed that bilateral absence of the standard manual pupillary light reflex at day 3 following cardiac arrest was a strong predictor of poor outcome [4] . however, these patients may be under opioid sedation and the pupillary light reflex may be subject to confounding effects, therefore reducing the prognostic accuracy. behrends et al. [5] were the first to show that quantitative pupillometry had strong prognostic predictive value during cardiopulmonary resuscitation (cpr) in in-hospital cardiac arrest patients and strong correlations between return to spontaneous circulation and quantitative pupillary were also demonstrated by yokobori et al. [6] . pupillometry has been shown to be equally accurate in predicting poor 1-year outcome compared to absent reactivity on the eeg and bilaterally absent n20 waves on sseps [5, 6] . one multicenter study recently compared quantitative automated pupillary light reflex and neurological pupillary index (npi; using the neuroptics npi-200, neuroptics, laguna hills, ca) to manual pupillary light reflex in comatose cardiac arrest patients and found that an npi ≤2, performed between days 1 and 3 following cardiac arrest, was 100% specific for an unfavorable 3-month neurological outcome when compared to manual pupillary light reflex [7] . pupillary light reactivity is a well-described prognostic variable in the setting of severe head injury. the literature is full of evidence demonstrating that alterations of the pupillary pupil dilation to pain pupillary dilation reflex (%) * * 33 pupillary pain index * * depends on intensity of stimulation [16] [17] [18] [19] plr pupillary light reflex light reflex, pupil size, and/or anisocoria are correlated with outcome following traumatic brain injury (tbi) [8] . in fact, neurosurgeons triage patients to surgical evacuation of mass lesions or conservative therapy according to the pupillary status [9] . it has also been shown that patients who undergo prompt treatment after a new pupil abnormality, whether it be medical or surgical, have a better outcome [3] . in patients with acute traumatic epidural hematoma and glasgow coma scale (gcs) score <8, anisocoria was present in 67% of patients and reducing the surgery interval to <90 min was associated with a better outcome [10] . tbi patients with a gcs = 3 and fixed, dilated pupils had no chance of survival, whereas patients with a gcs = 3 with pupils that were not fixed or dilated had an excellent survival rate [11] . intracranial hypertension is associated with decreased npi, and patients with elevated icp had an improvement in npi values after treatment with osmotic therapy. therefore, pupillometry has the potential as a noninvasive tool to assess the efficacy of osmotic therapy [12] . stevens et al. performed a prospective observational study on 40 patients with tbi requiring invasive icp monitoring and showed a weak relationship between icp events and a preceding npi event. the strength of this trend appeared to diminish post-decompressive surgery [13] . jahns et al. assessed 54 patients with severe tbi with abnormal lesions on head computed tomography (ct) imaging who underwent parenchymal icp monitoring and repeated npi assessment through four consecutive measurements over intervals of 6 h prior to sustained elevated icp >20 mmhg and found that episodes of elevated icp correlated with a concomitant decrease in npi. sustained abnormal npi was in turn associated with a more complicated icp course and worse outcome [14] . vassilieva et al. assessed the feasibility of automated pupillometry for the detection of command following in patients with altered consciousness. they enrolled 20 healthy volunteers and 48 patients with a wide range of neurological disorders who were asked to engage in mental arithmetic [15] . fourteen of 20 (70%) healthy volunteers and 17 of 43 (39.5%) neurological patients fulfilled pre-specified criteria for command following by showing pupillary dilations during 4 or 5 arithmetic tasks. none of the five sedated and unconscious icu patients passed this threshold. therefore, automated infrared pupillometry combined with mental arithmetic appears to be a promising paradigm for the detection of covert consciousness in unresponsive patients with brain injury and may have potential in the future of providing a tool that can reveal covert consciousness in patients in whom standard investigations have failed to detect signs of consciousness (fig. 2 ). objective nociceptive assessment and optimal pain management have gained increasing attention and adequate nociceptive monitoring remains challenging in noncommunicative, critically ill adults. in the intensive care unit (icu), routine nociceptive evaluation in mechanically ventilated patients is usually carried out through scales such as the behavior pain scale (bps). however, this assessment is limited by medication use (e.g., neuromuscular blocking agents) and the inherent subjective character of nociceptive evaluation by third parties. since pupillary reflexes are submitted to controlled regulation by the autonomic nervous system, pupillometry allows the assessment of pain in patients subjected to painful stimulation. in fact, pupillary constriction is mediated by the parasympathetic system, whereas dilation is mediated by the noradrenergic sympathetic fibers that are under the influence of stimuli, including stress and pain. a painful stimulus would typically evoke a pupillary dilation reflex. the potential for application of pupillometry for pain evaluation becomes even greater when dealing with the unconscious patient, during general anesthesia for example, where pain assessment scores have no value. several studies have suggested the use of pupillometry in noncommunicative icu adults. paulus et al. demonstrated that pupillary dilation reflex evaluation may predict analgesia requirements during endotracheal aspiration [16] . moreover, this method may be able to reveal different levels of analgesia and could have discriminatory properties regarding different types of noxious procedures [17] . recently, scientific interest has been directed toward the use of specific protocols for pupillary dilation reflex assessment because of their low stimulation currents. the pupillary pain index protocol suggested in our approach has been previously investigated in anesthetized adults, revealing a significant correlation between pupillary dilation reflex and opioid administration [18] . furthermore, sabourdin et al. demonstrated that pupillary dilation reflex can be used to guide individual intraoperative remifentanil administration and therefore reduce intraoperative opioid consumption and postoperative rescue analgesia requirements [19] . bedside ultrasonography is becoming increasingly widespread in modern medicine, especially in the intensive care setting where this kind of resource is easily accessible and always available to physicians. brain ultrasonography is a safe, noninvasive way to assess brain anatomy, pathology, and intracranial blood flow. transcranial doppler was first introduced in 1982 by aaslid et al. to record flow velocity in basal cerebral arteries [20] . advances in technology introduced transcranial colorcoded duplex ultrasonography which allows us to assess anatomical features of the brain, rather than just identify brain vessels blindly. brain ultrasonography can be applied in different settings, even outside of neurosurgical icus: stroke units, enabling physicians to assess the effectiveness of a fibrinolytic therapy, and operating rooms for monitoring cbf during carotid vascular surgery are just some examples of its potential. despite being less reliable compared to ct scans and magnetic resonance imaging (mri), transcranial colorcoded duplex ultrasonography is a useful tool to monitor intracranial lesions, such as hematomas, which might cause a midline shift. it might even enable the clinician to assess the ventricles and parenchyma in selected patients with a good acoustic window [21] . there are four main acoustic windows accessible for brain ultrasonography, usually performed with a 2-2.5 mhz probe (fig. 3 ): 1. transtemporal approach: between the tragus and the lateral orbit wall, with the probe marker facing toward the eye. the first landmark is the contralateral skull, which is normally around 15 cm deep. the midbrain (fig. 4 left panel) appears as a hypoechoic shaped heart in the middle of the scan. once found, the power doppler can be selected to explore the circle of willis. this approach is generally used to identify midline shifts (when scanning the third ventricle, which appears as a hypoechoic band between two hyperechoic lines, as shown in fig. 5 ) and assess blood flow (fig. 6 ). 2. transorbital approach: through transorbital ultrasonography it is possible to assess the optic nerve sheath diameter (fig. 7) , as well as blood flow in the ophthalmic artery. occipital approach: the landmark for this approach is 1 cm below the external occipital protuberance, aiming forward and superiorly (toward the eyes), starting with a large scale (11-13 cm); the anatomic landmarks which can be seen with ultrasound are the clivus (hyperechoic structure) and the foramen magnum (hypoechoic). using the power doppler function, it is possible to scan for both vertebral arteries ending the basilar artery (fig. 8 ). submandibular approach: the submandibular window allows assessment of the extracranial and intracranial or extradural segment of the internal carotid artery. the probe should be placed at the angle of the mandible, directed slightly medially and posteriorly. the internal carotid artery can usually be identified at a depth of 40-60 mm. the optic nerve sheath diameter is a good surrogate measurement for icp [22] ; cutoffs >0.5 cm correlate well with an icp >20 mmhg. this noninvasive, quick, repeatable way to assess icp carries a sensitivity of 0.90 and therefore a good level of diagnostic accuracy to quickly detect increased icp [23] . using a linear probe placed transversally over the closed eyelid of the patient, the clinician can scan the optic nerve behind the eye, as a hypoechoic structure extending posteriorly from the retina. measurements of its diameter should be taken 3 mm from the globe perpendicularly (as shown in fig. 7) , using an electronic caliper. the rationale behind this technique is related to the anatomy of the optic nerve, which originates directly from the central nervous system (cns) and is surrounded by the meningeal sheaths and cerebrospinal fluid (csf): increases in icp shift csf into this space, which increases in diameter. this easy and repeatable technique carries one important pitfall, which is the artifact created by the retinal artery. this vessel runs close to the nerve and might appear as a hypoechoic bump that is particularly difficult to distinguish from the optic nerve. when any suspicion arises, color doppler mode should be used to evaluate the presence of blood flow. icp can be estimated using brain ultrasonography, through a transtemporal approach, assessing blood flow in the middle cerebral artery. the formula used was first introduced by czosnyka et al. in 1998 [24] , originally to estimate cpp noninvasively: the third ventricle appears as a hypoechoic band between two hyperechoic lines where map is the mean arterial pressure, fvd the diastolic flow velocity, and fvm the mean flow velocity. however, given that map-icp=cpp, the formula can be written as evidence shows that this method can accurately exclude intracranial hypertension in patients with acute brain injury. the best icp threshold estimated was 24.8 mmhg, which carried a sensitivity of 100% and a specificity of 91.2% [25] . another useful tool to consider while estimating icp using this technique is the pulsatility index. this is calculated as the difference between systolic and diastolic flow velocities, divided by the mean velocity. many studies have supported the interpretation of the pulsatility index as a tool to reflect distal cerebrovascular resistances, attributing a higher pulsatility index to higher cerebrovascular resistances [26] . however, the pulsatility index is not dependent solely on cerebrovascular resistances, but its value is the result of an interplay between cerebrovascular resistances, cpp, and compliance of the arterial bed. some authors consider this parameter as less reliable for estimation of icp [27] , and it should therefore be used together with other noninvasive methods for estimation of icp (transcranial color-coded duplex ultrasonographyoptic nerve sheath diameter, as already described). vasospasm after aneurysmal subarachnoid hemorrhage (sah) is the main cause of delayed cerebral ischemia and is associated with severe mortality and morbidity. guidelines agree on the importance of monitoring blood flow velocities noninvasively [28] . transcranial doppler and transcranial color-coded duplex ultrasonography play a pivotal role in the detection of this complication after aneurysmal sah. monitoring mean flow velocities is not enough, as an increase in flow velocity does not necessarily imply arterial narrowing. to differentiate this from cerebral hyperemia, lindegaard et al. [29] introduced a ratio between either the middle cerebral artery fig. 6 the circle of willis, as scanned from a transtemporal approach in a patient who underwent a decompressive craniectomy. the different shapes of the arterial flows are shown in the picture fig. 7 the optic nerve sheath diameter can be measured using a transorbital approach fig. 8 an occipital approach to assess vertebral and basilar blood flow. landmarks are the hyperechoic clivus and hypoechoic foramen magnum or the anterior cerebral artery and the internal carotid artery, using a threshold of 3 as a diagnostic criterion. a lindegaard ratio of 3 or above was diagnostic for vasospasm, a lindegaard ratio of less than 3 indicated hyperemia, and a lindegaard ratio of 6 was highly predictive of severe vasospasm. a blunt increase in flow velocities of 50 cm/s or more within 24 h is also predictive of vasospasm. in 2002, a modified lindegaard ratio was published for the assessment of basilar vasospasm as a ratio between basilar artery and extracranial vertebral artery, using a cutoff of 2 to differentiate between vasospasm and hyperemia [30] . midline shift can be effectively determined using the transtemporal window, axial plane on ultrasound. the main landmarks are the contralateral skull bone and the mesencephalon, and once those are found and centered in the image, the probe can be tilted cranially 10°until the third ventricle appears in the middle of the scan (diencephalic plane), as two parallel hyperechoic lines in the middle of the field, according to the technique described by seidel et al. in 1996 [19] . having identified the third ventricle, the clinician should use an electronic caliper to measure the distance between the ventricle and the inner part of the skull bone, bilaterally. the difference between the two measurements divided by two is the estimation of the midline shift. this relates well with the midline shift measured on ct scan (compared with the bland-altman method), regardless of the cause of the shift (spaceoccupying lesion, hematoma) [31] (fig. 5) . digital subtraction angiography is considered the gold standard for the confirmation of cerebral circulatory arrest and brain death. however, it requires transport of a hemodynamically unstable patient to the radiology suite to perform an invasive procedure. cbf can be assessed using transcranial doppler. increased icp blunts diastolic flow velocities and, when icp equals the diastolic arterial blood pressure, flow velocity becomes zero. when icp increases even further, there is a backflow of blood during the diastolic phase. this phenomenon is called reverberating flow, after diastolic peak blood flows in the opposite direction, and can be assessed with transcranial doppler. brunser et al. reported that power mode transcranial doppler had high sensitivity and specificity for diagnosis of brain death, respectively 100% and 98% (flow velocity was assessed in the middle cerebral artery using a transtemporal approach) [32] (fig. 9 ). precision medicine represents "a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care." with these words, barack obama, former president of the united states, launched the precision medicine initiative on january 20, 2015. funds were dedicated to creating treatments tailored to individual patients' biologic (genetic and molecular) profiles. interestingly, current attempts toward standardization of care-protocols, checklists, algorithms, evidence-based medicine, guidelines, consensus papers, and enhanced recovery after surgery programs-challenge precision medicine. while protocols provide guidelines derived from strong evidence that decreases standard variability of care, eventual personalization discovered through clinical algorithms may provide better outcomes [33] . drug response to sedatives and hypnotics is just one example of interindividual variability related to pharmacogenomics. in this light, identification of the correct dose of sedatives for optimal sedation in the icu, through proper monitoring and within specific institutional protocols, matches well with the concept of precision and personalized medicine. intensivists continuously monitor their patients' organs and systems during the icu stay: of the cardiovascular system using invasive and noninvasive methods; the respiratory system using blood gas and ventilator curve analysis; and renal function using urine output, creatinine, and biomarker levels. the brain is the main target of the sedatives frequently administered to critically ill patients, but no monitor is usually applied to monitor their effect on brain electrical activity, at least outside the neuro-icu. the main reason for this reality is that electroencephalography (eeg) [34] is a complex investigation system that few intensivists can interpret. technological evolution has developed a variety of fig. 9 reverberating flow in a patient with severe brain injury who developed an isoelectric encephalogram trace minutes after this recording and was confirmed brain dead a few hours later (simplified) eeg-derived indices that can be used to make this information more available. use of processed eeg indices has been shown to improve intraoperative anesthetic titration during anesthesia but also sedation in the icu: bispectral index [bis, medtronic, boulder, co), e-entropy (ge healthcare, helsinki, finland), narcotrend (narcotrend gruppe, hannover, germany), masimo sedline (sedline, masimo corp, irvine, ca), and neurosense (neurowave systems, inc., cleveland heights, oh) are a few examples of the tools now available on the market (fig. 10 ). there is as yet no evidence for superiority of one device over the others and differences in trace visualization, shape and characteristics of the sensor, institutional habits, and budgets are the main reasons for operator choice [35] . a detailed description of the eeg signal recording and processing is beyond the aim of this chapter, and the reader is referred to dedicated articles [36] . briefly, subcortical regions (e.g., the thalamus) produce small potentials that cannot be identified from electrodes placed on the scalp because an electric field decreases in strength by the square of the distance from its source (fig. 11) . however, because of the close and continuous interconnection between superficial and deep brain structures, surface eeg reflects the states of both cortical and subcortical areas. dedicated monitors that automatically elaborate the frontal eeg trace are needed because a full-montage eeg during sedation requires cumbersome equipment and specialized training, not available to all intensivists. moreover, a frontal processed eeg trace is considered reliable for the purposes of anesthesia/sedation monitoring even if some clinical conditions (see later) eventually require some knowledge of basic eeg principles. processed eeg monitors deliver three main pieces of information: (1) the raw trace, (2) the numerical index of anesthesia/sedation depth, and (3) the 2d spectrogram (fig. 12) . the reader is referred to dedicated articles for details about the specific parameters [37] . processed eeg was originally intended for the management of the anesthetic state during surgery to avoid accidental awareness and to titrate sedation in critically ill patients where clinical scales represent the gold standard. the inclusion of processed eeg into many multiparametric icu monitors reflects the perceived need for icu caregivers to use a comprehensive approach in the management of sedated patients. deep sedation is clearly associated with poor short-and long-term outcomes in critically ill patients: prolonged mechanical ventilation and cognitive and psychological complications all increase hospital and icu length of stay and mortality [38] . although light sedation, with patients being able to communicate and cooperate at any time, represents a modern target of sedation and a standard of care in icus, moderate-to-deep sedation (e.g., a richmond agitation-sedation scale [rass] ≤3) may be needed in a nonnegligible number of patients, including those with alcohol weaning syndromes complicated by uncontrolled agitation; complex ventilator-patient desynchrony; refractory status epilepticus; intracranial hypertension; patients receiving neuromuscular blocking agents; postsurgical patients requiring hemodynamic, temperature, or bleeding stabilization; post-cardiac arrest therapy (post-resuscitation care); or tbi. in these categories of patients, clinical scales (e.g., rass, riker sedation-agitation scale [sas]), unless they represent standardized assessment of sedation levels, cannot be applied. moreover, they are commonly evaluated every 4-6 h, and may not detect periods of inadequate sedation occurring between assessments, whereas processed eeg is a continuous method of analysis. in addition, clinical scale assessment is performed by disturbing sedated or sleeping patients (processed eeg does not require modification of the sedation state) and can never identify phases of burst suppression or isoelectric traces (total suppression) [39] , which are associated with negative outcomes (e.g., delirium occurrence, prolonged mechanical ventilation, mortality). in this context, in a post hoc analysis of a prospective observational study performed in 125 icu patients under mechanical ventilation, burst suppression occurred in 39% of the cases and was an independent predictor of increased risk of death at 6 months [40] . processed eeg values can vary greatly in patients sedated in the icu because, unlike those undergoing painful surgery, patients in the icu may not experience strong stimulation and therefore require relatively low levels of sedation, appearing calm with bis values of around 60-80. clinical procedures, spontaneous patient arousal, physiological sleep cycles, noise, and nursing activities may cause sedation levels to fluctuate. what is important to consider is that muscle activity (mainly) and electric devices (less frequently) may interfere with the ability of the system to process the raw trace, leading to falsely increased sedation indexes [41] . in order to limit this sort of artifact the companies are improving their devices keeping them more "resistant" to emg interference. in a change from the previous version published in 2013, the recent international guidelines on sedation practice in the icu [42] (clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu) report that processed eeg monitoring systems, although best suited for sedative titration during deep sedation or for patients who receive neuromuscular blockade, may also have potential benefits in lighter sedation states and that processed eeg monitoring, compared with the standard clinical scales, may improve sedative titration [43] . using processed eeg systems as an objective guide for sedative dosing in critically ill patients can decrease the medical complications of oversedation, such as depressed cardiac contractility and hypotension. there are few studies on processed eeg monitoring in the icu. the first was a prospective trial that randomized patient sedation to be assessed using the ramsay scale or bis monitoring during propofol sedation that was stopped every 2 h [44] . a nurse-guided ramsey score of 4 was the target in controls, and a bis value of 70-80 was the target for the study group. a reduction in propofol of 50% was obtained in the bis group versus controls. the second study [45] was a prospective randomized trial in which patients sedated with morphine and midazolam were randomized to sedation titration based on a bis >0 versus clinical assessment. no difference was found in the total amount of administered sedative drugs, length of mechanical ventilation, or icu length of stay. in a recent study on 110 trauma patients, use of bis resulted in a decrease in sedation and analgesia use, decrease in agitation, less failure to extubate, and fewer tracheostomies, with an approximate 4-day decreased length of stay [46] . beyond its use for sedative titration purposes, processed eeg may have some additional applications in icu patients, including identification of subclinical/ unrecognized seizures or seizures occurring when neuromuscular blocking agents are administered. nevertheless, depending on the frequencies of the ictal waveforms, processed eeg may have variable values that only skilled intensivists are able to read on the raw eeg trace to successfully understand this clinical condition. processed eeg monitors can also be used to guide therapy aimed at minimizing cerebral metabolism rate to reach predefined levels of burst suppression [47] . a significant proportion of critically ill patients with altered mental status have nonconvulsive subclinical seizures and nonconvulsive status epilepticus [48] . continuous eeg assessment for nonconvulsive subclinical seizures and nonconvulsive status epilepticus in patients with altered mental status can be indicated in patients with a history of epilepsy, fluctuating level of consciousness, acute brain injury, recent convulsive status epilepticus, stereotyped activity such as paroxysmal movements, nystagmus, twitching, jerking, hippus, and autonomic variability [49] . nonconvulsive subclinical seizures, seizures with little or no overt clinical manifestations, can be detected with eeg monitoring. noninvasive neuro-multimodality monitoring is now possible. we present an essential bundle of noninvasive neuromonitoring composed of pupillometry, brain ultrasound, and processed eeg. although some of these noninvasive tools are not yet reliable enough to completely substitute invasive monitoring, they do represent an important adjunct for the clinician in both neuroanesthesia and neurocritical care environments. we have only described the basic features and the potential that transcranial color-coded duplex doppler and brain ultrasonography have to offer to the clinician. bedside ultrasounds are becoming increasingly popular with clinicians because they are quick, reliable, and repeatable. while not yet being a substitute for invasive icp monitoring, ultrasound can give the clinician useful information when indications for such invasive devices are blurred or contraindicated (liver failure, anticoagulation). moreover, it has become a mainstay for the early detection of vasospasm in patients with aneurysmal sah. in the emergency department, expanding focused assessment with sonography in trauma (fast) assessment to brain ultrasound may enable the physician to become aware of increased icp even before the patient is transported for a ct scan, and prompt early neuroprotective medical intervention. eeg is a fundamental tool for monitoring human brain electrical activity during changing states of consciousness like sleep, sedation, or general anesthesia. processed eeg may contribute to help anesthesiologists and intensivists optimize drug doses in individuals with different pharmacogenomics and clearance of sedatives. processed eeg devices are not simple plug-and-play units providing a wellinterpretable dimensionless number. they require a global knowledge of technology and of eeg tracings to avoid misinterpretation, especially when muscle activity interferes with the processing algorithm. the use of processed eeg in the icu could be much more complex than during anesthesia in the operating rooms. nevertheless, processed eeg monitors offer advantages in the management of patients under moderate and deep sedation and in patients receiving neuromuscular blocking agents to avoid both awareness and burst suppression. some pathological states, such as seizures or altered eeg states (iatrogenic burst suppression or 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of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu a randomized evaluation of bispectral index-augmented sedation assessment in neurological patients the impact of bispectral index monitoring on sedation administration in mechanically ventilated patients utility of bispectral index in the management of multiple trauma patients can bis monitoring be used to assess the depth of propofol anesthesia in the treatment of refractory status epilepticus? prevalence of nonconvulsive status epilepticus in comatose patients continuous electroencephalogram monitoring in the intensive care unit publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations each author (far, tt, sr) has made substantial contributions to the conception, design of the work, drafted the work and substantively revised it. all authors, (far, tt, sr) have approved the submitted and final version of the manuscript (and any substantially modified version that involves the author's contribution to the study) all authors, (far, tt, sr) have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. publication costs were funded by the corresponding author's private university funds (university of brescia, italy). ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests.author details key: cord-030677-t94cu81n authors: burstein, barry; tabi, meir; barsness, gregory w.; bell, malcolm r.; kashani, kianoush; jentzer, jacob c. title: association between mean arterial pressure during the first 24 hours and hospital mortality in patients with cardiogenic shock date: 2020-08-20 journal: crit care doi: 10.1186/s13054-020-03217-6 sha: doc_id: 30677 cord_uid: t94cu81n background: the optimal map target for patients with cardiogenic shock (cs) remains unknown. we sought to determine the relationship between mean arterial pressure (map) and mortality in the cardiac intensive care unit (cicu) patients with cs. methods: using a single-center database of cicu patients admitted between 2007 and 2015, we identified patients with an admission diagnosis of cs. map was measured every 15 min, and the mean of all map values during the first 24 h (mmap(24)) was recorded. multivariable logistic regression determined the relationship between mmap(24) and adjusted hospital mortality. results: we included 1002 patients with a mean age of 68 ± 13.7 years, including 36% females. admission diagnoses included acute coronary syndrome in 60%, heart failure in 74%, and cardiac arrest in 38%. vasoactive drugs were used in 72%. the mmap(24) was higher (75 vs. 71 mmhg, p < 0.001) among hospital survivors (66%) compared with non-survivors (34%). hospital mortality was inversely associated with mmap(24) (adjusted or 0.9 per 5 mmhg higher mmap(24), p = 0.01), with a stepwise increase in hospital mortality at lower mmap(24). patients with mmap(24) < 65 mmhg were at higher risk of hospital mortality (57% vs. 28%, adjusted or 2.0, 95% ci 1.4–3.0, p < 0.001); no differences were observed between patients with mmap(24) 65–74 vs. ≥ 75 mmhg (p > 0.1). conclusion: in patients with cs, we observed an inverse relationship between mmap(24) and hospital mortality. the poor outcomes in patients with mmap(24) < 65 mmhg provide indirect evidence supporting a map goal of 65 mmhg for patients with cs. cardiogenic shock (cs) is the second-most common form of circulatory shock in all critical care units and the most common form of shock among patients admitted to cardiac intensive care units (cicus) [1, 2] . cs manifests in clinical, hemodynamic, and biochemical derangements characterized by arterial hypotension and tissue hypoperfusion, resulting in significant morbidity and mortality despite appropriate treatment [3] . the mainstay of management is early intervention to address the inciting cause, in conjunction with supportive care, to restore end-organ perfusion and prevent multi-organ failure and death [3] . in cases of acute myocardial infarction, emergency revascularization is indicated in order to improve cardiac function [4] . immediate restoration of adequate systemic blood pressure using intravenous inotropes, vasopressors, and/ or mechanical circulatory support is a priority in cs [3] . the optimal blood pressure target in cs must balance the maintenance of adequate end-organ perfusion with the adverse effects of excessive cardiac afterload and arrhythmias induced by catecholamine vasopressors. the ideal target mean arterial pressure (map) for patients with cs is unclear, and current strategies are based on evidence from patients with vasodilatory shock and cardiac arrest (ca) [3, 5, 6] . furthermore, it has been suggested that patients with pre-existing hypertension may benefit from higher map goals [7] , and a history of hypertension is common among patients with cardiovascular disease [8] . by contrast, recent evidence has demonstrated favorable outcomes among older patients supported with permissive hypotension (map 60-65 mmhg) [9] . given the sparsity of evidence to support specific map targets in patients with cs, we sought to describe the relationship between map and hospital mortality among patients with cs. we hypothesized that hospital mortality among patients with cs would increase as a function of lower map and that a threshold map may identify an optimal map range. our secondary aim was to evaluate the prevalence of organ failure as a function of map. this study was approved by the institutional review board of mayo clinic (irb # 16-000722) as posing minimal risk to patients and was performed under a waiver of informed consent. we retrospectively analyzed a database containing data from the initial cicu admission for consecutive unique adult patients aged ≥ 18 years admitted to the cicu at mayo clinic hospital st. mary's campus between january 1, 2007, and december 31, 2015 [10] [11] [12] . the mayo clinic cicu is a closed unit serving critically ill cardiac medical patients, but not postoperative cardiac surgery patients and patients receiving extracorporeal membrane oxygenation (ecmo) support. we included only those patients with an admission diagnosis of cs, defined as an international classification of diseases (icd)-9 code of 785.51 documented within 1 day of cicu admission. we excluded all patients without an admission diagnosis of cs (including those without available admission diagnosis data), even if they had an icd-9 code for cs documented at another time during hospitalization. patients without available data on map were also excluded. patients who declined minnesota research authorization, according to minnesota state law statute 144.295, were excluded from the study. we recorded demographic, vital sign, laboratory, clinical, and outcome data, as well as procedures and therapies performed during the cicu and hospital stay, as previously described [10] [11] [12] . all relevant data were extracted electronically from the medical record using the mayo clinic multidisciplinary epidemiology and translational research in intensive care data mart [13] . the admission value of all vital signs, clinical measurements, and laboratory values was defined as either the first value recorded after cicu admission or the value recorded closest to cicu admission. in addition, vital signs were recorded every 15 min, and the maximum, minimum, and mean values over the first 1, 6, and 24 h were recorded. blood pressure was preferentially recorded from invasive measurements, when available, and otherwise was recorded from noninvasive measurements. peak vasopressor and inotrope doses were used to calculate the vasoactive-inotropic score [14] . admission diagnoses included all icd-9 diagnostic codes recorded on the day of cicu admission and the day before or after cicu admission; these admission diagnoses were not mutually exclusive, and the primary admission diagnosis could not be determined. admission diagnoses of interest included cs, acute coronary syndrome (acs), heart failure (hf), supraventricular tachycardia, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, ca, respiratory failure, and sepsis. discharge icd-9 diagnostic codes were reviewed for a diagnosis of hypertension. severe acute kidney injury (aki) was defined as kdigo stage 2 or 3 aki during the cicu stay (i.e., doubling of serum creatinine or increase in serum creatinine to ≥ 4.0 mg/dl or new dialysis initiation in the cicu); mild aki was defined as kdigo stage 1 aki (an increase in creatinine by ≥ 0.3 mg/dl or 50% from baseline) [11, 15] . baseline creatinine was considered to be the latest creatinine within 1 year prior to the index hospital admission, and patients who had previously received dialysis were excluded from this aki analysis. non-cardiovascular organ failure was defined as a score ≥ 3 on any day 1 sofa organ subscore [16] . the primary endpoint was all-cause hospital mortality; secondary endpoints included cicu mortality and postdischarge mortality up to 1 year among hospital survivors. mortality and other outcome data were extracted from mayo clinic electronic databases, the state of minnesota electronic death certificates, and the rochester epidemiology project database [17] . categorical variables are reported as number (percentage), and the pearson chi-squared test was used to compare groups. continuous variables are reported as mean (± standard deviation); the wilcoxon rank-sum test was used to compare groups. the calculation of 24-h mean map (mmap 24 ) was performed using invasive blood pressure measurements, if available; otherwise, mmap 24 was calculated using noninvasive blood pressure values. logistic regression was used to determine the association between mmap 24 with hospital mortality before and after adjusting for age, gender, race, charlson comorbidity index (cci), and acute physiology and chronic health evaluation iv (apache-iv) predicted mortality; admission diagnoses of ca, sepsis, hf, and acs; peak 24-h vis; and the use of intra-aortic balloon pump (iabp), dialysis, pulmonary artery catheter (pac), coronary angiography, percutaneous coronary intervention (pci), and mechanical ventilation. subgroup analysis was performed by repeating multivariable logistic regression after excluding patients with scai shock stages a or b or sepsis; besides, logistic regression was repeated in the overall cohort after adjusting for scai shock stages. discrimination was assessed using the area under the receiver-operator characteristic curve (auc, c-statistic) value, and the optimal cutoff defined using youden's j index. post-discharge survival among hospital survivors was evaluated using the kaplan-meier survival analysis and cox proportional-hazards analysis. two-tailed p values < 0.05 were considered statistically significant. statistical analyses were performed using jmp pro version 14.1.0 (sas institute, cary, nc). the database included 10,004 unique cicu patient admissions, of whom 1078 had an admission diagnosis cs and were potentially eligible for inclusion [10] . we excluded 76 of these patients due to lack of available data for map (supplemental figure 1 ). the final study population of 1002 unique patients had a mean age of 67.7 ± 13.7 years, including 36.4% females ( patients with a mmap 24 < 65 mmhg differed from patients with a mmap 24 65-75 mmhg or mmap 24 ≥ 75 mmhg (table 1) , with greater severity of illness (apac he-iii score 100.8 ± 35.3 vs. 87.5 ± 32.0 vs. 77.9 ± 30.2, p < 0.001), more severe cs based on society for cardiovascular angiography and interventions (scai) staging, increased incidence of severe aki (30.0% vs. 19.8% vs. 14.8%, p = 0.001, fig. 1a ), greater use of vasoactive infusions (85.5% vs. 78.9% vs. 54.4%, p < 0.001), and an increased number of non-cardiac organ injury (mean 1.4 vs. 1.1 vs. 0.9, < 0.001, fig. 1b) . conversely, patients with mmap 24 < 65 mmhg underwent fewer coronary angiograms (52.5% vs. 64.6% vs. 70.5%, p < 0.001) and were less often supported with an iabp or impella device (abiomed, danvers, ma, usa) (30.1% vs. 50.5% vs. 46.4%, respectively, p < 0.001). hospital mortality was 33.7%, including 23.4% of patients who died in the cicu. patients who died in the hospital had lower mmap 24 (70.8 vs. 74.7 mmhg, p < 0.001). crude hospital mortality was higher in patients with mmap 24 < 65 mmhg compared with patients with mmap 24 65-75 mmhg or mmap 24 ≥ 75 mmhg (57.0% vs. 29.8% vs. 26.9%, p < 0.001 for mmap 24 < 65 mmhg vs. other groups and p = 0.36 between other groups). the mmap 24 was inversely associated with hospital mortality (unadjusted or 0.82 per 5 mmhg higher mmap 24 , 95% ci 0.76-0.88, p < 0.001; optimal cutoff 64.6 mmhg; fig. 2 figures 4a and 4b) , and patients aged 65 years and older (supplemental figure 5) . mean values of systolic, diastolic, and mean bp were significantly lower for inpatient deaths at all time points (1, 6, and 24 h), although the magnitude of these differences was relatively modest (supplemental figure 6 ). the association between mmap 24 and mortality remained after excluding patients with scai stages a and b of cs (adjusted or 0.850 per 5 mmhg higher, 95% ci 0.755-0.957, p = 0.007), as well as in the overall cohort after adjusting for scai cs stage (adjusted or 0.913 per 5 mmhg, 95% ci 0.838-0.994, p = 0.035). the association between mmap 24 and hospital mortality persisted after excluding patients with an admission diagnosis of sepsis (adjusted or 0.873, 95% ci 0.794-0.960, p = 0.0052). the association between mmap 24 and hospital mortality was present in patients without sepsis (adjusted or 0.873, 95% ci 0.794-0.960, p = 0.0052). the optimal mmap 24 cutoff for predicting hospital mortality was 65.2 mmhg in patients with acs and 70.0 mmhg in patients with hf. hospital mortality varied as a function of mmap 24 and the maximum number of vasopressors during the first 24 h and the peak vis during the first 24 h (fig. 3) . in subgroups of patients with and without a diagnosis of hypertension, there was no association figures 4a and 4b) . after multivariable adjustment, mmap 24 remained inversely associated with hospital mortality (adjusted or 0.89 per 5 mmhg higher mmap 24 , 95% ci 0.82-0.97, p = 0.01, table 2 ). patients with a mmap 24 < 65 mmhg were at higher risk of hospital mortality (adjusted or 2.05, 95% ci 1.38-3.02, p < 0.001), with no difference between patients with mmap 24 65-75 mmhg and mmap 24 ≥ 75 mmhg (p = 0.77). in this retrospective study of a large tertiary cicu patient population with cs, we demonstrate that mmap 24 is inversely associated with cicu and hospital mortality after adjusting for illness severity and cicu therapies, including patients with common cicu diagnoses such as acs, hf, and ca. these data suggest that mmap 24 is an independent predictor of hospital mortality in cs patients across subgroups, even when accounting for vasopressor requirements. the association between mmap 24 and hospital mortality remained even after adjustment for the scai shock stage, suggesting that the importance of mmap 24 extends beyond initial shock severity alone. patients who were able to maintain a map above 65 mmhg had lower hospital mortality; similar results were seen among patients with acs, whereas unexpectedly patients with hf seemed to have better outcomes at a map above 70 mmhg. among patients with a map below 65 mmhg, hospital mortality increased in proportion to the severity of hypotension, and patients with the most severe hypotension were at highest risk of mortality. we observed a threshold effect, such that patients with progressively higher mmap 24 above these levels did not have further decreases in mortality. the prevalence of non-cardiovascular organ failure and severe aki was higher among patients with lower map, potentially explaining why these patients had higher mortality. notably, not all patients who had an admission diagnosis of cs received vasopressors, mechanical circulatory support, or had manifest hypoperfusion on cicu admission, suggesting that some patients had resolved cs. these data suggest that maintaining map goals lower than 65 mmhg may not be adequate to preserve organ perfusion. however, targeting map goals higher than 65 mmhg may potentially expose patients to added hazards from the known adverse effects of vasoactive drugs without definite benefit. we did not observe a difference in map thresholds in patients with a pre-existing history of hypertension, and our findings do not suggest that a higher map is preferentially associated with any decrease in mortality or end-organ injury among this subgroup of patients. evidence-based therapies available to patients with cs remain limited, and much of the critical care strategies in the cicu have been extrapolated from other non-cs populations [3] . the optimal map goal in patients with cs has not been well defined. current strategies are based on evidence from patients with other forms of circulatory shock, particularly patients with sepsis whose physiology is entirely different from cs due to the presence of a low diastolic blood pressure from vasoplegia which drives down the map [7, 18] . the sepsispam trial compared a vasopressor strategy targeting map of 80-85 mmhg to a target of 65-70 mmhg in patients with septic shock and found no difference in death or aki at 28 days despite more arrhythmias in the higher map arm; patients with chronic hypertension maintained at the higher map target were less likely to suffer from aki [7] . by contrast, a recent multicenter randomized controlled trial of patients 65 years and older who were admitted to the icu with septic shock demonstrated that permissive hypotension (map 60-65 mmhg) reduced vasopressor exposure without increasing the risk of mortality or aki (including patients with and without hypertension) [9] . the findings of our study indirectly support the safety of a lower map target (i.e., 65-70 mmhg) in cs patients, but did not show a benefit of higher map targets among patients with a history of hypertension. evidence supports the use of vasopressors such as norepinephrine that have a lower rate of cardiovascular adverse events, including increased myocardial oxygen demand, ischemia, arrhythmias, and mortality [1, 14] . in general, increasing doses of vasoactive agents increase the risk of cardiovascular adverse events and are associated with higher mortality, and current recommendations suggest the lowest effective dose necessary to achieve a target map [3, 14] . we observed a strong independent association between higher vasopressor doses based on vis 24 and higher hospital mortality. many cs patients are already maximally vasoconstricted due to cardiac pump failure, and further increasing afterload with vasopressors may be deleterious, particularly when targeting higher map goals [3] . in the distinct high-risk subgroup of patients with ca, which is commonly associated with abnormal cerebral blood flow autoregulation, retrospective evidence suggests that maintenance of a higher map may be considered to improve cerebral perfusion and neurological outcomes [6] . however, randomized controlled trials of higher map targets (80 or 85 to 100 mmhg) have not shown an improvement in neurological outcomes when compared to a target of 65 mmhg [18, 19] . likewise, we did not observe a different map threshold for patients with ca and cs in our study. the use of higher vasopressor doses to achieve a higher target map after ca poses a risk of increasing the arrhythmia burden, which may be particularly harmful in ca patients with an arrhythmic substrate. as a result, current society guidelines for patients with septic shock or ca recommend map targets of 65-70 mmhg [6, 20] . it is crucial to note that the observed association between outcomes and mmap 24 demonstrated in our retrospective observational study is not the same as testing specific map goals for titrating vasopressor therapy in cs patients. we could not determine the map goals used by the treatment team, and therefore, we could not distinguish patients who had low map due to failure to achieve a prescribed map goal from those in whom a lower map was successfully targeted. besides, patients with lower map had more severe illness by all relevant metrics and did not receive as many supportive cardiovascular procedures; we could not exclude the possibility that these patient-specific factors drove the adverse outcomes as opposed to the lower map itself. importantly, cs patients may preferentially benefit from tailored vasopressor and inotropic support guided by hemodynamic data, such as those derived from a pulmonary artery catheter, rather than a "one-size-fits-all" approach [3] . nonetheless, our data clearly show that an inability to maintain map ≥ 65 mmhg during the first 24 h after cicu admission is associated with adverse outcomes in cicu patients with cs. this retrospective cohort study has a number of inherent limitations, including the potential for unmeasured confounders and missing data to have influenced the results. this single-center cohort may not fully represent the general patient population with cs. the mmap 24 values included both invasive and noninvasive map measurements, but we could not determine which map measurements were made using each method, and mmap 24 potentially included a mixture of both. admission diagnoses are based on icd-9 coding and may underrepresent the number of patients with cs and associated comorbidities. the inclusion of a mixed cicu population without available hemodynamic or echocardiographic data implies that some patients may have had patients with mmap 24 < 65 mmhg were less likely to undergo pci; the reasons for this are likely multifactorial and largely dependent on clinical factors and contraindications (e.g., severe shock, renal injury, or concern for cerebral anoxia). unfortunately, our retrospective dataset cannot account for these clinical decisions. in addition, we could not determine the incidence of relevant cardiovascular adverse events attributable to vasopressor and inotrope therapy. due to lack of data availability, we could not account for patient-level variables before cicu admission, including specific diagnostic or therapeutic interventions which took place before cicu admission. there was an inverse correlation between mmap in the first 24 h and hospital mortality among patients with cs admitted to the cicu. patients with a map below 65 mmhg during the first 24 h after cicu admission had an increased risk of mortality. these findings provide indirect support for a map target of 65 mmhg for most cicu patients with cs. further prospective research should evaluate which, if any, map goals are optimal for patients with specific hemodynamic or etiologic subtypes of cs. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03217-6. additional file 1: supplemental figure 1 . patient flow diagram describing inclusion/exclusion criteria and patient groups. supplemental figure 2ab . hospital mortality as a function of the 24-hour average mean arterial pressure (mmap 24 ), among patients with acute coronary syndrome (a) or heart failure (b). supplemental figure 3ab . hospital mortality and incidence of severe acute kidney injury (aki) as a function of the 24-hour average mean arterial pressure (mmap 24 ), among patients with (a) and without (b) cardiac arrest. supplemental figure 4ab . hospital mortality and incidence of severe acute kidney injury (aki) as a function of the 24-hour average mean arterial pressure (mmap 24 ), among patients with (a) and without (b) a pre-admission diagnosis of hypertension. supplemental figure 5 . hospital mortality as a function of the 24hour average mean arterial pressure (mmap 24 ), among patients age 65 and older. supplemental figure 6 . mean values of systolic (circles), diastolic (arrows), and mean (diamonds) blood pressure over the first 1, 6, and 24 hours of the cicu stay. abbreviations acs: acute coronary syndrome; aki: acute kidney injury; ca: cardiac arrest; cicu: cardiac intensive care unit; cs: cardiogenic shock; hf: heart failure; map: mean arterial pressure; mmap 24 : average mean arterial pressure during first 24 h of cicu admission authors' contributions jcj helped conceive of the study, designed the data analysis plan, acquired the data, performed the statistical analysis, and drafted the manuscript. bb helped conceive of the study, assisted with the analysis, and drafted the manuscript. mt, gwb, mrb, and kk contributed to the data analysis and drafting of the manuscript. all authors were involved in the data interpretation and manuscript revision for intellectual content. all authors have provided approval of the final manuscript. none declared. the dataset supporting the conclusions of this article is included within the article and its supplementary materials. this study was approved by the institutional review board of mayo clinic (irb # 16-000722) as posing minimal risk to patients and was performed under a waiver of informed consent. not applicable. comparison of dopamine and norepinephrine in the treatment of shock epidemiology of shock in contemporary cardiac intensive care units contemporary management of cardiogenic shock: a scientific statement from the american heart association aha/acc guideline for the management of patients with non-st-elevation acute coronary syndromes a report of the american college of cardiology/american heart association task force on practice guidelines cardiogenic shock due to myocardial infarction: diagnosis, monitoring and treatment a german-austrian s3 guideline american heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care high versus low blood-pressure target in patients with septic shock effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension predictive value of the sequential organ failure assessment score for mortality in a contemporary cardiac intensive care unit population comparison of mortality risk prediction among patients >/=70 versus <70 years of age in a cardiac intensive care unit severity of illness assessment with application of the apache iv predicted mortality and outcome trends analysis in an academic cardiac intensive care unit informatics infrastructure for syndrome surveillance, decision support, reporting, and modeling of critical illness temporal trends and clinical outcomes associated with vasopressor and inotrope use in the cardiac intensive care unit hyperkalemia is associated with increased mortality among unselected cardiac intensive care unit patients early noncardiovascular organ failure and mortality in the cardiac intensive care unit history of the rochester epidemiology project: half a century of medical records linkage in a us population targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial early goal-directed haemodynamic optimization of cerebral oxygenation in comatose survivors after cardiac arrest: the neuroprotect post-cardiac arrest trial surviving sepsis campaign: international guidelines for management of sepsis and septic shock publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors declare that they have no competing interests. key: cord-003307-snruk3j2 authors: schmidt, julius j.; lueck, catherina; ziesing, stefan; stoll, matthias; haller, hermann; gottlieb, jens; eder, matthias; welte, tobias; hoeper, marius m.; scherag, andré; david, sascha title: clinical course, treatment and outcome of pneumocystis pneumonia in immunocompromised adults: a retrospective analysis over 17 years date: 2018-11-19 journal: crit care doi: 10.1186/s13054-018-2221-8 sha: doc_id: 3307 cord_uid: snruk3j2 background: despite modern intensive care with standardized strategies against acute respiratory distress syndrome (ards), pneumocystis pneumonia (pcp) remains a life-threatening disease with a high mortality rate. here, we analyzed a large mixed cohort of immunocompromised patients with pcp, with regard to clinical course and treatment, and aimed at identifying predictors of outcome. methods: this was a single-center retrospective analysis in a tertiary care institution across 17 years. diagnosis of pcp required typical clinical features and microbiological confirmation of pneumocystis jirovecii. epidemiological, clinical, laboratory and outcome data were collected from patient records. results: a total of 52,364 specimens from 7504 patients were sent for microbiological assessment (3653 with clinical suspicion of pneumocystis pneumonia). pcp was confirmed in 240 patients, about half of them hiv positive (52%). the remaining subjects were either solid organ transplant recipients (16.3%) or suffered from malignancy (15.8%) or autoimmune diseases (11.7%). of note, 95% of patients with pcp were not receiving chemoprophylaxis. overall in-hospital mortality was 25.4%, increasing to 58% if icu admission was required. multivariable regression identified lactate dehydrogenase (ldh) as predictor of in-hospital mortality (adjusted or 1.17 (95% ci 1.09–1.27), p < 0.0001). mortality in ldh quartiles increased from 8% to 49%, and a cutoff value of 495 u/l predicted mortality with sensitivity and specificity of 70%. with regard to treatment, 40% of patients received trimethoprim-sulfamethoxazole at doses that were lower than recommended, and these patients had a higher mortality risk (hr 1.80 (95% ci 1.10–3.44), p = 0.02). conclusions: pcp remains a life-threatening disease among immunocompromised patients. about half of patients with pcp do not have hiv infection. initial ldh values might serve as a stratifying tool to identify those patients at high risk of death among patients with hiv and without hiv infection. electronic supplementary material: the online version of this article (10.1186/s13054-018-2221-8) contains supplementary material, which is available to authorized users. pneumocystis pneumonia (pcp) is a severe disease with high morbidity and mortality, which almost exclusively affects immunocompromised patients. pcp has long been known for its high prevalence among human immunodeficiency virus (hiv)-positive patients [1] . since the implementation of combination antiretroviral therapies (cart) and chemoprophylaxis its incidence has been continuously decreasing [2] . nowadays, most patients with hiv-associated pcp are treatment-naïve with very low cd4 cell counts; some of these patients do not know that they are hiv positive until they attend hospital [3] . on the other hand, pcp is also frequently diagnosed in non-hiv-positive patients as immunosuppressive regimens are being increasingly used in a wide range of patient populations. consistently, the incidence of pcp in non-hiv-positive patients is increasing [2] . pneumocystis infections have first been described in preterm infants following world war ii [4] and in patients with malignancies in the late 1960s [5] , more than a decade before the hiv epidemic emerged. defects in cell-mediated immunity and use of glucocorticoids are among the strongest risk factors for the development of pcp [6, 7] . the epidemiology of pcp has been described in several retrospective studies [2, 8] . a study from the mayo clinic in 116 non-hiv-positive patients found that most frequent underlying diseases were hematological malignancies (30%), organ transplantation (25%), autoimmune disease (22%), solid tumors (13%) and other reasons [6] . although, most of these reports were published more than a decade ago and might not reflect the current epidemiological situation, a report from france was published a few years ago [9] . roux et al. reported overall mortality of 17.4%, which was significantly higher in non-hiv-positive patients (27%) than in hiv-positive patients (4%) [9] . a few parameters such as age, prior episode of pcp, low cd4 cell count, lactate dehydrogenase (ldh), and coinfections have been reported to predict unfavorable outcome in patients with hiv infection [10] [11] [12] . reports on outcome predictors in non-hiv-positive patients are sparse. based on the high burden of pcp and the likelihood of unfavorable outcome particularly in non-hiv-positive patients, chemoprophylaxis with trimethoprim-sulfame thoxazole (tmp-smx) is recommended in high-risk populations [13] . tmp-smx is also the treatment of choice for pcp. adjunctive corticosteroid therapy is recommended in hiv-positive patients with severe respiratory failure [14, 15] . however, while beneficial outcomes of higher dosage of corticosteroids in hiv-positive patients during pcp are reported [16] , the outcome of using corticosteroids in non-hiv-positive patients is not clear [17] . we here report comprehensive epidemiological, clinical, laboratory, therapeutic and outcome data on 240 cases of pcp, including a high percentage of non-hiv-positive patients, in a tertiary care center over the last 17 years. additionally, we aimed at identifying predictors of outcome. we performed a retrospective, single-center cross-sectional analysis of all patients with a positive finding of pneumocystis jirovecii on direct immunofluorescence testing or detection by diff-quick staining in the bronchial washing fluid or broncho-alveolar lavage (bal) fluid, from january 2000 to june 2017. our hospital is a university tertiary care center with approximately 1500 beds. written informed consent was waived by the ethics committee due to the anonymized retrospective nature of the analysis. all bronchial washing fluids or bal samples from patients clinically suspected to have p. jirovecii pneumonia were evaluated within the study period. for every patient, clinical data on demographic characteristics, underlying disease, status of immune competence, treatment regimens of immunosuppression, pcp therapy regimen and mortality, were gathered in the study database. date of diagnosis was defined as the date of microbiological confirmation. p. jirovecii direct immunofluorescence was performed using the monofluo kit p. carinii (biorad laboratories, years 2000 to 2016) or the detect if pneumocystis carinii kit (axis-shield diagnostics ltd., year 2017). diff quick staining was performed using the stain sets provided by dade behring or siemens ag, respectively. standard descriptive statistics were used to summarize the data (e.g. continuous: mean ± standard deviation/ count: absolute and relative frequencies/time-to-event: kaplan-meier estimator). to identify predictors of in-hospital mortality or survival we applied logistic and cox proportional hazards models. consequently, both odds ratio (or) and hazard ratio (hr) estimates were reported. to obtain multivariable adjusted estimates, all main effects with univariate p values less than or equal to 0.15 were investigated simultaneously. in addition, confidence intervals (ci) were calculated with coverage of 95%. finally, we also created receiver operating characteristics (roc) curves for in-hospital death, which were summarized by area under the curve (auc) estimates. roc analyses were based on an increasingly complex (leave one out) logistic regression model with in-hospital mortality as the predicted outcome and the following predictors, which were all entered linearly: ldh alone, ldh + age, ldh + age + body mass index (bmi), and for ldh + age + bmi + estimated glomerular filtration rate (egfr). all reported p values are nominal and two-sided. in this explorative study, we applied a significance level of α = 0.05 (two-sided). all statistical analyses were done using graphpad prism 5.0 (la jolla, ca, usa) or r 3.4.2. during the observation period, 52,364 bal or bronchial washing fluid samples were investigated. a clinical suspicion of p. jirovecii infection was raised in 3652 of these specimens of which 252 (i.e. 6.9%) were microbiologically confirmed by immunofluorescence as positive for pcp. there were ultimately 240 patients enrolled into the study (12 were excluded due to incomplete data sets) (fig. 1 ). in the overall population, 67 patients were female (27.9%) and the average age was 45 ± 15 years. there were 125 patients (52%) with hiv infections; 39 (16.3%) had undergone solid organ transplant and 38 (15.8%) had undergone chemotherapy due to hematologic or oncologic malignancies: 28 patients (11.7%) received immunosuppressive therapy for rheumatoid autoimmune diseases (is/rd) and 10 patients (4.2%) had other underlying diseases (miscellaneous (misc)), e. g. common variable immune-deficiency (cvid) ( table 1) . five patients could be classified into multiple categories. after case reevaluation, patients were classified to the most recent active disease prior to the pcp event. the average cumulative incidence of pcp in our institution was 13 ± 5 cases per year, with a peak in the years 2005-2010 (additional file 1: figure s1a ). of the 240 patients with pcp, 41.7% were admitted to the intensive care unit (icu), with 36.6% in need of mechanical ventilation, 16.3% in need of renal replacement therapy (rrt), and 4.5% in need of extracorporeal membrane oxygenation (ecmo) support (fig. 2a) . the overall in-hospital mortality was 25.4%. the mortality was 58% in patients requiring icu treatment, 74.4% in patients requiring rrt and 81.8% in patients requiring ecmo support, and only 1.6% of patients died on regular (non-icu) wards (fig. 2b) . mortality during the observation time from 2000 to 2017 slightly fluctuated but did not trend toward an improvement in more recent years (additional file 1: figure s1b ). the underlying disease was associated with outcome ( table 1 ). the lowest mortality was observed in hiv-infected patients (12.8%); the respective mortality rates in the non-hiv group were 38.4% in solid organ transplant recipients, 30.0% in patients with rheumatic diseases and 44.7% in patients with hematologic -oncologic diseases, respectively (additional file 1: figure s1c ). figure 2c , d summarizes icu admission and icu mortality with regard to the etiology of the patients' immunosuppressive disease. of note, only 12 patients (5%) were receiving chemoprophylaxis with tmp-smx at the time when pcp was diagnosed ( table 1) . univariate regression analysis revealed that age, bmi, gfr and initial ldh were associated with death from pcp. both logistic and cox multivariable regression analyses identified ldh as a predictor of unfavorable outcome in pcp (table 2 , adjusted or 1.17 (95% ci 1.09-1.27) per 50 u/l, p < 0.0001, adjusted hr 1.07 (95% ci 1.04-1.10) per 50 u/l, p < 0.0001). the initial ldh levels were significantly higher in later non-survivors (443 ± 214 vs. 673 ± 373 iu/l, p < 0.0001, fig. 3a ) and in patients that required admission to the icu (411 ± 199 vs. 627 ± 328 iu/l, p < 0.0001, fig. 3b ). stratification of patients into ldh quartiles showed increasing (in-hospital) mortality rates among those. mortality ranged between 8% in the lowest and 49% in the highest ldh quartile (fig. 3c) . a roc curve for in-hospital death had an estimated auc of 0.724 (95% ci 0.65-0.80) (p < 0.0001 for ldh alone, additional file 1: figure s2 ). potential alternative cutoff values and their impact on usually reported statistics are summarized in additional file 2: table s1 for descriptive purposes. we used a cutoff of 496 iu/l for further analysis. patients with initial ldh below 496 iu/l had lower mortality than the overall population (13.1 vs. 25.4%) and lower mortality than those with initial ldh > 496 iu/l (13.1 vs. 43.9%, p < 0.001, fig. 3d, e) . the addition of other clinical quantitative variables to ldh in the auc model such as age, bmi and egfr did not improve the predictive value of ldh alone (additional file 1: figure s2 , additional file 2: table s2 ) in the overall cohort. however, when icu patients were analyzed separately, we observed that the addition of age as a variable increased the predictive performance of ldh alone from an auc of 0.61 (95% ci 0.49-0.72) to an auc of 0.71 (95% ci 0.60-0.81) (p = 0.024). of note, we did not detect any etiology subgroup that showed better performance in the roc analysis (additional file 1: figure s3 ), nor did we detect temporal trends when applying the ldh prediction models in three strata (2000) (2001) (2002) (2003) (2004) (2005) 2005 -2010, 2010-2017) (additional file 1: figure s4 ). fig. 3 influence of initial lactate dehydrogenase (ldh) as an outcome predictor. the scatter plot shows initial ldh levels at admission in later survivors (alive) and non-survivors (dead) (443 ± 214 vs. 673 ± 373 iu/l, p < 0.0001) (a) and in non-icu versus icu patients (411 ± 199 vs. 627 ± 328 iu/l, p < 0.0001) (b). c bar graph showing overall mortality (right y-axis) stratified for initial ldh quartiles (left y-axis) (q1, < 310; q2, 311-436; q3, 437-599; q4, > 600 iu/l). d mortality in all patients with pneumocystis pneumonia with ldh levels ≤ and > 496 iu/l (cutoff value was derived from roc curve of all patients, with sensitivity and specificity of 70%.) the gray area highlights the overall mortality of 24.8% without ldh risk stratification. e kaplan-meier analysis of survival in patients stratified for ldh ≤ and > 495 iu/l during 120 days (p log-rank test < 0.0001) there were 224/240 patients (93.3%) initially treated with the gold standard, tmp-smx. the remaining 16 patients had alternative regimens with chemotherapeutics from the second line, mostly due to side effects and intolerance of tmp/smx (e.g. atovaquone and/or pentamidine, fig. 1) . among the 224 patients treated with tmp-smx, 159 (71%) were dosed in the recommended range above 15 mg/kg bodyweight (bw) per day, while 65 patients (29%) received a dose lower than 15 mg/kg bw (additional file 1: figure s5a ). of note, these patients had a higher mortality risk (hr 1.80 (95% ci 1.10-3.44), p = 0.02). solid organ transplant (sot) recipients and patients with rheumatoid diseases were more likely to receive lower dosages (additional file 1: figure s5b ). on the other side, we observed that under-dosed patients also had significantly lower egfr (48.9 ± 43 ml/min vs. 104 ± 32 ml/min, p < 0.0001). interestingly, the absolute dose of tmp-smx was not different in survivors (16.9 ± 5.5 mg/kg) and non-survivors (15.6 ± 7.1 mg/kg, p = 0.93). still, kaplan-meier survival curves revealed a significant difference when patients were grouped into those treated with < 15 mg/kg and those treated with ≥ 15 mg/kg tmp-smx (additional file 1: figure s5c , p log-rang test = 0.02). however, tmp-smx dose did not independently predict outcome in the multivariable regression analyses. here we present the single-center experience with regard to epidemiology, treatment and outcome of pcp in a tertiary care center over a period of 17 years. a substantial group of our pcp cases (about 50%) were not related to hiv infections and these patients had a worse clinical course with higher icu admission and mortality rates than patients with hiv-associated pcp. three major non-hiv-positive groups were identified: (1) solid organ transplant recipients, (2) patients with malignancies and (3) patients with rheumatic diseases. pcp occurred almost exclusively in patients who did not receive chemoprophylaxis with tmp-smx. overall, about one quarter of all patients suffering from pcp did not survive the disease. in those who required intensive care (approximately 40% of all patients), the in-hospital mortality increased up to 58%. based on the -in principle -reversible nature of pcp, almost no patients were denied intensive care in the event of acute respiratory failure, as the in-hospital mortality rate in non-icu patients was 1.6%. moreover, we found that the extent of initial ldh elevation was a predictor of in-hospital mortality, and that in univariate comparisons, in-hospital mortality was higher in patients whose tmp-smx dose was below 15 mg/kg bw. non-hiv-positive populations at risk of pcp have been described before. the distribution across these risk groups varies widely (sot 3-31%, hematologic diseases 26-39%, rheumatic diseases 11-25%), which is likely due to the clinical emphasis in predominantly monocentric studies [9, [18] [19] [20] . several centers have reported a decrease in the percentage of hiv-infected patients among all cases of pcp in the era of cart [19, 21] . we did not confirm this decrease, nor did fillatre et al. [18] . our data showed that the clinical course and outcome of pcp differed between hiv-infected and non-hiv-infected patients. in general, hiv-infected patients require fewer icu admissions and have better overall survival than non-hiv-infected patients, which is in line with previous reports [9, 22] . the pcp mortality rate in hiv-positive patients was in the range of 1-15% [9, 18, 19] compared to 30-40% in hiv-negative patients [23] [24] [25] . the better outcome of hiv-positive patients might be the consequence of (1) lower age (− 3.8 years in our cohort), (2) fewer co-morbidities, (3) the reversible nature of the immune defect upon anti-viral treatment strategies and hypothetically (4) greater awareness of pcp in hiv-positive individuals, where it is the most common aids-defining disease. in mixed cohorts, icu admission and mechanical ventilation occurred in 22-40% and 13-22% of patients, respectively [9, 18, 22] . both events are frequently reported as negative predictors of survival. nevertheless, newer data on icu mortality in patients with pcp are scarce. only one recent study reported relatively high icu mortality in hiv-negative patients of 53% compared to 15% in hiv-positive patients [18] . mortality in patients with invasive mechanical ventilation was 60% and 28%, respectively, in these two groups [22] . compared to other reports [21, 26] , we had a relatively high icu admission rate of 25% in hiv-positive patients, which can in part be explained by the selective transfer of more patients with more progressive disease to our university hospital as a tertiary center. the literature is inconclusive on outcome predictors, but on multivariable analysis, a large prospective study from france demonstrated a significant survival benefit in younger patients [9] . although observed in hiv-positive patients before [27] , here we report for the first time that in a mixed population of hiv-positive and non-hiv-positive patients the initial levels of serum ldh at hospital admission are not only useful in the diagnostic evaluation [28] but may also be an independent predictor of survival. this might potentially help the clinician in early identification of the sickest patients at high risk of unfavorable outcome. with regard to the specificity/sensitivity, the ideal ldh cutoff value to predict outcome has yet to be defined. with regard to the actual treatment of pcp we found that a reduction in the recommended tmp-smx dose below 15 mg/kg bw (for whatever reason) might be associated with higher mortality (13.1 vs. 55.8%). given that this observation was not confirmed in the multivariable analysis, relevant confounders must be considered. our study has several limitations. this was a retrospective observational study based on the medical records of patients with pcp from a single institution. consequently, causal claims cannot be made. the observation that under-dosing with tmp-smx is associated with higher mortality might be confounded by a higher percentage of patients with renal impairment. more robust evidence from well-designed studies is needed to make firm conclusions or even to make implications about changes in standard pcp management. in summary, pcp is a rare but potentially fatal disease in immunocompromised patients with diseases of different etiology. about 50% of cases were non-hiv-associated. initial ldh levels -if validated by others -might be a useful predictor of in-hospital mortality, and tmp-smx treatment doses in patients at high risk of death (e.g. icu admission + ldh > 495 u/l) should probably not be reduced below 15 mg/kg bw. additional file 1: figure s1 . cumulative incidence of (a) and inhospital mortality in (b) pneumocystis pneumonia (pcp) at hannover medical school from 2000 to 2017. figure s2 . receiver operating characteristic (roc) curves for in-hospital mortality applied to the total sample. figure s3 . roc curves for in-hospital mortality applied to subgroups regarding underlying etiology of immunosuppression and for the icu cohort. figure s4 . roc curves for in-hospital mortality with the ldh prediction model applied in three strata (years 2000-2005, 2005-2010, 2010-2017) . figure s5 . association between trimethoprimsulfamethoxazole (tmp-smx) dose and mortality (docx 21 kb) additional file 2: table s1 . suggested, alternative data-derived ldh cutoff values and their impact on usually reported statistics (with 95% confidence interval in parenthesis) related to the prediction of in-hospital mortality in patients with pcp. table s2 . estimated aucs (with 95% confidence interval) of the ldh-related logistic regression models for the prediction of in-hospital mortality in patients with pcp. table s3 . additional descriptive information (with 95% confidence interval in parenthesis) on patient characteristics and their potential value as predictors of in-hospital mortality in patients with pcp. table s4 . pneumonia in the acquired immune deficiency syndrome opportunistic 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positively influences p. jiroveci pneumonia (pjp) outcome: a retrospective analysis of 116 hiv-positive and hiv-negative immunocompromised patients population-based analysis of invasive fungal infections pneumocystis pneumonia in hiv-infected and immunocompromised non-hiv infected patients: a retrospective study of two centers in china outcomes and prognostic factors of non-hiv patients with pneumocystis jirovecii pneumonia and pulmonary cmv co-infection: a retrospective cohort study predisposing factors, clinical characteristics and outcome of pneumonocystis jirovecii pneumonia in hiv-negative patients analysis of underlying diseases and prognosis factors associated with pneumocystis carinii pneumonia in immunocompromised hiv-negative patients intensive care of patients with hiv infection: utilization, critical illnesses, and outcomes. pulmonary complications of hiv infection study group plasma il-6/il-10 ratio and il-8, ldh, and hbdh level predict the severity and the risk of death in aids patients with pneumocystis pneumonia utility of lactate dehydrogenase vs radiographic severity in the differential diagnosis of pneumocystis carinii pneumonia no external funding was received to conduct this study. however, dr david's laboratory is supported by a grant from the german research foundation (da1209/4-3). the datasets used and analyzed during the current study are available from the corresponding author on reasonable request. carl-neuberg-strasse 1, 30625 hannover, germany. 2 authors' contributions jjs, cl, sd and sz collected the data. as performed the statistical analysis. experts in particular field were involved for specific data interpretation (ms for hiv; hh, jg, tb, mmh for transplantation; me for malignancies). jjs, cl, mmh, as and sd wrote the manuscript and all authors read, commented on and approved it.ethics approval and consent to participate written informed consent was waived by the local ethics committee at hannover medical school due to the anonymized retrospective nature of the analysis. not applicable. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-275012-fkawgh0e authors: tavazzi, guido; marco, pozzi; mongodi, silvia; dammassa, valentino; romito, giovanni; mojoli, francesco title: inhaled nitric oxide in patients admitted to intensive care unit with covid-19 pneumonia date: 2020-08-17 journal: crit care doi: 10.1186/s13054-020-03222-9 sha: doc_id: 275012 cord_uid: fkawgh0e nan old; 93% male). all patients required ino for refractory hypoxaemia of whom 4 (25%) had also superimposed rv dysfunction, in 1 case associated with pulmonary embolism. the ino dosage was 25 [20-30] parts per million (ppm). respiratory parameters at t 0 and t 1 are shown in table 1 . overall, ino did not improve oxygenation in our population. only 4 (25%) patients were responders, of whom 3 ino is a free radical gas that diffuses across the alveolar-capillary membrane into the subjacent smooth muscle of pulmonary vessels enhancing endotheliumdependent vasorelaxation and improving oxygenation by increasing blood flow to ventilated lung units [3] . in previous studies, ino was effective in improving pao 2 /fio 2 and oxygenation index, although it failed in reversing acute lung injury, reducing mechanical ventilation days and mortality [4] . in our population, the improvement of oxygenation in responders was probably magnified by an ino-induced decrease of rv afterload, enhancing cardiac output and finally leading to an increase of mixed venous oxygen saturation. although the reason why patients with refractory hypoxaemia without rv dysfunction were not responder is yet to be determined, some speculation can be done. severe endothelial injury with cytoplasmic vacuolization and cell detachment in pulmonary middle-small arteries can make the pulmonary vessels less reactive to ino stimulation [1, 5, 6] . this could also explain the loss of hypoxic vasoconstriction and lung perfusion regulation. however, whether vascular derangements in covid-19 are due to endothelial cell involvement by the virus, part of the ards pathophysiology or the intertwine of both is still undetermined. moreover, prone position and ino were used in refractory hypoxaemia as an escalating treatment strategy. therefore, a positive response to the prone position may have precluded the enrolment in our study of patients that could positively respond to ino. overall, ino did not improve oxygenation in covid-19 patients with refractory hypoxaemia, when administered as a rescue treatment after prone position. a subgroup of patients with rv dysfunction was better ino responders probably due to the haemodynamic improvement associated with rv unloading. the word count of our manuscript is just beyond the limit suggested by the editorial rules as we felt that the fluency and completeness would be sacrificed in further shorten the text. however, we are willing to cut some part if strongly advised by the editorial office. management of covid-19 respiratory distress. jama. 2020. online ahead of print update in management of severe hypoxemic respiratory failure inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential inhaled nitric oxide for acute respiratory distress syndrome (ards) in children and adults time to consider histologic pattern of lung injury to treat critically ill patients with covid-19 infection endothelial cell infection and endotheliitis in covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all the nurses and physicians involved in the management of such epidemics ( all authors contributed equally to the data collection and redaction, writing and final revision before submission of the paper. the author(s) read and approved the final manuscript. no funding were received for the submitted work. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.ethics approval and consent to participate informed consent was collected following the ad hoc procedures defined by the local ethics committee of fondazione policlinico san matteo irccs for the covid-19 pandemic.competing interests fm received fees for lectures from ge healthcare, hamilton medical, seda spa, outside the present work. sm received fees for lectures from ge healthcare, outside the present work. gt received fees for lectures by ge healthcare, outside the present work. mp, vd and gr have nothing to disclose.received: 22 july 2020 accepted: 3 august 2020 key: cord-271751-46oo9xv5 authors: ingraham, nicholas e.; boulware, david; sparks, matthew a.; schacker, timothy; benson, bradley; sparks, jeffrey a.; murray, thomas; connett, john; chipman, jeffrey g.; charles, anthony; tignanelli, christopher j. title: shining a light on the evidence for hydroxychloroquine in sars-cov-2 date: 2020-04-28 journal: crit care doi: 10.1186/s13054-020-02894-7 sha: doc_id: 271751 cord_uid: 46oo9xv5 nan the 2020 covid-19 pandemic has stunned the world, financial markets, and healthcare systems. researchers are rushing to identify effective treatments while maintaining rigorous adherence to the scientific method. clinicians are doing their best to provide evidence-based care in a setting of very little good evidence. to date, no effective treatments exist for covid-19 management. unfortunately, traditional and social media coupled with world leader commentary have led some to believe hydroxychloroquine offers a bona fide cure and even prevention. the purpose of this commentary is to review the medical literature related to hydroxychloroquine building on knowledge over the past 17 years since the 2003 sars-cov epidemic. hydroxychloroquine has been used for the treatment of malaria since 1955 and is approved for the treatment of rheumatoid arthritis and lupus. currently, the potential mechanism of action for hydroxychloroquine's effect on sars-cov1 and sars-cov2 is not fully known. it is hypothesized that increases in endosomal ph may inhibit viral fusion and replication with interference in ace2 receptor glycosylation or sigma-1 receptor [1, 2] . chloroquine and hydroxychloroquine seem effective in killing sars-cov in vitro [1, 3] . recent reports show it also may be effective at killing sars-cov-2-infected cells in vitro [4] . unfortunately, effective treatments in vitro frequently do not translate in vivo and the efficacy of hydroxychloroquine is yet to be determined. pre-clinical animal (in vivo) models more accurately model human safety and efficacy and enable better prediction of translational failure into humans. chloroquine was not found to be efficacious in mouse models infected with sars-cov despite multiple dosing schedules and treatment routes [5] . to date, no pre-clinical studies have evaluated the efficacy of hydroxychloroquine in the current sars-cov-2 pandemic. a recent article published in chinese found no benefit with chloroquine in a 1:1 randomized trial with 30 patients [6] . as yet there are no published randomized controlled trials of hydroxycholoroquine in sars-cov-1 or 2. recently, a publication by gautret et al. has been touted by nonmedical public figures as proof of a cure for covid-19 [7] . this has led to significant interest in news outlets, social media, and the general public. this study was a nonrandomized, non-blinded, open label, and underpowered trial. given these limitations, it does not meet the rigor for evaluation of scientific efficacy. to illustrate, gautret et al. treated 26 patients with hydroxychloroquine (six received concomitant azithromycin) that met study inclusion criteria. the control group was subsequently made up of 16 patients who did not meet the study inclusion criteria. the primary outcome was viral load, defined by a cycle time (ct) threshold of 35. ct is the number of reverse transcription pcr cycles necessary to detect the presence of viral rna. a lower ct is associated with increased viral load. a ct greater than or equal to 35 was deemed as a negative viral titer. it was unclear whether this threshold was set a priori or post hoc. after enrollment of 42 patients, an interim analysis was conducted and published. a critical result was the exclusion of six patients from the treatment arm. one died, three decompensated requiring transfer to the icu, one withdrew from the study due to drug-related complications, and one was lost to follow-up. these patients were excluded by the authors from final analysis. the authors then compared viral titers from 20 patients that received hydroxychloroquine (or combination with azithromycin) with the 16 control patients that were ineligible to receive hydroxychloroquine. in unadjusted analyses, the authors identified significantly reduced viral titers in the hydroxychloroquine arm. no comment was made regarding the higher mortality, complication, and adverse event rate in the hydroxychloroquine group. excluding those who did poorly with hydroxychloroquine is a biased analysis that impacts the potential validity of the study. reincorporation of the 6 patients into the statistical analysis would have significantly changed the results of this study. in the hydroxychloroquine group, 5 of 26 (19.2%) of covid-19 patients suffered death, medical deterioration, or adverse event compared with 0 (0%) in the control arm (barnard's test: p = 0.07) with a number needed to harm (nnh) of 5.2. until data from randomized controlled trials are available, we suggest caution utilizing hydroxychloroquine off label for patients with covid-19. reports of overdoses are now occurring. there are currently no evidence supporting hydroxychloroquine as prophylaxis, but unfortunately these data are being extrapolated to the indication potentially resulting in drug shortages for patients with rheumatic diseases who require this medication. furthermore, we caution medical and world leaders against premature comments of treatment efficacy during the covid-19 pandemic. such comments may exacerbate shortages for patients reliant on these medications or cause harm due to medication side effects and overdose [8] . chloroquine is a potent inhibitor of sars coronavirus infection and spread a sars-cov-2-human proteinprotein interaction map reveals drug targets and potential drugrepurposing design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro evaluation of immunomodulators, interferons and known in vitro sars-cov inhibitors for inhibition of sars-cov replication in balb/c mice preliminary study of hydroxychloroquine sulfate in treating common coronavirus disease (covid-19) patients in 2019 hydroxychloroquine and azithromycin as a treatment of covid-19: preliminary results of an open-label nonrandomized clinical trial nigeria reports chloroquine poisonings after trump praised drug publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. all authors significantly contributed to developing, writing, and revising this manuscript. all authors read and approved the final manuscript.funding nicholas e. ingraham is supported by the nih nhlbi t32hl07741 grant.availability of data and materials not applicable. this manuscript did not require ethics approval or consent. not applicable. 1. cjt: pi for 2 rcts investigating arbs in the treatment of covid-19 among inpatient and outpatients. cois for these trials include nei, ts, and jgc. 2. db is the pi for an rct investigating hcq as prophylaxis for high-risk individuals with recent exposure to covid-19. 3. jas: site pi of a phase 2 rct investigating hcq for the prevention of rheumatoid arthritis (funded by nih/niaid/autoimmune centers of excellence) and has performed consultancy for bristol-myers squibb, gilead, inova, janssen, and optum unrelated to this work. key: cord-003832-q1422ydi authors: koyama, kansuke; katayama, shinshu; tonai, ken; shima, jun; koinuma, toshitaka; nunomiya, shin title: biomarker profiles of coagulopathy and alveolar epithelial injury in acute respiratory distress syndrome with idiopathic/immune-related disease or common direct risk factors date: 2019-08-19 journal: crit care doi: 10.1186/s13054-019-2559-6 sha: doc_id: 3832 cord_uid: q1422ydi background: altered coagulation and alveolar injury are the hallmarks of acute respiratory distress syndrome (ards). however, whether the biomarkers that reflect pathophysiology differ depending on the etiology of ards has not been examined. this study aimed to investigate the biomarker profiles of coagulopathy and alveolar epithelial injury in two subtypes of ards: patients with direct common risk factors (dards) and those with idiopathic or immune-related diseases (iards), which are classified as “ards without common risk factors” based on the berlin definition. methods: this retrospective, observational study included adult patients who were admitted to the intensive care unit (icu) at a university hospital with a diagnosis of ards with no indirect risk factors. plasma biomarkers (thrombin–antithrombin complex [tat], plasminogen activator inhibitor [pai]-1, protein c [pc] activity, procalcitonin [pct], surfactant protein [sp]-d, and kl-6) were routinely measured during the first 5 days of the patient’s icu stay. results: among 138 eligible patients with ards, 51 were excluded based on the exclusion criteria (n = 41) or other causes of ards (n = 10). of the remaining 87 patients, 56 were identified as having dards and 31 as having iards. among the iards patients, tat (marker of thrombin generation) and pai-1 (marker of inhibited fibrinolysis) were increased, and pc activity was above normal. in contrast, pc activity was significantly decreased, and tat or pai-1 was present at much higher levels in dards compared with iards patients. significant differences were also observed in pct, sp-d, and kl-6 between patients with dards and iards. the receiver operating characteristic (roc) analysis showed that areas under the roc curve for pc activity, pai-1, pct, sp-d, and kl-6 were similarly high for distinguishing between dards and iards (pc 0.86, p = 0.33; pai-1 0.89, p = 0.95; pct 0.89, p = 0.66; and sp-d 0.88, p = 0.16 vs. kl-6 0.90, respectively). conclusions: coagulopathy and alveolar epithelial injury were observed in both patients with dards and with iards. however, their biomarker profiles were significantly different between the two groups. the different patterns of pai-1, pc activity, sp-d, and kl-6 may help in differentiating between these ards subtypes. electronic supplementary material: the online version of this article (10.1186/s13054-019-2559-6) contains supplementary material, which is available to authorized users. acute respiratory distress syndrome (ards) comprises acute-onset respiratory failure, which is characterized by hypoxemia and radiographic bilateral lung opacities that result from various direct or indirect injuries to the pulmonary parenchyma or vasculature [1] . the most recent berlin definition provides common risk factors for ards, which are classified as direct factors (e.g., pneumonia, aspiration of gastric contents) or indirect factors (e.g., nonpulmonary sepsis, major trauma, pancreatitis) [2] . some patients presenting with ards, however, lack exposure to common risk factors, resulting in the condition called an ards "imitator" or "mimic" [3, 4] . in a large cohort study, gibelin et al. reported a 7.5% prevalence of ards without a common risk factor [5] . a secondary analysis of the lung safe study confirmed that 8.3% of ards patients had no common risk factors that were identified when ards was recognized [6] . these ards patients who lacked exposure to common risk factors can be categorized as having immune, idiopathic, drug-induced, and malignant diseases [6, 7] . connective tissue disease-associated interstitial lung disease (ctd-ild) is considered to be a main cause of immune-related forms of ards. ctd-ild may precede the clinical and laboratory manifestations of ctd and therefore could present as lone ards [8] . acute onset or acute exacerbation of idiopathic interstitial lung diseases may refer to idiopathic forms of ards. although no risk factors or causes are identified in this subgroup of ards, recent studies have shown that many patients with idiopathic interstitial pneumonia have clinical features that suggest an underlying immune process, indicating that the pathobiology of idiopathic and immunerelated diseases may partially overlap [9, 10] . early identification of these subsets of ards based on the pathophysiology is of clinical interest and may lead to the development of specific therapeutic intervention. however, the lesions of these idiopathic and immune-related ards may be mostly limited to the lung, and it is often difficult in the acute phase to distinguish between idiopathic/immune-related diseases and ards with common direct risk factors, based solely on the clinical findings. activation of coagulation and alveolar epithelial injury are the hallmarks of ards (fig. 1) [11, 12] . the biomarkers may reflect activation and injuries of different cell populations in the lung and thereby help to improve the understanding about pathogenic processes and to improve diagnostics. thrombin-antithrombin complex (tat) levels are increased in ards patients, reflecting tissue factor-and contact phase-mediated activation of coagulation cascade and excessive thrombin generation. thrombin and proinflammatory cytokines activate endothelial cells, leading to expression of plasminogen activator inhibitor (pai)-1, which inhibits fibrinolysis. the levels of natural anticoagulants such as protein c (pc) are reduced because of increased consumption, impaired synthesis, and mostly capillary leakage that results from endothelial damage. surfactant protein (sp)-d and a membrane glycoprotein kl-6 are also increased in the plasma of ards patients, reflecting type ii alveolar cell injury [13, 14] . the alterations in biomarkers that indicate thrombin generation, inhibited fibrinolysis, decreased anticoagulant, and epithelial injury are distinctive patterns of ards. however, whether these biomarker profiles may differ depending on the ards etiologies has not been examined. the aim of this study was to examine the profiles of the plasma biomarkers that reflect coagulopathy and alveolar epithelial injury in patients with idiopathic/immune-related ards (iards) and in those with common direct risk factors (dards). we investigated the baseline levels and time courses of hemostatic and type ii pneumocyte biomarkers and compared the discriminative ability of those biomarkers between iards and dards. we also evaluated the biomarkers in patients with unilateral pneumonia who were admitted during the same period for reference purposes. this single-center, retrospective, observational study was conducted at a 14-bed medicosurgical intensive care unit (icu) at jichi medical university hospital (tochigi, japan). medical records for all patients admitted to the icu between april 2011 and march 2018 were reviewed. adult patients admitted because of ards without indirect risk factors or unilateral pneumonia who underwent invasive mechanical ventilation within 48 h of admission were included in the study. exclusion criteria were age < 18 years, > 1 week of respiratory disease progression before icu admission, previously known interstitial pneumonia or ipf, or a diagnosis of pneumocystis pneumonia. we also excluded patients with bone marrow failure, decompensated liver cirrhosis or failure, a history of chemotherapy, therapeutic anticoagulation, or blood transfusion during the preceding 4 weeks. the institutional research ethics committee at jichi medical university approved this study and waived the requirement for informed consent because of the study's retrospective design. the ards without indirect risk factors was diagnosed according to the berlin definition with the following criteria: within 1 week of new or worsening respiratory symptoms, bilateral lung opacities were found on chest radiography, and the pao 2 /f i o 2 ratio was ≤ 300 mmhg with a positive end-expiratory pressure of ≥ 5 cmh 2 o. additionally, no cardiac failure or fluid overload and no common indirect risk factors for ards, such as nonpulmonary sepsis, major trauma, or pancreatitis could be found [2] . direct lung injury risk factors were defined as pneumonia, aspiration of gastric contents, pulmonary contusion, inhalation injury, and near drowning, based on the berlin definitions. patients with vasculitis were classified as having ards without common risk factors because vasculitis is not pathologically characterized by diffuse alveolar damage (dad). the diagnosis of pneumonia was based on infectious diseases society of america/american thoracic society consensus guidelines combined with clinical data and microbiological diagnostic testing (including a blood culture, sputum culture, or culture of endotracheal aspirate, and a urinary antigen test for streptococcus pneumoniae and legionella pneumophila) [15, 16] . bronchoalveolar lavage (bal) fluid for gram staining and culture, direct fluorescence assay for pneumocystis jirovecii, and a rapid influenza a/b diagnostic test (immunochromatographic assays for specific influenza viral antigens) were also performed, as needed. ards without common risk factors were separated into four etiological groups, as described below [7] . idiopathic ards was defined as the absence of any ards etiology including common risk factors despite a comprehensive diagnostic work-up, or acute presentation of idiopathic interstitial pneumonia [17] . immunerelated ards was defined as an acute presentation of ctd-ild as defined in accordance with established ctd criteria (e.g., american college of rheumatology criteria [18] ) during hospitalization, or hypersensitive pneumonitis [19] . malignancy-associated ards was defined as requiring cytological or pathological evidence of hematological or solid malignancy. drug-induced ards was defined as previous exposure to a drug that is known to be a pneumonia inducer in the absence of any other risk factor for ards [20] . descriptive data (including demographic, diagnostic, clinical, and laboratory data) were collected from the electronic medical records of all eligible patients. initial severity indices, including the acute physiology and chronic health evaluation (apache) ii and simplified acute physiology score (saps) ii, were calculated on the day of icu admission [21, 22] . sequential organ failure assessment (sofa) scores were calculated during the first 7 days [23] . clinical outcomes were assessed according to icu days, ventilator-free days, and allcause 28-and 90-day mortality. for the patients with idiopathic and immune-related ards, bal fluid cytological analysis and autoimmunity tests were extracted from the medical charts when available. at our institute, the biomarkers of coagulation and type ii pneumonocytes are routinely measured for the patients who are admitted to the icu with respiratory failure and/or with suspected sepsis. plasma biomarkers were measured at the time of icu admission (icu day 1) and on icu days 2-5. coagulation and fibrinolytic markers included global markers (platelet count, immature platelet fraction, prothrombin time-international normalized ratio [pt-inr], fibrin degradation product [fdp]), markers of thrombin generation (tat), markers of anticoagulant activity (pc activity), and markers of fibrinolytic activity (plasmin-α 2 -plasmin inhibitor complex [pic], pai-1). global markers were assayed using an xe-5000 hematology analyzer (sysmex, kobe, japan) and a cs-2100i automatic coagulation analyzer (sysmex). berichrom assays (siemens healthcare diagnostics, tokyo, japan) were used to assay pc activity. the tat/pic test f enzyme immunoassay (sysmex) was used to measure tat and pic levels. the pai-1 was measured using the tpai test (mitsubishi chemical medience, tokyo, japan). surfactant protein (sp)-d, kl-6, c-reactive protein (crp), and procalcitonin (pct) were measured using the sp-d kit enzyme immunoassay (yamasa, chiba, japan), presto ii kl-6 chemiluminescent enzyme immunoassay (sekisui medical, tokyo, japan), crp-hg latex immunoassay (eiken kagaku, tokyo, japan), and brahms pct chemiluminescent enzyme immunoassay (roche diagnostic, tokyo, japan), respectively. differences in clinical characteristics and laboratory data among the groups were analyzed using the χ 2 test or fisher's exact test for categorical variables and the wilcoxon rank-sum test or kruskal-wallis test with/without steel-dwass pairwise comparisons for continuous variables, as appropriate. changes in the biomarker concentrations over time in the groups were compared with multiple analysis of variance. a multivariate logistic regression model based on a forward stepwise method was used to identify the best combination of coagulation biomarkers to diagnose iards. receiver operating characteristic (roc) curve analysis was performed to calculate the area under the receiver operating characteristic curve (auc) of the biomarkers at day 1 to evaluate the discriminative capacity between the two groups. all p values were two-tailed, and p < 0.05 was considered to indicate statistical significance. data were analyzed using jmp version 12 (sas institute, tokyo, japan). overall, 138 ards patients with no indirect risk factors were admitted to the icu during the study period. among them, 41 were excluded based on the exclusion criteria: history of known interstitial pneumonia, 5; pneumocystis pneumonia, 8; hematological malignancy with bone marrow failure, 10; liver failure, 2; anticoagulation therapy, 7; inconclusive diagnosis, 4; and insufficient data, 5. data from the remaining 97 patients were included in the study. in addition, 39 patients who were admitted to the icu with unilateral pneumonia during the same period were enrolled for comparison. among the 97 patients with pulmonary ards, 56 had been exposed to direct lung injury risk factors and 41 had not been exposed to any of the common risk factors. the direct risk factors of lung injury included pneumonia (42; 75.0%), aspiration (13; 23.2%), and drowning (1; 1.8%). the 41 ards patients without common risk factors were classified as idiopathic (17; 41.5%), immunerelated (14; 34.1%), malignancy-associated (7; 17.1%), and drug-induced (3; 7.3%). table 1 shows the baseline characteristics and outcomes of the study patients with iards and dards and those with unilateral pneumonia. patients with dards were more severely ill, with higher apache ii, saps ii, and sofa scores on icu admission compared with patients with iards. the pao 2 /f i o 2 ratio on admission and the severity of ards, however, were not different between patients with dards and those with iards. ventilator-free days, length of icu stay, and mortality were also similar for the two groups. the distribution of pathogens in patients with dards and those with pneumonia are shown in additional file 1: table s1 . in patients with dards, the most common causative microorganisms were klebsiella pneumoniae (17.9%), followed by streptococcus pneumoniae (12.5%) and methicillin-susceptible staphylococcus aureus (10.7%). among the 31 patients with iards, 17 (54.8%) were diagnosed with idiopathic ards and 14 (45.2%) with immune-related ards, which included the following: rheumatoid arthritis (n = 5), dermatomyositis (n = 3), systemic lupus erythematosus (n = 2), scleroderma (n = 1), microscopic polyangiitis (n = 1), granulomatosis with polyangiitis (n = 1), and hypersensitivity pneumonitis (n = 1). table 2 shows the bal findings and autoantibodies in patients with iards. in about half of these patients (idiopathic, 62.5%; immune-related, 42.9%), neutrophils and lymphocytes were both elevated in bal fluid, showing a mixed cellular pattern (defined as neutrophil > 3% and lymphocyte > 15% on bal differential cell counts). antinuclear antibody was positive (with > 1:160 titers) in 64.3%, and anticyclic citrullinated peptide antibody was positive in 35.7% of the patients with immune-related ards. notably, 23.5% of the patients with idiopathic ards were positive for autoantibodies against aminoacyl-trna synthetase. data are expressed as the median (interquartile range) or n (%) ihd ischemic heart disease, chf chronic heart failure, copd chronic obstructive pulmonary disease, ckd chronic kidney disease, cvd cerebrovascular disease, apache acute physiology and chronic health evaluation, saps simplified acute physiology score, sofa sequential organ failure assessment, peep positive end-expiratory pressure *comparison between patients with direct risk factor-associated ards and idiopathic/immune-related ards **comparison among the three groups. italic numbers indicate statistical significance groups. the tat levels were increased in the three groups, but those levels were much lower in iards patients compared with dards patients on day 1 (9. pct levels (marker of infection) on day 1 were increased in the dards and pneumonia patients but were lower than the reference value for infection in patients with iards. however, levels of crp, a widely used marker of inflammation and mechanistically downstream of il-6, were not different among the three groups. the markers of type ii pneumocyte injury, sp-d, and kl-6 were markedly increased in patients with iards compared with those with dards or pneumonia (figs. 4 and 5) . to compare the abilities of the plasma biomarkers to distinguish between ards subtypes, we conducted a roc curve analysis to calculate the aucs of biomarkers for coagulation, infection, and pneumocytes ( in this retrospective analysis of ards subtypes, we evaluated the changes in coagulation and alveolar epithelial cell biomarkers over time in patients with iards and dards. tat and pai-1 levels were increased in patients in both ards subgroups, but a significantly higher increase in those biomarkers were observed in patients with dards. additionally, pc activity decreased in dards, whereas that in iards was normal or even increased. there were also significant differences in pct, sp-d, and kl-6 levels between the two groups on the day of icu admission. these results suggest that each iards and dards may have its distinct patterns of plasma biomarkers, which could help to differentiate between these ards subgroups. alterations in coagulation and fibrinolytic abnormalities have been observed in animal models of lung injury and in human patients with ards or ild [24] [25] [26] . chambers reported that uncontrolled activation of the coagulation cascade might contribute to the development of fibrosis in both ards and ipf, suggesting that coagulopathy is pivotal as a common pathophysiological factor in these diseases [27] . in our study, increased coagulation (suggested by increased tat) and suppressed fibrinolysis (suggested by elevated pai-1 levels) were observed in patients with dards but were less prominent in iards patients. these results are in line with gunther et al.'s study that showed enhanced procoagulant and depressed fibrinolytic capacities were greater in patients with ards than in those with pneumonia or in healthy controls [28, 29] . in addition, there were significant differences in coagulation inhibition or the levels of natural anticoagulant between dards and iards. to the best of our knowledge, this is the first study to show differences in the coagulation profile between ards with and without common risk factors, or ards mimics. the pathophysiology accounting for these different coagulopathic patterns has not been identified. one explanation might be that inflammation and coagulopathy fig. 3 changes in coagulation biomarkers during days 1-5 in the intensive care unit (icu) for patients with iards, dards, or pneumonia. pt-inr, prothrombin time-international normalized ratio; fdp, fibrin degradation products; tat, thrombin-antithrombin complex; pic, plasmin-α 2plasmin inhibitor complex; pai-1, plasminogen activator inhibitor-1. data are expressed as the mean, with the 95% confidence interval shown by the error bars are relatively limited to the lung in iards, whereas dards is a more systemic disease. although the cause of dards is direct lung injury, indicators of systemic involvement, reflected in the apache ii or sofa scores, were significantly higher in patients with dards compared with those with iards. another possible mechanism might be explained by the different pathological findings of iards and dards. lorente et al. showed that ards patients with dad had higher pt-inr and lower platelet counts than ards patients without dad [30] . pc activities were within the normal range or even increased in iards patients, whereas those in dards patients remained significantly decreased throughout the observational period. these results are somewhat consistent with the meta-analysis conducted by terpstra et al., which showed that the pc level was decreased in ards and was associated with increased odds for an ards diagnosis [14] . in the presence of sepsis or ards, anticoagulation pathways, such as the pc system, are impaired because of increased consumption, decreased protein synthesis, extravasation from vessels, and degradation by several proteolytic enzymes. particularly, extravascular leakage resulting from endothelial damage may be the main mechanism during the acute phase [31, 32] . decreased pc activity in dards patients, therefore, may reflect systemic endothelial dysfunction. in contrast, bargagli et al. reported that pc activity increased during acute exacerbation of usual ip but was normal in stable usual ip or nsip [33] . they postulated that increased pc activity was associated with upregulation of the fibrinolytic response to a procoagulant state caused by fibrosis. although the pathophysiological mechanisms of altered pc activity in patients with ards have not been clarified, our findings indicate that the differences in the anticoagulant response to increased coagulation may be useful for distinguishing the ards etiologies. we analyzed idiopathic and immune-related ards within the same category, although these two disorders are classified as having different etiologies. idiopathic interstitial pneumonias (iips) are diffuse inflammatory lung diseases that are grouped together with similar clinical, radiological, and histopathological features. the diagnosis of an iip is based on the exclusion of known causes of ip, such as drugs, environmental exposure, or ctds [17] . ctd-ilds are the lung manifestation of ctds, where the underlying mechanism is systemic autoimmunity. thus, the diagnosis is based on specific extra-thoracic features of ctds with/without the existence of autoantibodies. recent studies have shown, however, that some patients with ild have certain clinical features that suggest an underlying autoimmune process, although they do not fully meet the diagnostic criteria for any characterizable ctd. the european respiratory society/american thoracic society task force on undifferentiated forms of connective tissue disease-associated interstitial lung disease proposed the term "interstitial pneumonia with autoimmune features" for such diseases [9] . in our study, approximately 20% of the idiopathic ards patients were diagnosed as having antisynthetase syndrome without myositis or arthritis and 10% were positive for anticyclic citrullinated peptide antibody. the biomarker profiles were similar in patients with idiopathic ards and those with immune-related ards, which indicates overlapping pathophysiology of coagulopathy and epithelial injury in these two subsets. sp-d and kl-6, which are glycoproteins secreted by type ii alveolar epithelial cells, are widely used as potential surrogate markers of alveolar injury, or alveolitis. the roles of sp-d and kl-6 are well established for improving diagnostic accuracy, predicting the prognosis, or predicting the risk of acute exacerbation, especially in patients with nsip or ipf [13, 34, 35] . sp-d and kl-6 are also known to be elevated in ards patients [14, 36] , but no published reports have compared the biomarker levels according to different ards etiologies. using data from korea and the usa, park et al. showed that plasma sp-d levels were there were some potential limitations to our study. first, this was a retrospective, observational study conducted at a single center with a relatively small population. a large validation study is needed to confirm our results. second, we could not perform serological tests for non-influenza respiratory viruses, such as the respiratory syncytial virus or human metapneumovirus. although we ruled out the common ards risk factors and known causes of interstitial pneumonia (e.g., drugs, environmental agents, ctds) to diagnose idiopathic ards, we could not completely exclude the possibility of viral infections or environmental antigen exposures, which could subside spontaneously. third, we could perform bal for only about half of iards patients, which may not be generalizable to the whole population. finally, we did not measure the biomarkers in the bal fluid. although systemic markers are easier to obtain and the bal procedure may not always be possible because of the risk of respiratory and hemodynamic complications, the biomarkers in the bal fluid would more specifically reflect the regional pathophysiology in the alveoli. further studies are needed to evaluate the pathogenic processes of these biomarkers from the pulmonary compartment to the circulation. changes in the biomarkers of coagulopathy and alveolar epithelial injury were observed in both patients with dards and with iards, but those biomarker profiles were significantly different between the two groups. pai-1 and pc activity, as well as pct, sp-d, and kl-6, discriminated well between dards and iards on the day of icu admission. these preliminary findings indicate that the biomarker profiles may help to understand the pathogenic processes and improve the prompt differentiation between ards subtypes. additional file 1: table s1 . distribution of microorganisms in patients with dards or pneumonia. 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pneumonitis drugassociated acute lung injury: a population-based cohort study apache ii: a severity of disease classification system a new simplified acute physiology score (saps ii) based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine acute respiratory distress syndrome and diffuse alveolar damage. new insights on a complex relationship coagulation, fibrinolysis, and fibrin deposition in acute lung injury tissue factor expression and fibrin deposition in the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. comparison with the acute respiratory distress syndrome acute respiratory distress syndrome in patients with and without diffuse alveolar damage: an autopsy study decreased plasma activity of antithrombin or protein c is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation decreased antithrombin activity in the early phase of trauma is strongly associated with extravascular leakage, but not with antithrombin consumption: a prospective observational study serum analysis of coagulation factors in ipf and nsip idiopathic pulmonary fibrosis: from epithelial injury to biomarkers--insights from the bench side pneumocyte biomarkers kl-6 and surfactant protein d reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia pathophysiology and biomarkers of acute respiratory distress syndrome plasma surfactant protein-d as a diagnostic biomarker for acute respiratory distress syndrome: validation in us and korean cohorts we appreciate the assistance of the nursing staff at the intensive care unit at jichi medical university hospital, tochigi, japan. we thank nancy schatken, bs, mt (ascp), and jodi smith, phd, from edanz group (http://www. edanzediting.com/), for editing a draft of this manuscript. authors' contributions kk contributed to the conception and design, data acquisition, analysis and interpretation of the data, and writing and drafting of the manuscript. sk and kt contributed to the patient recruitment, data acquisition, analysis, and review of the manuscript. tk and js helped review the draft manuscript. sn supervised the study and reviewed the manuscript. all authors read and approved the final manuscript. the study was not funded. the dataset generated and/or analyzed during the current study is not publicly available because of patient-related confidentiality, but is available from the corresponding author upon reasonable request. this study was approved by the institutional research ethics committee of jichi medical university. informed consent was waived based on the study's retrospective, observational design, which preserves the confidentiality of personal information. not applicable. the authors declare that they have no competing interests. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-276561-b4cspbuf authors: liaudet, lucas; szabo, csaba title: blocking mineralocorticoid receptor with spironolactone may have a wide range of therapeutic actions in severe covid-19 disease date: 2020-06-08 journal: crit care doi: 10.1186/s13054-020-03055-6 sha: doc_id: 276561 cord_uid: b4cspbuf nan blocking mineralocorticoid receptor with spironolactone may have a wide range of therapeutic actions in severe covid-19 disease lucas liaudet 1* and csaba szabo 2 the pulmonary renin angiotensin (ang) system (ras) comprises two pathways whose balance is important for lung homeostasis. endothelial ace generates ang ii, acting on at1 receptors to promote vasoconstriction and pro-inflammatory effects, whereas epithelial ace2 cleaves ang ii into ang1-7, acting on the mas receptor to exert vasodilatory and anti-inflammatory effects. a shift towards predominant ace-dependent ang ii formation has been postulated as an important pathophysiological mechanism in various forms of ards [1] . sars-cov-2 uses lung ace2 as its cellular receptor, resulting in ace2 degradation and ace/ace2 imbalance, which could drive ang ii-mediated vascular inflammation and lung injury in severe covid-19 disease [1] . furthermore, ang ii induces the release of aldosterone, which can promote further vascular damage via mineralocorticoid receptor (mr) activation [2] . aldosterone also exerts multiple actions on immune cells, which express the mr [3] . mr activation polarizes macrophages towards the m1 proinflammatory phenotype. in lymphocytes, mr activation promotes the differentiation of pro-inflammatory th17 cd4 + cells and of cytotoxic ifnγ + -cd8 + t cells ( fig. 1 ), indicating that mr activation in immune cells promotes a hyperinflammatory profile [3] . it is particularly noticeable that th17 t cells increase and high cd8 + cells cytotoxicity have been proposed to be involved in the hyperinflammatory state characterizing covid-19 ards [4] . signaling with enhanced aldosterone-mediated mr activation could represent an important link between sars-cov-2/ace2 interaction and inflammatory lung injury, suggesting an interesting therapeutic potential of ras inhibitors [1] and in particular mr antagonists. however, it has been claimed that ras inhibitors could enhance ace2 expression, which might represent a possible drawback of this therapeutic strategy, as this might influence sars-cov-2 infectivity [1] . importantly, in contrast to other ras inhibitors, the mr antagonist spironolactone also possesses significant antiandrogenic actions [5] . such effects may be particularly useful in the context of sars-cov-2 infection, by inhibiting the androgen-dependent expression of tmprss2, a transmembrane protease crucial for viral entry through its priming effect on the viral s protein [5] . therefore, by its dual actions as an mr antagonist and an androgenic inhibitor, spironolactone might provide significant benefits in covid-19 ards. naturally, the primary action of spironolactone (reduction of pulmonary edema) would also be beneficial in covid-19 ards. thus, we hypothesize that through its combined pharmacological actions, spironolactone may provide therapeutic benefit, when applied in the later stage of covid-19 ards. clinical trials may be warranted to evaluate its therapeutic potential. fig. 1 sites of potential pharmacological actions of spironolactone in covid-19 ards. sars-cov-2 infects type ii alveolar epithelial cells (type ii aec) via interaction between its spike s protein and ace2 receptor, promoting internalization and degradation of ace2 and pulmonary ace/ace2 imbalance. in turn, the degradation of angiotensin ii (at ii) into angiotensin 1-7 (at 1-7 ) is prevented (dotted lines), reducing anti-inflammatory signaling through the mas receptor (masr), and promoting pro-inflammatory at ii signaling through the angiotensin receptor type i (at1r) in vascular endothelial cells. increased at ii results in aldosterone formation, which signals through the mineralocorticoid receptor (mr), leading to vascular inflammation and immune cells activation. mr activation polarizes macrophages towards the m1 pro-inflammatory phenotype (m1mϕ), favors cd4 + lymphocytes differentiation towards pro-inflammatory th17 cells, and induces cytotoxic ifnγ + -cd8 + lymphocytes. the development of a hyper-inflammatory state may trigger ards. mr inhibition with spironolactone may interrupt the deleterious actions of aldosterone. furthermore, via its anti-androgenic effects, spironolactone may decrease the expression of tmprss2, a serine protease priming the s protein for its interaction with ace2. abbreviations: ace, angiotensin-converting enzyme; andr, androgen receptor; at i, angiotensin i; at ii, angiotensin ii; at 1-7 , angiotensin 1-7; at1r, angiotensin receptor type i; mr, mineralocorticoid receptor; masr, mas receptor; no, nitric oxide; ros, reactive oxygen species; tmprss2, transmembrane serine protease 2 controversies of renin-angiotensin system inhibition during the covid-19 pandemic vascular mineralocorticoid receptor: evolutionary mediator of wound healing turned harmful by our modern lifestyle the role of the mineralocorticoid receptor in inflammation: focus on kidney and vasculature pathological findings of covid-19 associated with acute respiratory distress syndrome tmprss2 transcriptional inhibition as a therapeutic strategy for covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-255216-87ursh0s authors: de castro, isabel fernández; guzmán-fulgencio, maría; garcía-álvarez, mónica; resino, salvador title: first evidence of a pro-inflammatory response to severe infection with influenza virus h1n1 date: 2010-02-11 journal: crit care doi: 10.1186/cc8846 sha: doc_id: 255216 cord_uid: 87ursh0s the great majority of infections caused by the pandemic variant of the influenza virus (nvh1n1) are self-limited, but a small percentage of patients develop severe symptoms requiring hospitalization. bermejo-martin and colleagues have presented a pilot study describing the differences in the early immune response for patients both mildly and severely infected with nvh1n1. patients who develop severe symptoms after nvh1n1 infection showed th1 and th17 'hypercytokinemia', compared to mildly infected patients and healthy controls. the mediators involved with the th1 and th17 profiles are known to be involved in antiviral, pro-inflammatory and autoimmune responses. this is the first work reporting the association of a pro-inflamatory immune response with a severe pandemic infection, although it is likely that more studies are needed to understand the detrimental or beneficial roles these cytokines play in the evolution of mild and severe nvh1n1 infection. by analyzing 29 cytokines and chemokines and the hemagglutination inhibition activity, bermejo-martin and colleagues [1] assessed the early host innate and adaptive immune responses in patients both mildly and severely infected with nvh1n1. while infection with nvh1n1 induces a typical innate response in both mild and severe cases, severe infections with respiratory involvement are characterized by an early secretion of th 17 and th 1 cytokines. th us, hospitalized patients tend to show high systemic levels of mediators that stimulate th 17 (il-8, il-9, il-17, il-6) and th 1 responses (ifn-γ, tnf-α, il-15, il-12p70) [1] . based on this fi nding, this study was able to highlight similarities between the cytokine response to severe h1n1 infection and the pathogenesis of asthma and some autoimmune diseases. th e th 1 response is primarily involved with host immune defense against intracellular pathogens by activating cellular immunity. th is response is eff ective in eradicating infectious agents such as viruses [3] . indeed, th 1 cells produce ifn-γ and cytokines that are involved in monocyte/macrophage-mediated infl ammatory respon ses [4] . when the th 1 response is exhaustively prolonged, it may result in host damage. moreover, other authors have reported that th 1-dominated responses may be implicated in the pathogenesis of autoimmune disorders and chronic infl ammatory diseases [5] . bermejo-martin and colleagues [1] found il-15, il-12p70, and il-6 to be particularly elevated following severe nvh1n1 infection. th ese three cytokines are known to mediate both antiviral and pro-infl ammatory responses. th e authors [1] also found a signifi cant inverse relationship of il-6 and il-8 with the pressure of oxygen in arterial blood in severely infected patients. interestingly, previous studies had already reported high levels of specifi c proinfl ammatory cytokines and chemokines in severe sars coronavirus, h5n1 and respiratory syncytial virus infections [6] [7] [8] [9] [10] [11] . th 17 cells are required for host defense against intracellular pathogens [12] . th 17 promotes infl ammation by inducing various pro-infl ammatory cytokines and chemo kines, recruiting neutrophils, enhancing antibody production, and activating t cells [12] . th 17 cells secrete the great majority of infections caused by the pandemic variant of the infl uenza virus (nvh1n1) are self-limited, but a small percentage of patients develop severe symptoms requiring hospitalization. bermejo-martin and colleagues have presented a pilot study describing the diff erences in the early immune response for patients both mildly and severely infected with nvh1n1. patients who develop severe symptoms after nvh1n1 infection showed th1 and th17 'hypercytokinemia' , compared to mildly infected patients and healthy controls. the mediators involved with the th1 and th17 profi les are known to be involved in antiviral, pro-infl ammatory and autoimmune responses. this is the fi rst work reporting the association of a pro-infl amatory immune response with a severe pandemic infection, although it is likely that more studies are needed to understand the detrimental or benefi cial roles these cytokines play in the evolution of mild and severe nvh1n1 infection. il-17, il-17f, and il-22, thereby inducing a massive tissue reaction. also, these cells secrete il-21 to communicate with the cells of the immune system [13] . however, uncontrolled production of these cytokines induces tissue damage in infected tissues [12] . in addition, th 17 cells have a well-known role in clearing pathogens during infections and inducing tissue infl ammation in autoimmune disease [13] . interestingly, the key role of il-17 and its receptor in the immunopathology of infl uenza infection in a mouse model has just recently been reported [14] . taken together, these fi ndings show that severe pandemic h1n1 infection is characterized by early elevation of key immune pro-infl ammatory mediators participating in both th 1 and th 17 infl ammatory responses. th is pro-infl ammatory response may be the cause of the severe respiratory symptoms caused by nvh1n1 infection. however, the authors also provide an alternative version of the story: th 1 and th 17 cytokines may refl ect a vigorous antiviral host response necessary for viral clearance. th is article [1] is the fi rst that describes an association between severe infl uenza infection and a th 17 response in humans. th e researchers correctly bring up the fact that a better understanding of the immune response to the new h1n1 virus could contribute to the design of more eff ective therapies. similarly, the results of this study reinforce the importance of early treatment with antivirals in those patients with high risk factors, such as pregnancy, asthma, and obesity, among others, to avoid triggering unwanted infl ammatory phenomena, which could explain the appearance of pneumonia in these patients. th e results of this work also support the study of drugs that modulate the immune response in the treatment of this disease [15] . moreover, the study of genetic polymorphisms of relevant genes involved in the development of th 1 and th 17 immune responses in severely infected patients could be of interest, since these polymorphisms could strongly infl uence gene expression. further studies would help to understand the harmful or benefi cial roles that these cytokines play in the evolution of mild and severe nvh1n1 infection. but this report confi rms that th 1 and th 17 responses are distinctive hallmarks of severe respiratory compromise following nvh1n1 infection. th1 and th17 hypercytokinemia as early host response signature in severe pandemic infl uenza europe's initial experience with pandemic (h1n1) 2009 -mitigation and delaying policies and practices th1/th2 cells. infl amm bowel dis revisiting the th1/th2 paradigm th1 and th2 in human diseases arranz e: persistence of proinfl ammatory response after severe respiratory syncytial virus disease in children gene expression analysis of host innate immune responses during lethal h5n1 infection in ferrets human immunopathogenesis of severe acute respiratory syndrome (sars) dj: interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome fatal outcome of human infl uenza a (h5n1) is associated with high viral load and hypercytokinemia molecular pathogenesis of infl uenza a virus infection and virus-induced regulation of cytokine gene expression the roles of il-17a in infl ammatory immune responses and host defense against pathogens il-17 and th17 cells critical role of il-17ra in immunopathology of infl uenza infection macrolides for the treatment of severe respiratory illness caused by novel h1n1 swine infl uenza viral strains this work was supported by grants from instituto de salud carlos iii (pi08/0738; uipy 1467/07) to sr. mg-f is supported by a grant of instituto de salud carlos iii (cm09/00031). mg-a is supported by a grant of instituto de salud carlos iii (cm08/00101). the authors declare that they have no competing interests.published: 11 february 2010 key: cord-048449-mzn448zk authors: challen, kirsty; bentley, andrew; bright, john; walter, darren title: clinical review: mass casualty triage – pandemic influenza and critical care date: 2007-04-30 journal: crit care doi: 10.1186/cc5732 sha: doc_id: 48449 cord_uid: mzn448zk worst case scenarios for pandemic influenza planning in the us involve over 700,000 patients requiring mechanical ventilation. uk planning predicts a 231% occupancy of current level 3 (intensive care unit) bed capacity. critical care planners need to recognise that mortality is likely to be high and the risk to healthcare workers significant. contingency planning should, therefore, be multi-faceted, involving a robust health command structure, the facility to expand critical care provision in terms of space, equipment and staff and cohorting of affected patients in the early stages. it should also be recognised that despite this expansion of critical care, demand will exceed supply and a process for triage needs to be developed that is valid, reproducible, transparent and consistent with distributive justice. we advocate the development and validation of physiological scores for use as a triage tool, coupled with candid public discussion of the process. it is widely accepted that conditions exist for the evolution of a new strain of influenza virus with the potential to cause a human pandemic [1] . the biggest challenge in planning for an influenza pandemic is the range of unknown factors; its nature and impact cannot be fully predicted until the pandemic virus actually emerges. those planning for a pandemic must, therefore, work from a number of assumptions based on knowledge gained from previous pandemics and scientific modelling of a range of potential scenarios. the uk pandemic influenza plan [2] sets out a range of possible scenarios for clinical attack rates and case fatality rates during a pandemic, including the potential for more than one wave. the base scenario assumes a clinical attack rate of 25% and a case fatality rate of 0.37%, giving rise to 53,700 excess deaths in the uk. a reasonable worst case scenario involves a cumulative clinical attack rate of 50% with 2.5% case fatality, causing 709,300 excess deaths. similarly, the us department of health and human services predicts that in a "moderate" scenario based on a virus with 1968-like pathogenicity, 865,000 will require hospitalisation and 65,000 (7.5%) will require ventilation. they also outline a "severe" 1918-like scenario with 9.9 million hospitalisations and 743,000 patients requiring ventilation [3] . an influenza pandemic will undoubtedly create a major increase in demand for critical care services. the majority of uk hospital intensive care units (icus) are already operating at > 98% bed occupancy. integral to the success of any emergency planning strategy is 'surge capability', incorporating the ability to scale up the delivery of appropriate specialist care to those that require it [4] . modelling of the impact of an influenza pandemic on uk critical care services has been carried out using the flusurge 1.0 programme developed at the us centers for disease control [5] . with simulation of an 8-week epidemic and 25% attack rate the demand for critical care beds from patients with influenza would represent 208% of current combined level 2 (highdependency unit) and level 3 (icu) bed capacity, and 231% of current level 3 capacity [6] . even allowing for optimistic estimates of other modulating factors (50% reduction in icu demand with use of neuraminidase inhibitors and 50% upgrade of level 2 to level 3 beds), level 3 bed occupancy due to the pandemic would remain at 75%. furthermore, occupancy of level 3 beds by 'flu patients' was unsustainable at approximately 50% in terms of care for other patients even in the most optimistic conditions. sars outbreak, up to 32% of cases were admitted to icu, 25% were mechanically ventilated and 28 day mortality for ventilated patients was 45% [13] . in singaporean sars patients admitted to icu, 98% developed ards [13] . properly constructed plans for the delivery of critical care during an influenza pandemic must include the ability to deal with excessive demand, high and possibly extreme mortality, and the risk to the health of critical care staff. the consequences of a pandemic, both in terms of numbers of patients and the effect on the healthcare system, are likely to precipitate a 'major incident' where special arrangements are needed to manage the system while it is under extreme pressure. it is anticipated that there will be an overwhelming demand for critical care services, not only for respiratory support through mechanical ventilation but also for a full range of care to manage multi-organ failure. assuming that the next pandemic derives from the h5n1 strain, the epidemiological evidence to date suggests extremely high mortality and, although not precisely quantifiable, a significant risk to health care workers. both of these will undermine the ability to deliver critical care to influenza patients even before consideration is given to the duty of care to other critically ill patients. coherent incident response requires a robust command and control structure, with the ability to make rapid informed decisions across an organisation and also across a health economy. in the uk, health incident management is based on a 'medallion' structure, with gold, silver and bronze corresponding to strategic, tactical and operational command levels [14] . north american and asian health institutions tend to use the hospital emergency incident command system [15] . the common theme in both systems is a clear command and control structure with which healthcare staff should be familiar [4, 14, [16] [17] [18] [19] . their generic hierarchical structure allows application to a wide range of incidents whilst retaining familiarity gained from training and exercises. the importance of familiarity with the command and control structure was highlighted in a recent delphi study [20] and european survey [21] . critical care contingency planning guidance from the uk department of health places an expectation on providers to expand their level 3 bed capacity by a factor of 3 but no more. provision of full multiorgan level 3 support is recognised to be unrealistic, but principally respiratory support is felt to be achievable. cancellation of elective surgery to minimise alternative sources of demand for critical care, upgrading level 2 to level 3 facilities and recruitment of theatre recovery areas and even operating theatres may allow expansion of icu-like care capacity. staff in these areas already have the competencies to manage sedated patients and those receiving respiratory support. escalating their clinical role should require relatively limited focussed training [22] . other staff may need to be redeployed and receive training in the management of critical care patients to support fully trained staff, permitting a dilution of the standard critical care nurse to patient ratio [23] . flexibility around dependency level and staff experience will be required [24] . the expansion of icu capacity to provide critical care in other areas will require the pre-emptive identification, tracing and maintenance of all usable equipment and potentially the stockpiling of key items to allow for rapid up-scaling of activity in response to demand. it is likely that there will be some variability in the prevalence of influenza across the country during a pandemic wave, with peaks in demand staggered across geographical areas. it may be possible to disperse some of the patient load by interfacility transfer if this occurs to any significant extent. the expansion of icu facilities during the sars epidemic in hong kong and singapore was recently described [25] . infection control is recognised as an overriding priority for the delivery of critical care, including the ability, in the early stages, to cohort cases. this should ideally include the use of separate entrances and exits, isolation rooms with negative pressure ventilation and dedicated separate healthcare staff. the toronto experience identified 21 secondary cases of nosocomial transmission of sars in icu from an initial index case before infection control measures were introduced. even following the introduction of extensive protective equipment, nine healthcare workers developed sars as a result of being present in the room during the intubation of a single patient. in terms of personal protection, planning and practice in the donning of protective equipment (ppe) and prior fit testing is essential [26] . the practicalities of being able to manage patients when fully attired must be understood and consideration given to the fact that any procedure or task will take longer. this will impact on care efficiency and the staff to patient ratio. while beds can be scaled up and extra areas recruited to provide critical care, without trained staff the planning will be ineffective. staff illness rates and the risk to staff must be factored into the planning process. in the uk, staff illness has been estimated at 30% with work absences of up to 8 days [2] . normal working patterns may need to be revised and facilities provided for staff to stay on site rather than go home to their families. staff absence tends to be greater the longer special circumstances apply and the greater the impact on the lives of the staff [27] . the preventive effectiveness of neuraminidase inhibitors may make focussed chemoprophylaxis a strategy for reducing staff illness in critical care areas [28] . the evolution of a new pandemic strain of influenza will inevitably result in a major increase in demand for critical care services. it is likely that these services will rapidly reach their capacity and even their contingency arrangements for extended facilities will be overwhelmed. excessive demand where resources are finite creates an ethical dilemma and many emergency plans apply a utilitarian approach of 'best care for the greatest number' [29] . there is a legitimate debate about how limited capacity can best be utilised, but a number of themes are recurrent. there needs to be a legal and ethical framework for the process decided in advance, the rationale for triage should be fair and transparent and it should meet the principles of distributive justice [30] [31] [32] . triage can conflict with human rights legislation and even humanitarian laws but 'accountability for reasonableness' can temper the disagreements about priority setting [33] . the decision making process needs to be valid and reproducible. although there are a number of triage systems available for mass casualty incidents, there has been little validation of any of them in the field [34] , and what there has been relates to 'big bang' single incidents and the apparent unreliability of triage [35, 36] . while it does not need to be explicit ahead of time, the decision thresholds should be based on both the cumulative evidence about the disease process and prognosis, and the number of patients and severity of illness making the demands on the service [31] . in effect, triage may result in a gradual degradation of care with the increasing scale of the incident and become a 'societally mandated do not resuscitate order'. on these grounds the process needs to be carefully considered at an appropriately senior level and applied consistently [32] . allowing for the utilitarian approach, it is recognised that in mass casualty incidents, the standard of care for all patients, including those not immediately related to the incident, may need to be adjusted and reduced. while this may infringe individual rights, the higher ethical principle of 'wellness of society as a whole' allows for the direction of resources to those where it is felt most effective. it may also allow for an expansion in the scope of practice of non-physicians [37] . it may be unrealistic and impractical to expect that senior medical intensive care staff will make all decisions regarding instituting critical care and there will be a need to empower more referring general clinicians to do so. this is at odds with the need for decision making by the most senior person [32] and will require a change in practice for many clinicians; it is not current practice in the uk. the use of track and triage protocols will be essential to direct this decision making and ensure its consistency. ardagh [38] has developed a set of pragmatic questions for the clinician facing acute problems of resource allocation; the only point lacking in his assessment process is a tool for the 'ranking' of patients in terms of likelihood of benefit from the limited resources. we believe that the basic criteria for a system for triage to critical care in a pandemic are fourfold; it should identify patients sick enough to require higher level care at some stage in their illness, it should be able to recognise those patients who are too acutely or chronically unwell to benefit from critical care, it should be consistently applicable by healthcare professionals and support workers from a variety of backgrounds within the constraints of the pandemic and should ideally also be scalable to reflect any mismatch between need and capacity. in order to fairly allocate resources across both flu and non-flu patients it should also be disease non-specific and allow prognostic comparisons across disease categories. a number of scoring systems have been advocated for use in a pandemic. the uk department of health currently recommends a six-point pneumonia severity score [2] . although us guidelines emphasise the importance of triage in primary influenza, specific tools are only recommended for assessment of post-influenza bacterial pneumonia [39] . the majority of available potential scores were developed as mortality indicators and perform less well for predicting critical care usage. amongst icu admissions with community-acquired pneumonia in massachusetts in 1996 to 1997, 10/32 scored curb-65 1 or 2 (that is, low risk) and 5/32 were classified as psi (pneumonia severity index) class iii (intermediate risk) [40] . even amongst patients with pneumonia included in the prowess study, only 90.5% were psi class iv or v, and only 70.3% had a curb-65 score of 3 or above [41] . there is no guarantee that pandemic influenza will be primarily pneumonic in its presentation; case reports have documented h5n1 influenza presenting with diarrhoea [42, 43] and coma [43] and a world health organisation summary has described absence of respiratory symptoms in a number of cases [44] . the utility of disease-specific pneumonia scores may also be limited by mortality from comorbidities such as cardiovascular disease. a number of intensive care scoring systems have demonstrated their power in using physiological derangement to predict mortality or higher resource requirements, whatever the presenting diagnosis [45] [46] [47] [48] [49] . physiological scores have also been demonstrated to be good predictors of requirement for higher level care on hospital wards [50] , in medical assessment units [51, 52] and in the emergency department [53] . we have demonstrated that a purely clinical score incorporating acute physiological derangement and chronic health and performance status can reliably predict requirement for critical care [54] . it is inevitable that if an influenza pandemic reaches the scale of some predictions, some patients who, in normal circumstances, would benefit from critical care will not be offered it. critical care triage will need to evolve from a process of identifying cases who need high level care to one that determines those patients most likely to benefit from the limited resources available and distinguishes them from those where care is likely to be futile. this is recognised by the emergency medicine community and the us administration in terms of disaster triage [37, 55] . the american thoracic society adopted the utilitarian principle a decade ago, stating that "the duty of health providers to benefit an individual patient has limits when doing so unfairly compromises the availability of resources needed by others" [56] . the problem now facing policymakers and clinicians is defining a process for resource allocation that meets the requirements of distributive justice and accountability for reasonableness [33] . as the working group on emergency mass critical care of the society for critical care medicine recognised, "an ideal triage system is based on data collected at hospital admission, requires little or no laboratory testing, and has been proven to predict hospital survival" [57] . the ontario ministry of health long-term care working group have courageously taken the first steps in defining a triage protocol for critical care [58] and their use of serial sequential organ failure assessment (sofa) scores to place a ceiling on care provided to non-responding patients is to be supported. however, it is unlikely to be feasible for all patients to have a trial of inotropes and/or ventilation and some way of screening out the sicker patients at ward/floor level will be required. we are not aware of the use of objective prognostic scores to allocate or refuse critical care resources at present and indeed most research demonstrates the ad hoc nature of admission decision-making [59] . however, if, as is likely, review by experienced critical care physicians is impractical, decision support will be required for the non-critical care specialist. emergency physicians, for example, had a positive predictive value (ppv) of only 73% in identifying those with a low chance of survival, as opposed to critical care fellows (ppv 83%) and the mortality probability model (mpm 0 ; ppv 86%) [60] . sofa scoring has previously been demonstrated on a multinational basis to predict high risk of mortality (a sofa score of over 15 was 98.9% specific for mortality) [61] . other critical care scoring systems show comparable performance in mortality prediction; discrimination as measured by area under receiver operator characteristic (roc) curve was 0.825 to 0.901 for acute physiology and chronic health evaluation iii (apache iii) [62] [63] [64] [65] , 0.79 to 0.846 for simplified acute physiology score ii (saps ii) [62, 64, 66] , and 0.928 for the multiple organ dysfunction score [67] . however, calibration of these scores to give absolute risks of mortality has not always been reliable [65] and has required customisation for international use [68, 69] . concentrated work is clearly required to amend and validate existing scoring systems so that they are suitable for use as triage tools. we suggest that this should be done on two levels. while disease specific scoring systems are valuable and should continue to be refined, there is a need to develop an appropriately generalisable scoring system for as unselected a group of patients as possible. to have the discriminating power, it will need to take place on a multicentre or, preferably, on a multi-national basis. it is a general principle of major incident planning that procedures should not be changed at precisely the moment when the system or institution is under its greatest stress, so planning for pandemic flu needs to make use as much as possible of systems and procedures already in place. development of a triage system and tool needs to be accompanied by planning for hospital command and control (to dictate scalability as related to available resources) and by training for staff whose roles may change. researchers, clinicians and policymakers in the field need to analyse systems and scores already in existence and improve and validate them as triage tools (though this may not be the purpose for which they were originally developed). at the same time ethical principles require transparency and consistency in the decision-making process, and involvement of public in its development. in reality, perhaps the question we need to address is the action required when critical care services are overwhelmed. the scalability of triage tools may aid in decision making by objectively altering the threshold for admission to critical care. however, the time may come when we need realistically to evaluate the effectiveness of critical care in influenza. if survival with the benefit of critical care is marginal (for example, <10%) and there is a significant cross-infection risk, perhaps critical care should then close and concentrate its efforts on outreach to other areas, including wards. direction and support from professional bodies and health departments will be required to support the medical staff with such difficult decisions possibly against a ground swell of media-driven public opinion. dw is a member of the uk department of health critical care contingency planning working group. the other authors declare that they have no competing interests. health protection agency: influenza pandemic contingency plan uk health departments' uk influenza pandemic contingency plan united states department of health and human services: pandemic influenza plan cantrill s: health care facility and community strategies for patient care surge capacity modelling the impact of an influenza pandemic on critical care 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management in a hospital: how well are we prepared? defining the ratio of outcomes to resources for triage of burn patients in mass casualties unstable ethical plateaus and disaster triage accountability for reasonableness mass-casualty triage systems: a hint of science precision of in-hospital triage in mass-casualty incidents after terror attacks casualties treated at the closest hospital in the madrid altered standards of care in mass casualty events. rockville: agency for healthcare research and quality criteria for prioritising access to healthcare resources in new zealand during an influenza pandemic or at other times of overwhelming demand united states department of health and human services: pandemic influenza plan -clinical guidelines applicability of prediction rules in patients with community-acquired pneumonia requiring intensive care: a pilot study severe community-acquired pneumonia as a cause of severe sepsis: data from the prowess study atypical avian influenza (h5n1). emerging infect dis fatal avian influenza a (h5n1) in a child presenting with diarrhea followed by coma writing committee of the world health organization (who) consultation on human influenza a/h5: avian influenza a (h5n1) infection in humans acute physiology and chronic health evaluation (apache) iv: hospital mortality assessment for today's critically ill patients a comparison of severity of illness scoring systems for intensive care unit patients: results of a multicenter, multinational study characterization of intensive care unit patients using a model based on the presence or absence of organ dysfunctions and/or infection: the odin model simplified acute physiological score for intensive care patients the use of maximum sofa score to quantify organ dysfunction/failure in intensive care. results of a prospective, multicentre study a physiologically-based early warning score for ward patients: the association between score and outcome the simple clinical score predicts mortality for 30 days after admission to an acute medical unit validation of a modified early warning score in medical admissions the association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection physiological-social score (pmews) vs. curb-65 to triage pandemic influenza: a comparative validation study using community-acquired pneumonia as a proxy population-based triage management in response to surge-capacity requirements during a large-scale bioevent disaster bioethics task force: fair allocation of intensive care unit resources augmentation of hospital critical care capacity after bioterrorist attacks or epidemics: recommendations of the working group on emergency mass critical care development of a triage protocol for critical care during an influenza pandemic priority setting in a hospital critical care unit: qualitative case study prediction of poor outcome of intensive care unit patients admitted from the emergency department use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter prospective study comparison of acute physiology and chronic health evaluations ii and iii and simplified acute physiology score ii: a prospective cohort study evaluating these methods to predict outcome in a german interdisciplinary intensive care unit comparison of multiple organ dysfunction scores in the prediction of hospital mortality in the critically ill mortality discrimination in acute myocardial infarction: comparison between apache iii and saps ii prognosis systems community-wide assessment of intensive care outcomes using a physiologically based prognostic measure the influence of length of stay in the icu on power of discrimination of a multipurpose severity score (saps) multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome the effect of casemix adjustment on mortality as predicted by apache ii the performance of saps ii in a cohort of patients admitted to 99 italian icus: results from giviti. intensive care med disaster management edited by j christopher farmer.other articles in this series can be found online at http://ccforum.com/articles/ theme-series.asp?series=cc_disaster key: cord-258087-93yfs7ve authors: flores, carlos; del mar pino-yanes, maria; villar, jesús title: a quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury date: 2008-10-25 journal: crit care doi: 10.1186/cc7098 sha: doc_id: 258087 cord_uid: 93yfs7ve introduction: clinical observations and animal models provide evidence that the development of acute lung injury (ali), a phenomenon of acute diffuse lung inflammation in critically ill patients, is influenced by genetic factors. association studies are the main tool for exploring common genetic variations underlying ali susceptibility and/or outcome. we aimed to assess the quality of positive genetic association studies with ali susceptibility and/or outcome in adults in order to highlight their consistency and major limitations. methods: we conducted a broad pubmed literature search from 1996 to june 2008 for original articles in english supporting a positive association (p ≤ 0.05) of genetic variants contributing to all-cause ali susceptibility and/or outcome. studies were evaluated based on current recommendations using a 10-point quality scoring system derived from 14 criteria, and the gene was considered as the unit of replication. genes were also categorized according to biological processes using the gene ontology. results: our search identified a total of 29 studies reporting positive findings for 16 genes involved mainly in the response to external stimulus and cell signal transduction. the genes encoding for interleukin-6, mannose-binding lectin, surfactant protein b, and angiotensin-converting enzyme were the most replicated across the studies. on average, the studies had an intermediate quality score (median of 4.62 and interquartile range of 3.33 to 6.15). conclusions: although the quality of association studies seems to have improved over the years, more and better designed studies, including the replication of previous findings, with larger sample sizes extended to population groups other than those of european descent, are needed for identifying firm genetic modifiers of ali. critical illness in adults often is followed by acute lung injury (ali). ali and its most severe form, the acute respiratory distress syndrome (ards), are currently defined as a phenomenon of acute diffuse lung inflammation pathologically characterized by an acute onset of non-cardiogenic pulmonary edema resulting from increased capillary-alveolar permeability. both are clinically manifested by hypoxemia under mechanical ventilation (arterial partial pressure of oxygen/fraction of inspired oxygen [pao 2 /fio 2 ] of less than or equal to 300 mm hg for ali and pao 2 /fio 2 of less than or equal to 200 mm hg for ards), diffuse bilateral pulmonary infiltrates on chest radi-ographs, and reduced lung compliance [1] . pneumonia and sepsis are the main and most common risk conditions associated with the development of both disorders [2] . ali and ards remain a major health problem worldwide: it has been estimated that each year in the us there are 190,600 cases of ali, which are associated with 74,500 deaths and 3.6 million hospital days [3] . our understanding of the pathogenesis of ali and ards has improved in recent years with the appreciation that inflammation is a fundamental component of the pathophysiology of these two clinical manifestations of the same syndrome. ali: acute lung injury; ards: acute respiratory distress syndrome; ci: confidence interval; fio 2 : fraction of inspired oxygen; il-6: interleukin-6; iqr: interquartile range; ld: linkage disequilibrium; ncbi: national center for biotechnology information; pao 2 : arterial partial pressure of oxygen. clinicians have long recognized that all critically ill patients with ali are not alike. it is becoming apparent that the diversity of clinical manifestations and the response to treatment and outcome among patients with the same disease process are influenced by genetic factors [4] [5] [6] . the first piece of evidence supporting a role for genetic differences in infection risk and outcome came from an epidemiological study reporting a strong association between death from infection in adoptees and their biological, but not adoptive, parents [7] . for ali, this is further strengthened by the mortality rate disparities across the different ethnic groups in the us [8] . in addition, ali models in inbred rodents have demonstrated differences for susceptibility and severity traits, allowing the identification of several loci and pinpointing the multigenic nature of the condition [9] [10] [11] . in our attempt to better define patients at risk, recent trends have turned our attention to the search for common genetic variation underlying ali susceptibility and/or outcome. based on the extensive evidence that common genetic variation with modest effects underlies susceptibility to common complex diseases [12] and on the impossibility of linkage analysis to detect such signals [13] , association studies have constituted the main tool for improving our understanding of the genetic factors affecting ali susceptibility and outcome. association studies compare two groups of samples (cases and controls) for statistical differences in the frequency of variants at one or more sites of the genome. although the international hapmap project and the development of genotyping technologies have made possible the testing of more than one million of these variants in a single experiment [14] , they have been available for a short period of time [15] . thus, currently, association studies in ali have exclusively used a candidate gene approach, in which one or several genes -known to be etiologically involved in the disease -are studied for relevant variant sites. in general, the inconsistency of findings across association studies [16] -partially attributed to inappropriate designs, implementations, and/or interpretations of studieshas motivated the formulation of standards to improve their quality and to help perform meta-analysis [17] under the premise that the replication of previous findings most likely reflects interesting biological processes rather than methodological quirks. here, we aimed to examine studies reporting positive findings with all-cause ali susceptibility and/or outcome in adults in order to evaluate their relative merits and caveats based on actual recommendations. we conducted a broad pubmed literature search from 1996 to june 2008 for original articles by querying for 'polymorphism and acute lung injury' and 'polymorphism and ards'. the retrieved references were then manually curated, and those reporting genetic association studies and published in english were sought. studies were considered if a positive association (p ≤ 0.05) was reported with either susceptibility or outcomes of all-cause ali or ards. since the current tendency to perform association analysis at the individual variant level may be problematic (for example, there may be important differences in allele frequency or linkage disequilibrium [ld] structure across different populations), we instead considered the gene as the unit of replication [18] . the gene ontology was used to categorize associated genes according to biological processes [19] . among reports with positive associations, study qualityrather than significance value -was reviewed based on current recommendations. since performing a checklist of all issues to consider in association studies would require more than a single article, we have focused on the most relevant criteria from a checklist suggested recently [20] . all together, 14 criteria were considered and each of them was scored as 1 if present or 0 if absent. scoring was performed independently by two authors. studies were divided into case-control or cohort studies based on the design in which the authors reported the positive association. if a case-control study reported a positive association with an outcome in the case series, the positive finding of the study was also considered as found in a cohort design. a final quality score was obtained by adding up scores from all criteria (see below). a reported association could have a maximum score of 14 points for casecontrol studies if more than one polymorphism was analyzed, a maximum of 13 points if reporting a case-control study for a single polymorphism (multiple testing adjustment not needed) or for a cohort with more than one polymorphism analyzed (definition of the control group not needed), or a maximum of 12 points for cohorts analyzing a single locus (definition of the control group and the multiple testing adjustment are not needed). to facilitate comparison across study designs, scores were then transformed to a 0-to 10-point scale. criteria that were evaluated in relation to the study design included power calculation, characterization of cases and controls or the cohort, and whether the study considered common gene-wide variation. power calculation was scored as present only if it was explored prospectively or retrospectively as part of the original study. controls were considered to be adequate if obtained from the same population as cases and described in such a way that could be replicated. this criterion was not scored in the cohort studies. adequacy of case groups was considered if demographical and clinical data were reported in sufficient detail in the text and/or a table. mentioning accepted international guidelines for phenotype definition [1] as the sole description of cases was not considered to be acceptable. to cover the adequacy of exploring gene-wide variation in the association, ld must have been explored for polymorphism selection and/or for the interpretation of results. to evaluate study reproducibility, unambiguous identification of polymorphisms by means of national center for biotechnology information (ncbi) reference numbers or flanking sequences was scored as present. the sole description of amplification primer pairs and/or a reference to a previous publication that reported the assay was not considered to be acceptable. the three other criteria evaluated as part of study reproducibility relate to genotyping quality control measures. duplicate genotyping of a portion of individuals by means of the same or alternative genotyping techniques to calculate an error rate was considered to be adequate and scored as present. testing of hardy-weinberg equilibrium was scored as present even when significant p values were reported for any of the groups as long as a duplicate genotyping was performed. finally, adequate studies performed an interpretation of results blind to the clinical status of samples. to evaluate the statistical analyses, we considered the presence of multiple testing adjustments to be adequate. however, note that this category was not scored if a single polymorphism was assessed since we did not consider an adjustment for the multiple explored phenotypes or outcomes for the adequacy of the study to be necessary. three other categories scored as adequate included an evaluation of other recorded risk factors by means of regression models, reporting major findings in terms of risks (as hazard or odds ratios) and their 95% confidence intervals (cis), and an empirical assessment or adjustment for population stratification by means of an independent set of polymorphic markers. finally, we scored as adequate additional support from studies performing a validation in at least a second independent sample as part of the original study. studies designed to confirm previously associated polymorphisms were not considered to be acceptable for this category. studies that also included experiments providing evidence of functionality for associated variant(s) were scored as adequate. the sole reference to previous publication(s) providing the functional evidence of the associated polymorphism was scored as absent. searching for 'polymorphism and acute lung injury' or 'polymorphism and ards', we retrieved 53 and 23 original articles, respectively. this allowed us to identify a total of 29 articles [21-49] on 16 genes that showed a positive association with susceptibility and/or outcomes of all-cause ali or ards in at least one study (table 1) . although we used broad terms for this search, the possibility for missing additional studies with positive findings might still exist. nevertheless, a complementary search querying for the disease name in the hugenet navigator [50] gave completely overlapping results, showing studies for additional genes, albeit reporting negative findings. most studies (72.3%) were carried out exclusively in populations of european descent (defined as 'whites' or caucasians). a minority of studies were performed in east asians (7%) and the remaining 20.7% of studies included populations of both european and african descent. among the 16 genes that showed a positive association in at least one study, four genes were replicated in at least a second article, three genes were replicated in at least three studies, and one gene was replicated in four studies (figure 1 ). since with only two exceptions [32, 35] none of these studies attempted to validate the association results in an independent sample, all studies were counted as a single contribution for the purpose of this assessment. ontology analysis of these genes showed that the majority of them were involved in the response to external stimulus (56.2%) and cellular signal transduction (50%). there was also a prominent representation of genes implicated in cell proliferation (43.8%), inflammatory response (37.5%), immune response (25%), and chemotaxis (25%). seventeen studies (58.6%) reported positive findings using a case-control design and 12 (41.4%) using a cohort. median sample sizes among studies were of 100 cases (interquartile range [iqr]: 85 to 212) and 200 controls (iqr: 88 to 519), whereas the median sample size for cohort studies was 183 patients (iqr: 100 to 273). overall median quality score was 4.62 (iqr: 3.33 to 6.15) and maximum and minimum scores were 7.14 and 0.71, respectively. when studies were classified by design, the median quality score in case-controlled studies (5.38; iqr: 4.29 to 6.43) was significantly higher than in cohort studies (3.33; iqr: 2.88 to 5) (p = 0.030, mann-whitney u test). when studies were explored by the year of publication, there was an improvement trend of association studies over time (spearman rho = 0.38, p = 0.041), but this was due mostly to case-controlled studies (spearman rho = 0.70, p = 0.002) since no significant trend was observed for cohort studies (spearman rho = 0.27, p = 0.40). genes that showed positive association with either susceptibility and/ or outcome with all-cause acute lung injury or acute respiratory distress syndrome genes that showed positive association with either susceptibility and/ or outcome with all-cause acute lung injury or acute respiratory distress syndrome. ace, angiotensin-converting enzyme; cxcl2, chemokine cxc motif ligand 2; f5, coagulation factor v; il-6, interleukin-6; il-10, interleukin-10; mbl2, mannose-binding lectin-2; mif, macrophage migration inhibitory factor; mylk, myosin light-chain kinase; nfkb1, nuclear factor kappa light polypeptide gene enhancer in b cells; nfk-bia, nuclear factor kappa light polypeptide gene enhancer in b cells inhibitor alpha; nrf2, nuclear factor erythroid-derived 2 factor; pbef, pre-b cell-enhancing factor; plau, plasminogen activator urokinase; sftpb, surfactant pulmonary-associated protein b; tnf, tumor necrosis factor; vegf, vascular endothelial growth factor. almost two thirds of the studies (62.1%) did not explore their power to detect positive findings. nearly all studies (97%) fulfilled the internationally accepted definition criteria for ali and ards [1] , and most studies (89.7%) appropriately described demographical and clinical data from cases ( figure 2 ). more heterogeneity was found for the criteria to select a control group: although most studies used healthy subjects or population-based controls (43%), a great proportion of studies preferred icu patients as controls (38%). in any case, 94.4% of studies fulfilled the required criteria to have an adequate control group. most studies (75.9%) analyzed a few variants per gene (34.5% analyzed a single variant with anticipated functionality) without providing appropriate coverage or discussion to other untyped common variation by means of ld-based methods. in almost half of the studies (44.8%), we were not able to identify the associated polymorphism(s) in ncbi databases straightforwardly and unambiguously since flanking sequences or genetic reference numbers were lacking. less than half of the studies reported genotyping error checks (48.3%) or a blinding strategy (34.5%) to avoid biased results ( figure 2 ). however, hardy-weinberg equilibrium was assessed separately in cases and controls or in the cohort in 89.7% of studies. remarkably, three of these studies reported a positive finding for polymorphisms that nominally deviated from hardy-weinberg expectations in control samples. adjustments for multiple testing were lacking in most studies since only 9.5% of them made adjustments during statistical interpretation. conversely, regression analyses to adjust for covariates were used in a high proportion of studies (72.4%). likewise, the magnitude of effects has been appropriately reported in terms of hazard or odds ratios and their 95% cis in most studies (75.9%). by contrast, adjustments for the underlying population stratification were nearly absent as part of the statistical toolbox of the studies (89.7%). as few as 2 studies (6.9%) supported the association in an independent validation sample [32, 35] . only 6 of 29 studies (20.7%) explored functional significance of variants associated with disease, either by evaluating the functionality of the associated polymorphism using gene reporter assays [26, 37] or by its correlation with serum protein levels [22, 27, 43, 46] . this quality assessment of genetic association studies with positive findings in susceptibility or outcome of ali and ards identified a total of 29 articles and 16 genes. due to our limited knowledge of the pathogenesis of these conditions and given that it is likely that many common genes and pathways contribute to the onset, course, or severity of these two forms of the same disease process, for the purpose of genetic susceptibility and outcome in this systematic review, we considered ali and ards as a single entity. the top gene ontologies represented in current association studies fit within the major biological processes underlying ali development on the basis of different microarray experiments among several studies using diverse animal models of the disease and cellular models of stretch-induced injury [51] . overall, the paucity and quality of association data in ali/ ards call for more and better designed studies with larger sample sizes with unambiguous identification of the studied variants and procedures that allow monitoring of genotyping quality for a consistent replication and with better statistical a names are those originally reported in the corresponding reference. ins/del, insertion-deletion polymorphism. ace, angiotensin-converting enzyme; ali, acute lung injury; ards, acute respiratory distress syndrome; cap, community-acquired pneumonia; cxcl2, chemokine cxc motif ligand 2; f5, coagulation factor v; il-6, interleukin-6; il-10, interleukin-10; mbl2, mannose-binding lectin-2; mif, macrophage migration inhibitory factor; mv, mechanical ventilation; mylk, myosin light-chain kinase; nfkb1, nuclear factor kappa light polypeptide gene enhancer in b cells; nfkbia, nuclear factor kappa light polypeptide gene enhancer in b cells inhibitor alpha; nrf2, nuclear factor erythroid-derived 2 factor; pbef, pre-b cell-enhancing factor; plau, plasminogen activator urokinase; sars, severe acute respiratory syndrome; sftpb, surfactant pulmonaryassociated protein b; sirs, systemic inflammatory response syndrome; snp, single-nucleotide polymorphism; tnf, tumor necrosis factor; tr, tandem repeat (polymorphism); vegf, vascular endothelial growth factor. positive genetic association studies with acute lung injury/acute respiratory distress syndrome susceptibility and/or outcome (by year of publication) percentage of studies scored as adequate for 14 criteria (x-axis) used for the quality assessment of genetic association studies supporting susceptibility and/or outcome in acute lung injury percentage of studies scored as adequate for 14 criteria (x-axis) used for the quality assessment of genetic association studies supporting susceptibility and/or outcome in acute lung injury. ld, linkage disequilibrium; pop. stratification adjust., population stratification adjustment. analyses. some of the reported associations, mostly in populations of european descent, have already set the bar high in the field with 'high-quality' studies, either with well-powered studies [36, 41] or with a functional correlation of the associated polymorphism [43] . however, most of those association studies examining the functional effects of polymorphisms have reported the plasma levels of the gene product (protein) at one time point during the development or evolution of the disease process, so the role of those protein levels in the natural history of ali or ards remains to be defined. additionally, positive association studies on ali/ards have focused essentially on exploring genetic risk effects of candidate gene variants in european populations. thus, future studies must try to fill this gap by extending the association analysis to other populations that might give us an overall picture of cosmopolitan and population-specific genetic risks. this also requires authors to give a more appropriate interpretation of results in light of power estimates since genetic effects are expected to be weak and sample sizes will rarely increase to the extent considered necessary [52] . the current evidence also encourages more replication studies, especially of those genes that have been positively associated in at least two studies [53] . a strong candidate would be the gene encoding the pro-inflammatory cytokine interleukin-6 (il-6). extensive cross-species gene expression pattern comparisons in experimental models of ali have shown that il-6 is highly upregulated [54] and at increased circulating concentrations in ali patients [55] . however, undisputed evidence supporting the association of il-6 gene variants with ali/ards susceptibility or outcome is still lacking, even though positive results have been found in four studies. one of the major reasons is that the predicated association has been explored in a single polymorphism of the il-6 gene (g/c at position -174 from the transcription start site). association studies using a gene-wide coverage of common variation may reveal more robust patterns of variation associated with the disease [28, 47] . in this sense, a (nearly) full coverage of common variation of the candidate gene in association studies of ali is especially important since no association is yet definitive and our understanding of the functional elements of our genome is incomplete [56] . classification and characterization of ali/ards across reviewed studies were highly concordant. however, another face of the problem is that ali/ards is still ill defined and the problem is further confounded by the diversity of etiological mechanisms such as sepsis, pneumonia, trauma, and massive transfusion that predispose patients to the condition. furthermore, it has been recently shown that patients meeting current american-european consensus conference ards criteria may have highly variable levels of lung injury and outcomes [2] . we believe that the development of novel diagnostic tools to precisely characterize the ali and ards phenotypes or the risk factors underlying disease development might result in associations that are more reproducible. as a result of the progress of our understanding of this disease and the use of high-throughput methodologies [57] , it is expected that robust well-replicated associations between genetic polymorphisms and ali/ards susceptibility and outcome will become a reality in the near future. to reach this point, guidelines to report genotype data fulfilling minimum quality standards need to be implemented to improve our understanding of the genetic architecture of this disease. in addition, statistical methodologies such as multiple testing and population stratification adjustments, which to date have been almost completely absent in these studies, need to be routinely employed as well. since all studied candidate genes await validation in independent studies using larger samples, the search for genetic variants determining susceptibility and outcome in ali or ards still needs to grow and continue improving for the identification of true associations between genotype and clinical outcomes important in the care of ali/ards patients. integration of data across studies (for example, gene expression profiling, association studies, and proteomics) may reveal novel insights into ali development which may allow us to identify cellular pathways specific to the disease. this knowledge will speed up the development of better and increasingly efficient tailored therapies for ali/ards patients admitted to the intensive care unit. tions, mechanisms, relevant outcomes and clinical trial coordination the help network: an early peep/fio 2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome incidence and outcomes of acute lung injury understanding genetic predisposition to sepsis injury research in the genomic era. lancet genetic determinants of phenotypic diversity in humans genetic and environmental influences on premature death in adult adoptees race and gender differences in acute respiratory distress syndrome deaths in the united states: an analysis of multiple-cause mortality data (1979 -1996) genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice use of consomic rats for genomic insights into ventilator-associated lung injury reciprocal congenic lines of mice capture the aliq1 effect on acute lung injury survival time genetic association studies the future of genetic studies of complex human diseases the international hapmap consortium: a second generation human haplotype map of over 3.1 million snps what can 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risk of direct pulmonary injury and ards pre-b-cell colony-enhancing factor as a potential novel biomarker in acute lung injury mannose-binding lectin in severe acute respiratory syndrome coronavirus infection the association of interleukin 6 haplotype clades with mortality in critically ill adults functional genomic insights into acute lung injury: role of ventilators and mechanical stress 308 and tnfb polymorphisms in acute respiratory distress syndrome vascular endothelial growth factor gene polymorphism and acute respiratory distress syndrome novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury interleukin-10 polymorphism in position -1082 and acute respiratory distress syndrome polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations pre-bcell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome functional polymorphisms in the transcription factor nrf2 in humans increase the risk of acute lung injury a cxcl2 polymorphism is associated with better outcomes in patients with severe sepsis polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome ace i/d but not agt (-6)a/g polymorphism is a risk factor for mortality in ards inhibitor kappab-alpha haplotype gtc is associated with susceptibility to acute respiratory distress syndrome in caucasians insertion/deletion polymorphism in the promoter of nfkb1 influences severity but not mortality of acute respiratory distress syndrome genotypes and haplotypes of the vegf gene are associated with higher mortality and lower vegf plasma levels in patients with ards association between urokinase haplotypes and outcome from infection-associated acute lung injury variation in the mylk gene is associated with development of acute lung injury after major trauma mannose-binding lectin and mannose-binding lectinassociated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults an il6 gene-wide haplotype is associated with susceptibility to acute lung injury the -1082 interleukin-10 polymorphism is associated with acute respiratory failure after major trauma: a prospective cohort study factor v leiden mutation is associated with improved 30-day survival in patients with acute respiratory distress syndrome a navigator for human genome epidemiology microarray-based analysis of ventilator-induced lung injury the complex interplay among factors that influence allelic association angiotensin-converting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome orthologous gene-expression profiling in multi-species models: search for candidate genes persistent elevation of inflammatory cytokines predicts a poor outcome in ards. plasma il-1 beta and il-6 levels are consistent and efficient predictors of outcome over time encode project consortium: identification and analysis of functional elements in 1% of the human genome by the encode pilot project highly parallel genomic assays this work was supported in part by ministerio de ciencia (spain) (saf2004/06833) and funcis (04/53). cf was supported by a specific agreement between instituto de salud carlos iii and funcis (emer07/001) under the encyt 2015 framework. the authors declare that they have no competing interests. all authors contributed equally in the assessment design and the literature search and read and approved the final manuscript. • current evidence suggests that acute lung injury (ali) and its most severe form, the acute respiratory distress syndrome, are influenced by genetic factors.• association studies, the main tool for the exploration of common genetic variation underlying ali, have thus far reported a total of 16 genes associated with ali susceptibility and/or outcome.• these genes are involved mainly in the response to external stimulus and cell signal transduction.• more studies with improved designs, as well as replication of previous findings with larger sample sizes, are needed to definitely identify genetic factors predisposing patients to ali. key: cord-000892-l9862er0 authors: richard, jean-christophe marie; pham, tài; brun-buisson, christian; reignier, jean; mercat, alain; beduneau, gaëtan; régnier, bernard; mourvillier, bruno; guitton, christophe; castanier, matthias; combes, alain; tulzo, yves le; brochard, laurent title: interest of a simple on-line screening registry for measuring icu burden related to an influenza pandemic date: 2012-07-09 journal: crit care doi: 10.1186/cc11412 sha: doc_id: 892 cord_uid: l9862er0 introduction: the specific burden imposed on intensive care units (icus) during the a/h1n1 influenza 2009 pandemic has been poorly explored. an on-line screening registry allowed a daily report of icu beds occupancy rate by flu infected patients (flu-or) admitted in french icus. methods: we conducted a prospective inception cohort study with results of an on-line screening registry designed for daily assessment of icu burden. results: among the 108 centers participating to the french h1n1 research network on mechanical ventilation (reva) french society of intensive care (srlf) registry, 69 icus belonging to seven large geographical areas voluntarily participated in a website screening-registry. the aim was to daily assess the icu beds occupancy rate by influenza-infected and non-infected patients for at least three weeks. three hundred ninety-one critically ill infected patients were enrolled in the cohort, representing a subset of 35% of the whole french 2009 pandemic cohort; 73% were mechanically ventilated, 13% required extra corporal membrane oxygenation (ecmo) and 22% died. the global flu-or in these icus was only 7.6%, but it exceeded a predefined 15% critical threshold in 32 icus for a total of 103 weeks. flu-ors were significantly higher in university than in non-university hospitals. the peak icu burden was poorly predicted by observations obtained at the level of large geographical areas. conclusions: the peak flu-or during the pandemic significantly exceeded a 15% critical threshold in almost half of the icus, with an uneven distribution with time, geographical areas and between university and non-university hospitals. an on-line assessment of flu-or via a simple dedicated registry may contribute to better match resources and needs. in the fall of 2009, the reported incidence of patients infected with the pandemic influenza a(h1n1) virus in france exceeded the usual incidence of seasonal flu [1, 2] . notification of all patients infected with a(h1n1) virus became mandatory from 1 july to 2 november 2009 but later was restricted to intensive care unit (icu) admissions because of a large and rapid increase in the number of cases [3] . taking into account observations made during the early stage of the pandemic in other countries [4] [5] [6] (especially in the southern hemisphere [7] [8] [9] [10] [11] ), the french ministry of health organized the response to the pandemic according to the possible needs of seven regions, so-called 'defense areas', in order to regulate the supply of equipment ( figure 1 ). the purpose of this plan was to distribute resources equitably across regions while avoiding any shortage in icu beds. extracorporal membrane oxygenation (ecmo) devices and icu ventilators were distributed in the reference centers of each defense area to cover the french territory. a 15% rate of icu bed occupancy by flu patients in a region was indicated as a critical threshold to consider cancellation of scheduled surgical activities. at the same time, we recorded data corresponding to the cohort of icu patients through a large research network on mechanical ventilation (reva-srlf registry) [12] . in addition, we designed a dedicated website screening registry to prospectively assess the specific burden related to the a(h1n1) pandemic in icus recruited on a voluntary basis. we proposed that a relatively simple screening registry would be able to give a much more exact picture of the respective burden on the different icus, geographical areas, and university versus non-university centers. here, we report the exact rate of icu bed occupancy by flu-infected patients (flu-or) during the pandemic in a representative subset of french icus. the french reva-srlf registry was a multi-center prospective observational survey based on a website registry, and several results of this registry have been published elsewhere [13] [14] [15] . in brief, from november 2009 (week 09-45) through january 2010 (week 10-03), 89 out of 108 icus participating in the general registry (representing one fourth of all french icus) accepted an invitation to participate in a website screening registry to do a daily assessment of the rate of icu bed occupancy by influenza-infected and non-infected patients. sixty-nine icus belonging to either referral university hospitals (31 icus) or general hospitals (38 icus) eventually completed the daily screening for at least three consecutive weeks and admitted at least one a(h1n1)-infected patient and were kept for the present analysis. twenty icus that, for organization reasons or for lack of a(h1n1) patients, did not complete three consecutive weeks were excluded from the analysis. recording of patients' data in the registry was approved by the national commission for protection of patients' rights and electronic data recording. the study was approved by the ethics committee of the french society of intensive care (srlf). informed consent was waived in agreement with the observational design of the study. suspected infection was proven by means of a polymerase chain reaction eventually completed by serologic analysis. when positive, the patient was considered a 'confirmed case'. a typical clinical flu presentation associated with a negative test was considered a 'suspected case' when no other etiology was found. suspected as well as confirmed cases were enrolled in the present study. admission data consisted of dates and times of admission to the hospital and icu; age; sex; pregnancy status; fatal underlying disease defined within the mccabe [16] classification; the simplified acute physiology score iii (saps iii) [17] , which is a severity score ranging from 0 to 217; immunosuppression and its cause; history of chronic respiratory disease, diabetes, or chronic heart failure; weight and height; and pregnancy. a follow-up during the icu hospitalization, including time and duration of ventilation, antiviral and corticosteroid use, use of rescue therapy including ecmo, and the cause of death, was also performed. a specific website registry (screening registry) was designed in order to do a daily assessment of the occupancy rate related to the management of a(h1n1) nonventilated or ventilated patients. isn't 'in order to daily assess the occupancy rate...' better? baseline information on the number of available beds, ventilators, and staffing was collected. for each participating unit, a customized table representing the number of available beds on each day of the week was displayed on the website ( figure 2 ). each available bed was characterized by using a specific code on a daily basis to identify whether it was occupied or used by a non-infected patient or a flu-infected patient; the ventilation status (mechanically ventilated or not) of each patient was also coded. the number of available beds could be modified each day in case of the closing or opening of additional beds. online completion of the registry required less than 30 minutes per day for a 20-bed icu and usually was performed every morning after checking the patients' status during the first round. to facilitate postponed data recording, a table corresponding to the week in progress was available on the website for printing. the website was designed by a professional who paid great attention to the user-friendliness of the interface. each participating center received a weekly electronic update to provide information on the evolution of the pandemic and encourage completion of the registry. when needed, reminders were automatically displayed on the website. based on these data, the icu bed flu-or was computed as the number of bed-days per week occupied by flu patients divided by the total number of bed-days occupied per week and was expressed as a percentage. a weekly flu-or was calculated for each participating icu and for each defense area in the course of the pandemic, differentiating ventilated from non-ventilated patients. we also differentiated flu-or observed in university hospitals from that in non-university hospitals. data collected were directly downloaded as electronic .xls files from the reva web registry. the data management and the analysis were performed by cb-b, tp, and j-cmr. the database was completed when needed after direct contact with the icu physicians. duplicate notifications were systematically checked, and patients transferred from one participating icu to another were counted as a single admission. descriptive statistics included frequency analysis -percentages and corresponding 95% confidence intervals (cis) -for categorical variables and means and standard deviations or medians and interquartile ranges (iqrs) for continuous variables. differences in medical and demographic characteristics according to outcomes or in flu-or between types of hospitals were tested by using a chi-squared test for categorical variables and a student t test for continuous parametric variables. all statistical tests were two-sided, and p values of 0.05 or less denoted statistical significance. statistical analysis was performed with r software packages [18] . three hundred ninety-one patients with a(h1n1) were admitted from 26 september 2009 to 10 february 2010 in the 69 icus participating in the screening registry and were included in this study. among them, 349 (89%) had a confirmed influenza a infection. this subset of 391 patients represents 36.7% of the whole cohort of french influenza-infected adult icu patients [3] ; they had the same overall characteristics, except for a higher rate of immunosuppression (table 1) . tables 2 and 3 show the baseline characteristics and main risk factors for flu recorded in these patients according to survival or to the intensity of ventilatory support. mechanical ventilation was provided to 286 (73%) patients, 231 (59%) fulfilled criteria for acute respiratory distress syndrome, and 50 (13%) required additional ecmo. the mortality rate of the whole cohort was 22%. figure 1 shows the distribution of the 69 icus participating in the screening registry across the seven defense areas as well as the distribution of icu beds belonging figure 3 shows the weekly and maximal flu-or in the seven defense areas. the peak of the pandemics varied across the different geographical defense areas as illustrated by the profiles of the mean flu-or in each region ( figure 3 ). the maximal flu-or observed in any icu in each region is also indicated. a flu-or of above 15% was recorded in 32 individual icus, for a total of 103 weeks out of the accumulated 623 weeks of screening across the 69 icus: 16.5% of the screening weeks (95% ci of 13.6% to 19.4%). the percentage of screened weeks with flu-or of above 15% varied between defense areas from 8.5% (east) to 34.3% (north). the pooled flu-or calculated over the whole study period (including university and non-university hospital) for the entire country was 7.6% and varied across the seven defense areas from 6.1% (east) to 10.5% (southeast). at each week, this rate was significantly higher in university hospitals than in non-university hospitals (figure 4 ). during the pandemic period, none of the participating hospitals used the threshold level of 15% icu bed occupancy rate to modify hospital admission policy or bed availability. in this prospective observational study using a dedicated online screening registry designed to assess the daily burden of the a(h1n1) influenza pandemic on french icus, we found important variations in the actual influenza burden between geographical areas, university and nonuniversity hospitals, and time. in several individual icus, our screening registry has permitted us to observe peak occupancy rates greatly exceeding those calculated by averaging data observed in the largest defense areas. our findings suggest that the organization of future pandemic response plans can greatly benefit from online data obtained in almost real time [19, 20] . a dedicated online registry able to assess the week-by-week flu-or in each icu may help to better distribute resources according to the actual needs. even if icus were encouraged to do a daily assessment of the presence of patients with a (h1n1), we chose to report the calculation per week first to be consistent with the french organization and the national institute for public health surveillance (niphs), which displayed the time course of the pandemic weekly, and also to simplify data notification for participating centers. in fact, in collaboration with the niphs, we developed a strong communication strategy via the reva website to simplify and therefore encourage rigorous notification. flu-ors calculated per week in the present study were comparable to and often higher than those observed in the southern hemisphere. over the 3-month pandemic period in australia and new zealand [11] , the anzics (australian and new zealand intensive care society) investigators reported that an average of 5.2% of available icu bed-days were occupied by patients with h1n1 infection, whereas the peak percentage ranged from 8.9% to 19% [11] . in our study, 7.6% of the beds of enrolled icus were occupied by influenza-infected patients during the whole study period, and a maximum flu-or recorded per week in individual icus reached 35%. inclusion of the 10 icus that had not admitted any patients with a(h1n1) would have lowered global flu-or but would not have changed the maximal flu-ors that we observed. the icu length of stay, however, may have impacted the flu-or since a large difference between the two reports was observed: the median durations of icu stay were 7.4 days (iqr of 3 to 16) in the anzics study and 10 days (iqr of 5 to 24) in french icus. uneven time and regional distribution may also impact the flu-or calculations. in the anzics investigation, the number of days that icu beds were occupied by infected patients per region was calculated by multiplying the total number of patients by their length of stay. this approach allowed us to estimate a peak flu-or per region but not per individual icu. the results of our registry show that this can greatly underestimate true peak activities in some icus. this is of particular importance since h1n1 burden changed rapidly over time and from one icu to the other. the web-based screening registry specifically developed for our study allowed a daily assessment of the icu occupancy rate in individual icus with an accuracy similar to that in larger regions. for example, observations reported from the paris area ( figure 3 ) showed that the maximal flu-or significantly differed from the weekly flu-or calculated within all icus belonging to that region. overall, our observations suggest that an accurate estimation of the influenza burden on icus requires a daily and real-time flu-or assessment, which seems feasible in view of our findings. in anticipation of the flu surge, health authorities decided that, in order to alleviate the pressure on icu beds, planned surgery activity should be cancelled when flu-or exceeded 15%. we contacted each participating icu and confirmed that no canceling of scheduled surgery had been decided although flu-or exceeded 15% in many icus. such peak activities occurred for more than 103 weeks among 32 units. future analysis may help to refine this threshold and thus may have to take into account how long it is exceeded. the magnitude of a pandemic and its consequences on the organization of a health-care system depend on several parameters and are notoriously difficult to predict [21, 22] . therefore, experiences reported during the first waves throughout the world were useful to better elaborate forecasts taking into account different attack rates and epidemic wave durations [23, 24] . data gathered in canada during the first wave were applied to a variety of second-wave models to determine its impact on icu and ventilator demand [21, 25] . an attack rate of greater than 20% can result in significant shortages in icu beds and ventilators [21] . retrospective estimations showed that attack rates in europe [26] , north america, and australia did not exceed 10% during each of the 2009 pandemic waves [27] . the overall impact also greatly depends on the durations of mechanical ventilation and icu stay. high attack rate combined with a short epidemic duration and long expected duration of mechanical ventilation represents the worst scenario in terms of bed occupancy rate and thus the maximal burden. given a 20% attack rate with a similar clinical presentation, french icu resources in university hospitals would probably have been overwhelmed, according to our observations. a weakness of our study is that only a subset of french icus participated in the screening. our cohort represented 35% of the whole french cohort reported during the same period to the health ministry. the distribution of the subset of university and non-university hospitals participating in this study within the seven areas (except in the northern area) suggests that french icu health-care resources were reasonably well represented (figure 1 ). this is supported by the comparability of baseline characteristics of patients within the present cohort to those of the entire french cohort (table 1 ) [3] . general inferences that can be made from this study are limited because of the difficulties in extrapolating from one health-care system to another. but regardless of the system, the primary goal here was to be able to assess, as closely to reality as possible, the related burden of an epidemic, and such an assessment was made possible by the specific screening registry. revisiting the pandemic plans in light of emergent findings is certainly a key issue to be able to cope with further pandemic waves. our observations suggest that the specific activity related to critically ill h1n1-infected (16) 40 (16) 52 (18) 48 (15) 37 (12) saps iii, mean (sd) 52 (17) 41 (13) 53 (14) 56.5 (17) 58.3 (17) duration of ventilation in days, median (iqr) 12 (5-24) 0 2 (4-10) 13 (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) 26 length of stay in icu in days, median (iqr) 10 (5-24) 4 (3-6) 8 (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) 17 (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) 26 obesity, number ( patients varied widely according to time, regions, and individual icus as well as within larger areas. we report maximal icu flu-ors that significantly exceed the 15% predefined critical threshold. the website registry described here and tested during the first pandemic wave in france allowed a real-time awareness of bed utilization and capacity. • a simple online registry permits us to accurately describe specific h1n1 icu burden in real time. • icu burden related to h1n1-infected patients varied widely according to time, regions, and individual icus. • in most icus, the maximal rate of bed occupancy by patients with flu exceeded the predefined 15% critical threshold. • online assessment of flu-or in the icu may help to better match resources and needs in case of new h1n1 pandemics. chausseret; ch d'annonay: v. cadiergue; ch d'armantières: c. canevet mourvillier; gh diaconesse croix saint simon flu-or) in university and non-university hospitals after all seven 'defense areas' were pooled together. for each week of the pandemic (from week 45 of 2009 to week 3 of 2010), national flu-or of university intensive care units (icus) (blue columns) was higher than that of non-university icus (red columns). *p < 0.05. richard et al sens: d. tonduangu; hopital de hautepierre f. blot; ch de versailles: m. henri-lagarrigue institute for biomedical research, 22 boulevard gambetta, rouen, 76183, france. 3 department of intensive care 19 bis rue la nouë bras de fer, nantes, 44200 france. 9 service de réanimation médicale chemin des bourelly, marseille, 13915, france. 12 service de réanimation médicale early estimates of 2009 pandemic influenza a(h1n1) virus activity in general practice in france: incidence of influenza-like illness and age distribution of reported cases real-time comparative 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french experience of 2009 a/h1n1v influenza in pregnant women gram negative bacteremia: i. etiology and ecology saps 3-from evaluation of the patient to evaluation of the intensive care unit. part 1: objectives, methods and cohort description the r project for statistical computing real-time epidemic forecasting for pandemic influenza modelling the impact of an influenza a/h1n1 pandemic on critical care demand from early pathogenicity data: the case for sentinel reporting potential intensive care unit ventilator demand/capacity mismatch due to novel swine-origin h1n1 in canada mortality and morbidity burden associated with a/h1n1pdm influenza virus pandemic a(h1n1) 2009 influenza: review of the southern hemisphere experience impact of pandemic (h1n1) 2009 influenza on critical care capacity in victoria critically ill patients with 2009 influenza a(h1n1) infection in canada triaging for adult critical care in the event of overwhelming need a lower than expected adult victorian community attack rate for pandemic (h1n1) 2009 interest of a simple on-line screening registry for measuring icu burden related to an influenza pandemic the reva registry was funded in part by the french ministry of health, the inserm-institut des maladies infectieuses, and the srlf. these funding sources had no role in the collection, analysis, or interpretation of the data.the authors acknowledge the help of isabelle bonmarin and claire fuhrman (french niphs, st maurice, france) for cross-checking notification forms. we thank didier potelune and catherine giguet (one science corporation, paris, france) and adrien constan (reva) for their contributions to the website design. we are indebted to the staff of the 89 icus for their active contributions to the study. reva correspondents for each participating center are listed in the list of contributors. we thank warren datziel for proofreading and english language editing. authors' contributions j-cmr helped to conceive of the study and participated in its design and coordination, helped to design the website registry and to coordinate data management, and participated in the editing of the manuscript. tp helped to conceive of the study and participated in its design and coordination, helped to coordinate data management, and participated in the editing of the manuscript. cb-b helped to conceive of the study and participated in its design and coordination and helped to design the website registry and to coordinate data management. am helped to conceive of the study and participated in its design and coordination and helped to design the website registry. lb helped to conceive of the study and participated in its design and coordination, helped to design the website registry, and participated in the editing of the manuscript. gb helped to design the website registry and actively participated in the study as a reva correspondent from the six most active centers. jr and br (president and member of the srlf, respectively) helped and encouraged participating centers to complete the screening registry. bm, cg, mc, ac, and ylt actively participated in the study as reva correspondents from the six most active centers. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord-252473-i4pmux28 authors: rogers, sharon title: why can't i visit? the ethics of visitation restrictions – lessons learned from sars date: 2004-08-31 journal: crit care doi: 10.1186/cc2930 sha: doc_id: 252473 cord_uid: i4pmux28 patients want, need and expect that their relatives will be able to visit them during inpatient admissions or accompany them during ambulatory visits. the sudden outbreak of severe acute respiratory syndrome (sars), or a similar contagious pathogen, will restrict the number of people entering the hospital. the ethical values that underlie visitor restrictions are discussed here. the sudden emergence of severe acute respiratory syndrome (sars) in april 2003 caused much concern and reaction. refereed medical journals ever since have been rife with articles about sars. the eventual containment and treatment of sars has seen a diminution of the massive media publicity and overt public concern. however, fears have recently surfaced about the potential for re-emergence of sars in the near future. as we confront the potential need to return to more stringent infection control measures once again, this is an appropriate time to reflect on the ethical values that underlay the strict visitation restrictions imposed in hospitals in ontario during the sars outbreak and the moderate restrictions in place since sars. this reflection will facilitate future decision making with respect to visitation restrictions. our infectious disease colleagues are adamant that restricting the movement of people into and around the hospital setting are effective clinical and epidemiological strategies that will help protect both the vulnerable patient population and health care providers themselves, who need to stay healthy so that they may care for their patients. one might argue, then, that visitation restrictions are both enhancing and supportive of public health protection. this position recognizes that there are times when public health protection overrides the protection of individual freedom. it could be argued that visitation restrictions, in light of a potential outbreak of a contagious disease, are ethically sound because of the compelling need to protect public health. however, even when public health concerns trump individual liberties, the ethical operationalization of this value would demand that 'those whose rights are being infringed' need to be managed in 'an ethical and even-handed manner so that they are not unfairly or disproportionately harmed by such measures' [1] . this is an important and far-reaching consideration because sars caused collateral damage and we know that the implementation of visitation restrictions will have an impact on a broad range of individuals. understandably, those patients who were confirmed or suspected of being carriers of contagious pathogens were easily and directly identified. however, there were people who had not demonstrated any risk or epidemiological link to a contagious disease but who experienced quarantine, restriction of movement, inconvenience, loss of pay, and inability to access important and sometimes vital services within the health care system. in fact, there was a general trend within the populace toward director, patient relations (the hospital ombudsman), university health network, toronto, ontario, canada avoiding meetings/gatherings, as well as kissing, hugging and even hand shaking. clearly, these restrictions are reflective of a loss of civil liberties in the general population and render expressions of caring difficult at a time when people may need them the most. in a health care institution, visitation restrictions not only affect inpatients but also have an impact on ambulatory patients who must come for diagnostic tests or interventions and who, if deprived access, might develop urgent or emergent conditions. restrictions are likely to cause distress, anxiety and increased complaints. in fact, on review of the university health network corporate complaint database, sars 1 (period march 28-april 20, 2003) and sars 2 (period may 12-august 10, 2003) generated a 27% increase in complaints over the expected number of complaints for that time period. specifically, during this time period there would normally have been 770 calls of complaint, but with sars 1 and 2 a total of 1052 calls of complaint were received. it should be stressed that these data are over and above the complaints received at each site of the corporation, which were not captured in the database. ultimately, this is a set of problems that must be managed with sensitivity and clarity (nyhof-young and colleagues, unpublished data). in view of the magnitude of implications of visitor restriction, it is important that policy decisions, at the micro or macro level, consider issues of equity, publicity, transparency and the appeal process. issues of equity must take into consideration the known facts from a scientific perspective as well as the range of approaches considered. in terms of transparency and due diligence, the rationale behind the policies and how they will be implemented should be as clear and unambiguous as possible. feedback should be sought from those individuals who would be affected by visitation restrictions, such as staff, patients and family members. the policy must be made accessible, printed and broadly circulated throughout the hospital so that people understand the rules, the rationale for those rules, the processes available to them to assist them in 'living with those rules' and ways to appeal in special circumstances. visitation policy developers must realize that there may be exceptional circumstances that demand exceptional latitude. the development of criteria for exceptionality must recognize the need for proportionality, ensuring that criteria are 'relevant, legitimate and necessary … and should be applied without discrimination' [1] . furthermore, to be consistent with expectations of transparency, the criteria by which exceptionality to the rules of visitation restriction exists should also be published openly throughout the organization for staff, patients and visitors. from our experience with sars, a corporate policy was developed and there was an expectation that there would be compliance with this corporate policy. however, it was also acknowledged that local patient needs would dictate more or less stringent adherence to these rules, and that the degree of adherence might change quickly without the opportunity for broad notification. for example, although current policy allows for specific times of visitation and numbers of visitors per day, a sudden outbreak might dictate a quick lockdown of the facility without patients or family members receiving prior notice. a health care professional has a duty to care, based on several ethical considerations [1] such as professional code of conduct, intrinsic requirements of the work and the acceptance of risk as part of the decision to do a specific type of work. part of this duty to care for patients encompasses a broader duty, in that one must care for their family as well. visitation restrictions impede this ability because health care providers find themselves in the awkward position of conveying very private, personal messages between patients and family members, of providing updates and of breaking bad news over the phone, thus losing their ability to convey empathy or judge the amount of support required effectively. moreover, health care workers, being in direct communication with patients and families, bear the brunt of their anger and frustration regarding any restriction in visitation. there is an implicit acceptance that reciprocity exists between the hospital organization and the individual staff member [1] . to this end, it is the organization that must accept responsibility for making rules and communicating them broadly to all staff, patients and visitors. similarly, it is the responsibility of the organization to enforce compliance with these rules; it is not the responsibility of staff, whose primary responsibility is to discharge the duty of care to the patient. the organization also has the responsibility of developing a set of criteria outlining exceptionality and a process to receive, review and adjudicate requests. a process must be developed (together with appropriate resources) so that staff members know who to access for support and are able to do this is in an easy and expeditious manner. in the interests of the public good, there may be times when information must be shared publicly, thereby impinging on the rights of the individual to privacy and confidentiality. with respect to restricted visitation, an ethical argument could be made that visitation restrictions (or latitude thereof) can be instituted generally, without specifically naming names. although the vigilant observer might be able to identify a specific person from a changed application of the rule, the organization cannot reasonably be expected to guard against every possible identification, but every effort should be made to protect the individual from easy identification. for example, if a family is allowed to visit a patient whose death is presumed to be imminent (within the next 24 hours), then the patient's identity should be protected by using privacy strategies. efforts to protect the patient's identity are consistent with the ethical value of 'protection of communities from undue stigmatization' [1] . given the risks associated with contagious pathogens and the easy mode of transmission globally, it is important that there be consistency in management. the ideal situation would be a consistent global approach to the management of each and every contagious pathogen. the notion of universal management strategies is very sensible (e.g. universal precautions with blood-borne conditions such hiv). however, given the political and economic disparities across the world as well as the lack of knowledge (particularly of newly evolving pathogens), a standardized approach is not possible. the experience of sars indicates that some patient populations require a level of vigilance that is more stringent than that required in others. for example, those individuals who reported recent travel to high risk areas, and those who worked in quarantined or contaminated hospitals or who exhibited clear symptoms (e.g. fever, persistent cough) were scrutinized with more vigilance and were in fact treated differently than other visitors, until they were cleared through the screening process. this type of variability in vigilance demands ethical management of differences, and there is a need to guard against overt bias or discrimination creeping into the process. it is difficult to expect that both standardization of approach and variability in approach can easily coexist, but the operational challenge is to exercise awareness of the ethical values discussed above and the appropriate due diligence in the implementation of processes. it is ethical to accept that public health protection trumps individual rights to liberal visitation. the rationale for this position must be fully outlined to patients, visitors and staff. in responding to visitors who may be deprived of visitation, it is ethical to recognize that there may be exceptional circumstances that demand exceptional latitude. a set of criteria outlining exceptionality should be developed, as should a process to receive, review and adjudicate requests. in the interests of equity, an appeal process should be made explicit and transparent to all. this information should be well publicized to staff, patients and visitors in a consistent and sensitive manner. every reasonable effort should be made to protect the individual patient's identity and their specific health status should exceptionality be considered. it is ethically the responsibility of the organization to enforce compliance with restricted visitation and a corporate department should be assigned this task. ethics and sars: learning lessons from the toronto experience. available from the centre for bioethics website thanks to dr laura hawryluck, co-editor of the medical ethics commentaries section of critical care, for her patient editing and insightful comments. although it is recognized that standardization in the application of visitation restrictions is necessary, there is recognition that there may be circumstances that would require deviation from the corporate position. the author declares that she has no competing interests. key: cord-000217-chd9ezba authors: anas, adam; poll, tom van der; de vos, alex f title: role of cd14 in lung inflammation and infection date: 2010-03-09 journal: crit care doi: 10.1186/cc8850 sha: doc_id: 217 cord_uid: chd9ezba this article is one of ten reviews selected from the yearbook of intensive care and emergency medicine 2010 (springer verlag) and co-published as a series in critical care. other articles in the series can be found online at http://ccforum.com/series/yearbook. further information about the yearbook of intensive care and emergency medicine is available from http://www.springer.com/series/2855. toll-like receptors (tlr) on the surface of cells of the respiratory tract play an essential role in sensing the presence of microorganisms in the airways and lungs. th ese receptors trigger infl ammatory responses, activate innate immune responses, and prime adaptive immune responses to eradicate invading microbes [1] . tlr are members of a family of pattern-recognition receptors, which recognize molecular structures of bacteria, viruses, fungi and protozoa (pathogen-associated molecular patterns or pamps), as well as endogenous structures and proteins released during infl ammation (damage/ danger-associated molecular patterns or damps). to date, ten diff erent tlr have been identifi ed in humans and twelve in mice. tlr are expressed on all cells of the immune system, but also on parenchymal cells of many organs and tissues. th e binding of a pamp to a tlr results in cellular activation and initiates a variety of eff ector functions, including cytokine secretion, prolifera tion, co-stimulation or phagocyte maturation. to facilitate microbial recognition and to amplify cellular responses, certain tlr require additional proteins, such as lipopolysaccharide (lps) binding protein (lbp), cd14, cd36 and high mobility group box-1 protein (hmgb-1). in this chapter, the role of cd14 as an accessory receptor for tlr in lung infl ammation and infection is discussed. th e central role of cd14 in the recognition of various pamps and amplifi cation of immune and infl ammatory responses in the lung is depicted in figure 1 . cd14 was characterized as a receptor for bacterial endotoxin (lps) in 1990, almost a decade before the discovery and characterization of tlr, and can be regarded as the fi rst described pattern-recognition receptor [2] . th e protein was fi rst identifi ed as a diff erentiation marker on the surface of monocytes and macrophages and was designated cd14 at the fi rst leukocyte typing workshop in paris in 1982. th e genomic dna of human cd14 was cloned in 1988 and the gene was later mapped to chromo some 5q23-31. several polymorphisms have been found in the cd14 gene, of which nucleotide polymorphisms at position -159 and -1619 correlated with decreased lung function in endotoxin-exposed farmers [3] . th e cd14 gene consists of two exons which code for a single mrna that is translated into a protein of 375 amino acids. th e cd14 protein is composed of eleven leucin-rich repeats, which are also found in tlr and which are important in pamp binding. moreover, the crystal structure of cd14 revealed that the protein has a `horseshoe' shape, similar to tlr4, and that lps is bound within the pocket [4] . in contrast to tlr, however, cd14 lacks a transmembrane domain, and thus cannot initiate intracellular signal transduction by itself. th e cd14 protein is processed in the endoplasmatic reticu lum and expressed as a 55 kda glycoprotein on the cell surface via a glycosylphosphatidyl (gpi) anchor [5] . like other gpianchored proteins, cd14 accumulates on the cell surface in microdomains known as lipid rafts, which are fairly rich in cholesterol and accumulate several kinases at the intracellular site. cd14 is expressed pre dominantly on the surface of `myeloid' cells, such as mono cytes, macrophages and neutrophils, but at lower levels also on epithelial cells, endothelial cells and fi broblasts. in addition to being expressed as a gpi-anchored membrane protein, cd14 is also expressed in a soluble form (scd14) [2] . scd14 may result from secretion of the protein before coupling to the gpi anchor or from shedding or cleavage from the surface of monocytes. scd14 is present in the circulation and other body fl uids and levels of scd14 in plasma increase during infl ammation and infection. since interleukin (il)-6 induces scd14 expression in liver cells it is regarded as an acute phase protein. in bronchoalveolar lavage (bal) fl uid from patients with acute respiratory distress syndrome (ards), scd14 levels were strongly increased and correlated with total protein levels and neutrophil numbers in the bal fl uid [6] , suggesting that scd14 contributes to the infl ammatory process in the lung. cd14 is a molecule with a wide range of functions. in addition to functioning as a pattern recognition receptor for a variety of microbial ligands, cd14 also acts as a receptor for endogenous molecules like intercellular adhesion molecule (icam)-3 on the surface of apoptotic cells, amyloid peptid, ceramide, and urate crystals. ligation of cd14 by these ligands, except for apoptotic cells, mediates activation of infl ammatory responses. lps is the major constituent of the outer membrane of gram-negative bacteria and is one of the most potent tlr ligands. cd14 together with lbp plays an essential role in binding of lps to the tlr4/md-2 complex [7] . lbp, which, among others, is present in the bloodstream and bal fl uid [8] , binds to lps aggregates and transfers lps monomers to cd14. cd14 associates with tlr4/ md-2 and transfers the lps monomer to this complex [7] . likewise, scd14 is able to mediate lps-activation of cells with low membrane cd14 expression, such as epithelial and endothelial cells [9] . however, at high con cen trations, lbp and scd14 are also able to downregulate lps-induced responses by transfer of lps to lipoproteins for subsequent removal [10] . recent data indicate that lps is bound by md-2 within the tlr4/ md-2 complex [11] and that subsequent conformational changes in tlr4 lead to reorganization of its cytoplasmic domain, enabling the recruitment of the adaptor proteins, myeloid diff erentiation primary-response protein 88 (myd88) and tir-domain-containing-adaptorprotein-inducing-inter feron (ifn)-β (trif) [12] . th ese adaptors initiate signal transduction to the nucleus by activation of nuclear factor (nf)-κb and ifn regulatory transcription factor (irf)-3, leading to the production of cytokines that regulate infl ammatory cells [12] . in macrophages, trif-dependent signaling is essential for the expression of the majority of lps-induced genes, including ifn-α/β. cd14, which lacks an intracellular domain for signal transduction, is expressed on the surface of alveolar macrophages, infi ltrating monocytes and neutrophils, and at lower levels also on epithelial and endothelial cells in the lung. cd14 recognizes and binds various structures from invading microbes, such as lipopolysaccharide (lps) from gram-negative bacteria, lipoteichoic acid (lta) from gram-positive bacteria, lipoarabinomannan (lam) from mycobacteria, viral double stranded (ds) rna and f glycoprotein (f-gp) from respiratory syncytial virus (rsv). cd14 subsequently transfers these bound components to toll-like receptors (tlr) which than trigger cell activation. binding of lps to cd14 is regulated by additional accessory receptors in the lung, including lps-binding protein (lbp) and a number of surfactant proteins (sp). furthermore, soluble cd14 (scd14) enhances lps-induced activation of cells with low cd14 expression. depending on the microbe and the pamps it expresses, cd14-amplifi ed responses can either be benefi cial to the host by induction of an adequate infl ammatory and immune response to eradicate the invading microbe, or detrimental to the host by excessive infl ammation and/or dissemination of the pathogen. recently, it was reported that, in the absence of cd14, the tlr4/md-2 complex can distinguish between diff erent chemotypes of lps [13] . smooth lps is synthesized by most gram-negative bacteria and consists of three modules: th e lipid a moiety, a core poly saccharide, and an o-polysaccharide of variable length (made up of 1 to over 50 monosaccharide units) [7] . gram-negative bacteria that fail to add the core polysaccharide or the o-polysaccharide chain to the lipid a moiety produce `rough' lps, named after the rough morphology of the colonies these bacteria form. lipid a, the bioactive part of both smooth and rough lps, is responsible for most of the pathogenic eff ects in gram-negative bacterial infections [7, 12] . murine macrophages lacking cd14 secreted equal amounts of tumor necrosis factor-α (tnf) to macrophages expressing cd14 upon stimulation with rough lps, but failed to secrete tnf in response to smooth lps, an eff ect which was reversed by addition of scd14 [13] . moreover, macrophages lacking cd14 failed to secrete ifn-α/β in response to either rough or smooth lps. th ese fi ndings indicate that cd14 is required for activation of the tlr4/trif pathway by either smooth or rough lps, and required for the activation of tlr4/ myd88 pathway by smooth but not by rough lps [13] . in addition to lps, cd14 also facilitates tlr4 activation by other pamps including certain viral components [13, 14] . in the lung, binding of lps to tlr4 is infl uenced by a number of surfactant proteins (sp), including sp-a, sp-c and sp-d [15] . th ese surfactants are able to infl uence the interaction between tlr4 and lps by direct binding to lps; i.e., sp-a binds to rough lps and lipid a, but not to smooth lps, sp-c also binds to rough lps, and sp-d binds to both rough and smooth lps. sp-a and sp-c binding to lps inhibits tnf secretion by alveolar macrophages, whereas sp-d binding to lps moderately enhances tnf secretion by alveolar macrophages. in addition, sp-a, sp-c and sp-d also bind to cd14 at the site which recognizes lps. strikingly, binding of sp-a to cd14 enhanced the binding of rough lps and binding of sp-c to cd14 augmented binding of smooth lps [15] , whereas binding of sp-a to cd14 reduced binding of smooth lps and binding of sp-d to cd14 decreased binding of both smooth and rough lps. furthermore, sp-d infl uences lps-induced tnf secretion by alveolar macrophages by regulating matrix metalloproteinasemediated cleavage of cd14 from the surface of these cells [16] . together, these fi ndings suggest that lps recognition in the lung and subsequent induction of infl ammatory immune response is a complexly regulated process. in addition to lps-induced activation of tlr4, cd14 also amplifi es a number of tlr-dependent responses triggered by other bacterial pamps, including peptidoglycan, lipoteichoic acid (lta) and lipoarabinomannan (lam) [17] [18] [19] . peptidoglycan is an essential cell wall component of virtually all bacteria. peptidoglycan is a polymer of nacetylglucosamine and n-acetylmuramic acid, crosslinked by short peptides. breakdown products of peptido glycan are recognized by diff erent classes of pattern-recognition receptors [19] . polymeric soluble peptidoglycan is recognized by tlr2 on the surface of cells, and the interaction of peptidoglycan with tlr2 triggers myd88-dependent activation and nuclear translocation of nf-κb, and subsequently the transcription and secretion of cytokines. muramyl dipeptide and γ-dglutamyl-meso-diaminopimelic acid, which are lowmolecular weight breakdown fragments of peptidoglycan, are recognized by intracellular pathogen recognition receptors, nucleotide-binding oligomerization domain containing (nod)2 and nod1, respectively [19] . ligand binding to these receptors triggers interaction with the receptor-interacting protein kinase, rip2, which activates nf-κb. of these peptidoglycan breakdown products, only polymeric peptidoglycan binds to cd14, and cd14 enhances polymeric peptidoglycan-induced tlr2 activation. th e low molecular weight fragments of peptidoglycan, like muramyl dipeptide, do not bind to cd14, do not induce cell activation through cd14 and also do not interfere with the binding of polymeric peptidoglycan to cd14 [19] . furthermore, unlike lps, peptidoglycan bound to scd14 is not able to activate epithelial and endothelial cells with low membrane cd14 expression. lta is a constituent of the cell wall of gram-positive bacteria, anchored on the outer face of the cytoplasmic membrane and commonly released during growth and antibiotic therapy. like polymeric peptidoglycan, lta induces nf-κb activation and cytokine secretion in a tlr2-dependent manner. lta is recognized by lbp and cd14, and these accessory receptors both enhance ltainduced cell activation [18] . presumably in a similar manner, cd14 also enhances tlr2-dependent cellular activation by lam derived from the cell-wall of mycobacteria. lam derived from slowly growing virulent mycobacteria like mycobacterium tuberculosis and m. leprae is capped with mannose (manlam), whereas lam from avirulent and fast growing mycobacterial species is uncapped (aralam). strikingly, aralam from avirulent mycobacteria is much more potent in inducing tnf secretion by macrophages than manlam from virulent mycobacterial strains [12] . aralam-, but not manlam-induced tnf secretion by monocytes and macrophages was largely cd14-, tlr2-and myd88dependent [17] . recently cd14 was also found to enhance the innate immune response triggered by the tlr3 ligand poly(i:c), a synthetic mimic of double stranded rna [20] . tlr3 together with tlr7 and tlr8 are regarded as sensors for viral infection, since these receptors recognize viral nucleic acids, like single and double stranded rna. th e potentiating eff ect of cd14 on tlr3 activation resulted from increased uptake of poly(i:c) and intracellular delivery to the compartment where tlr3 resides [20] . taken together, these fi ndings suggest that cd14 plays an important role in the induction and amplifi cation of infl ammatory responses evoked by a wide variety of pathogens. th e contribution of cd14 to tlr ligand-induced lung infl ammation has been investigated in several animal studies (table 1) . intratracheal administration of lps did not signifi cantly induce tnf release and neutrophil accumulation in the lungs of rabbits, unless lps was complexed with lbp [21] or the animals were subjected to mechanical ventilation [22] . intratracheal instillation of anti-cd14 antibodies together with lps/lbp or intravenous pretreatment with anti-cd14 or anti-tlr4 antibodies before mechanical ventilation markedly reduced these infl ammatory responses [21, 22] . despite a reduction in lung neutrophil number, intravenous anti-cd14 treatment of rabbits exposed to lps and subjected to ventilation did not cause a decrease in lung chemokines, including cxcl8 (il-8), growth related oncogene (gro) and monocyte chemoattractant protein (mcp)-1, whereas anti-tlr4 treatment did lower the level of gro moderately and of cxcl8 signifi cantly [22] . th ese fi ndings reveal that lps alone does not cause signifi cant lung infl ammation in rabbits and suggest that additional accessory signals are required. whether mechanical ventilation induces increased release of lbp or release of (endogenous) damps which potentiate the lps-induced response remains to be determined. in contrast to rabbits, administration of lps alone to lungs of naive mice induced severe pneumonitis, irrespective of the manner of lps delivery (inhalation or intra tracheal or intranasal instillation) or the source of lps (escherichia coli or acinetobacter baumannii). using antibody-treated and gene-defi cient mice, cd14 was found to be critically involved in the development of lps-induced lung infl ammation [23] [24] [25] [26] . a study with cd14-defi cient mice and tlr4 mutant mice (lacking a functional tlr4) showed that lps-induced vascular leakage, neutrophil infi ltration, nuclear translocation of nf-κb. th e release of cytokines (tnf and il-6) and chemo kines (cxcl1 and cxcl2) in the lung was completely dependent on these pattern recognition receptors [24] . similar observations were made by others using mice treated intravenously with anti-cd14 infl uenza a mouse cd14 -/-/~clearance, ~lymphocyte recruitment and activation, ~neutrophil infl ux, 50 ~cytokines antibodies [23] and by our group using cd14-defi cient and tlr4-defi cient mice [25] . furthermore, intratracheal treatment of cd14-defi cient mice with scd14 restored the infl ammatory response to the level present in wildtype mice, whereas treatment with wild-type alveolar macrophages restored the neutrophil infi ltration of the lung but not pulmonary tnf release [26] . moreover, treatment with wild-type alveolar macrophages also restored neutrophil infi ltration in the lung of lpsexposed tlr4-defi cient mice [27] . th ese fi ndings indicate that scd14, and cd14 and tlr4 on the surface of alveolar macrophages contribute to the development of lps-induced lung infl ammation. however, when a high dose of lps was administered to the lungs of mice, acute lung infl ammation was absent in mice lacking functional tlr4, but only partially reduced in cd14 defi cient mice [24] . th us, lps-induced lung infl am mation is entirely dependent on tlr4 and, depending on the dose of lps, also on the presence of cd14 in the lung. our group determined whether cd14 also contributes to the development of lung infl ammation induced by lta, a tlr2 ligand from the cell wall of gram-positive bacteria [28, 29] . lung infl ammation induced by staphylo coccus aureus lta was completely dependent on tlr2, but independent of lbp and only moderately dependent on cd14 expression. as compared to wildtype mice, s. aureus lta-induced neutrophil infl ux was unchanged in cd14-defi cient mice, whereas tnf and cxcl2 release in the lung were partially reduced [28] . strikingly, however, pulmonary infl ammation was also greatly diminished in tlr4-defi cient mice, as well as in mice defi cient for platelet activating factor receptor (pafr), a known receptor for lta on epithelial cells. similarly, lung infl ammation induced by streptococcus pneumoniae lta, which is less potent compared s. aureus lta, was also completely dependent on tlr2 expression. however, in contrast to s. aureus lta, neutrophil infi ltration of the lung was moderately reduced in cd14-defi cent mice treated with pneumococcal lta, whereas tnf and cxcl2 release in the lung was unchanged [29] . moreover, pneumococcal ltainduced lung infl ammation was moderately diminished in tlr4-defi cient mice. th us, despite the amplifying eff ect on lta-induced tlr2-mediated responses in vitro, cd14 contributes minimally to lung infl ammation induced by lta. th e unexpected contribution of tlr4 to lta-induced lung infl ammation may result from damps generated during the infl ammatory process in the respiratory tract. in line with the fi ndings that cd14 contributes to lpsinduced lung infl ammation in mice, a number of studies have shown that cd14 is essential for the host defense response in the lung against gram-negative bacteria, such as nontypeable haemophilus infl uenzae, a possible cause of community acquired pneumonia, and a. baumannii and e. coli, which are frequent inducers of nosocomial pneumonia (table 1) . nontypeable h. infl uenzae expresses the tlr4 ligands lps and lipooligosaccharide on its cell wall, as well as several tlr2 ligands, including lipoproteins and porins. previously, we found that activa tion of alveolar macrophages by nontypeable h. infl uenzae depended on expression of tlr4, tlr2, and cd14 [30] . moreover, bacterial clearance after intranasal infection with nontypeable h. infl uenzae was markedly reduced in cd14-defi cient and tlr4-defi cient mice, as well as in tlr2-defi cient mice at later stages of the disease [30] . interestingly, despite impaired bacterial clearance in cd14-defi cient and tlr4-defi cient mice, the infl ammatory response in the lung was strongly reduced in tlr4 defi cient mice, but elevated in cd14 defi cient mice. similar observations were made with encapsulated h. infl uenzae in tlr4-mutant mice [31] . furthermore, clearance of nontypeable h. infl uenzae was also significantly impaired in myd88-defi cient mice, but not in mice lacking functional trif [30] . in a similar manner, cd14 was involved in the host defense response against a. baumanii [25] . cd14-defi cient mice, like tlr4defi cient mice, suff ered from impaired bacterial clearance in the lungs and enhanced bacterial dissemination after intranasal infection with a. baumannii. however, unlike tlr4-defi cient mice, cd14-defi cient mice developed similar infl ammatory responses compared to wild-type mice. th ese fi ndings suggest a role for cd14 in antibacterial responses against nontypeable h. infl uenzae and a. baumannii. although the role of tlr4 (and tlr2) in phagocytic killing is controversial, it is unknown whether cd14 is involved in such processes. th e role of cd14 in e. coli-induced pneumonia was determined in anti-cd14 antibody treated rabbits. intravenous anti-cd14 antibody treatment of rabbits inoculated with e. coli by bronchial instillation, resulted in decreased bacterial clearance from the lungs, but had no eff ect on neutrophil infi ltration or cytokine release in the lungs [32] . however, anti-cd14 treatment protected against sustained hypotension and reduced the levels of nitrate and nitrite in the blood. th e contribution of cd14 to e. coli-induced pneumonia has not been investigated in mice, whereas the role of the other components of the lps receptor complex (tlr4, md-2, myd88, trif) has been determined using gene-defi cient or mutant mice. although analysis of bacterial clearance after intranasal infection of tlr4-mutant mice with e. coli produced inconsistent results [33] , lack of md-2 or trif resulted in impaired bacterial clearance after e. coli instillation in the lungs [34, 35] . moreover, e. coli-induced neutrophil accumulation and cytokine release was signifi cantly reduced in mice devoid of functional tlr4, md-2, myd88 or trif [33] [34] [35] . th ese fi ndings indicate that signaling through the tlr4 receptor complex is essential in the host defense response against e. coli, and suggests that cd14 may contribute to these e. coli-induced responses. to our knowledge, it is unclear whether cd14 contributes to host defense against pseudomonas aeruginosa, a frequent cause of nosocomial pneumonia, and burkholderia cepacia, a prevalent gram-negative bacterium, together with p. aeruginosa, in patients with cystic fi brosis. recently, it was found that both tlr4 and tlr5 are critical in the host response to p. aeruginosa and that tlr4-defi cient mice were not susceptible to intratracheal p. aeruginosa infection unless a bacterial mutant devoid of fl agellin production was used [36] . a similar approach is required to determine a role for cd14 in pseudomonas-induced pneumonia. it is plausible that cd14 also contributes to the host response against b. cepacia, since lps from this bacterium signals through tlr4 and anti-cd14 antibodies dramatically inhibited b. cepacia-induced chemokine secretion by lung epithelial cells [37] . whether cd14 contributes to host defense response against klebsiella pneumoniae, a known cause of nosocomial pneumonia, also remains to be determined, but data from our study with tlr4-mutant mice indicate that signaling through tlr4 is essential for successful clearance of this bacterium [38] . in contrast to the essential role of pulmonary tlr4 and cd14 in the host defense response against most gramnegative bacteria, we found that tlr4 was not involved and cd14 played a remarkable detrimental role in the host response to b. pseudomallei, the causative organism of melioidosis (the most common cause of communityacquired sepsis in southeast asia) [39, 40] . cd14defi cient mice infected intranasally with b. pseudomallei were protected from mortality, accompanied by enhanced bacterial clearance in the lung, blood and liver, and reduced cellular infi ltration in the lung [39] , whereas the course of disease in tlr4-defi cient mice was indistinguishable from wild-type mice [40] . moreover, intranasal administration of scd14 to cd14-defi cient mice partially reversed the phenotype into that of wild-type mice [40] . interestingly, these fi ndings in b. pseudo mallei-infected cd14-defi cient mice strongly resemble our previous results found with tlr2-defi cient mice, and are in line with the observation that b. pseudomallei expresses an atypical lps which signals through tlr2 [39] . whether cd14 interacts with tlr2 in b. pseudo mallei-induced responses, and by which mechanism these receptors facilitate the growth and dissemination of b. pseudomallei after intranasal infection remains to be determined. in the model for s. pneumoniae-induced pneumonia, we observed an unexpected detrimental role for cd14 in the innate host defense response. s. pneumoniae, a gram-positive bacterium and the single most frequent pathogen causing community-acquired pneumonia, induces severe lung infl ammation and sepsis in wild-type mice after intranasal instillation. strikingly, cd14defi cient mice were protected against pneumococcal pneumonia, presumably as a result of reduced bacterial spread to the circulation and reduced lung infl ammation [41] . in contrast, tlr2-defi cient and tlr4-mutant mice were not protected against pneumococcal pneumonia [38, 42] , but in fact tlr2 seemed redundant for effi cient bacterial clearance and tlr4-mutant mice were more susceptible to pneumonia, accompanied by impaired bacterial clearance. however, as in cd14-defi cient mice, lung infl ammation was also reduced in pneumococciinfected tlr2-defi cient mice [42] . since intrapulmonary treatment with scd14 rendered cd14-defi cient mice equally susceptible to s. pneumoniae as wild-type mice [41] , these results suggest that s. pneumoniae abuses (s) cd14 in the lung to cause invasive respiratory tract infection. interestingly, the phenotype of cd14 defi cient mice strongly resembled the phenotype of mice defi cient for pafr [43] , a receptor for phosphoryl choline from the pneumococcal cell wall which facilitates pneumococcal invasion of cells. further studies are required to determine whether cd14 serves as a chaperone in the presentation of s. pneumoniae to the pafr so that the phosphoryl-pafr-mediated invasion is facilitated. since m. tuberculosis expresses a number of molecules, such as lipoproteins, which activate immune cells in a cd14-dependent manner, we and others investigated whether cd14 also contributed to the host immune response in mice with lung tuberculosis [44] . although initially after intranasal infection of wild-type and cd14defi cient mice no diff erences in bacterial loads, cell infi ltration and release of most cytokines in the lung were found [44, 45] , at later time points (> 20 weeks after infection) cd14-defi cient mice were protected from mortality presumably as a result of a reduced infl ammatory response in the lungs [44] . th ese fi ndings are completely opposite to the results from m. tuberculosisinfected tlr2-defi cient and tlr4-mutant mice, which suff ered from reduced bacterial clearance, chronic infl ammation, increased cellular infi ltration of the lungs and reduced survival [46] [47] [48] . th e mechanism underlying the detrimental eff ect of cd14 in the host response against m. tuberculosis remains to be established. in addition to its role in (myco)bacterial infections, cd14 may also play a role in the pulmonary host response against respiratory syncytial virus (rsv), the most common cause of lower respiratory tract disease in infants and young children worldwide, and infl uenza a virus, a cause of pneumonia in very young children, the elderly and immunocompromised patients. th e envelop f glycoprotein from rsv and certain infl uenza a virus components activate macrophages in a cd14-dependent manner [14, 20] . experiments with wild-type and tlr4mutant mice infected intranasally with rsv showed that viral clearance was reduced in the absence of functional tlr4 [14] , due to impaired natural killer (nk) cell migration and function and impaired cytokine secretion. recently, it was found that tlr2 and tlr6 are also involved in recognition of rsv [49] . whether cd14 contributes to these tlr-mediated immune responses against rsv remains to be determined. using cd14defi cient mice, we demonstrated that cd14 played a minimal role in infl uenza a virus-induced pneumonia [50] . during the entire course of disease, viral loads were slightly reduced in cd14-defi cient mice, but this did not result from improved lymphocyte recruitment or lympho cyte activation, or consistent changes in pulmonary cytokines [50] . th us, despite the fact that infl uenza a expresses ligands that require cd14 for immune cell activation [20] , cd14 seems redundant in the host defense response against infl uenza a virus. cd14 plays a central role in the lung in the recognition and binding of a variety of (myco)bacterial and viral components, and in the amplifi cation of subsequent host responses. th e studies discussed in this chapter indicate that the contribution of cd14 to the pulmonary host defense responses may range from benefi cial to detrimental, depending on the microbe and the pamps it expresses. interfering with cd14-lps or cd14-lta inter actions reduced lung infl ammation. interference with cd14-pathogen interactions, however, did not have a signifi cant eff ect on m. tuberculosis or infl uenza a virus infection, resulted in reduced clearance of nontypeable h. infl uenzae, e. coli or a. baumannii in the lung, but enhanced clearance (and reduced dissemination) of b. pseudomallei or s. pneumoniae. th e latter observation indicates that certain pathogens may abuse cd14 in the lung to cause invasive disease. whether cd14 is a suitable target for intervention in these latter infectious diseases and/or in aberrant infl ammatory responses during pneumonia requires further study. abbreviations ards = acute respiratory distress syndrome, bal -broncoalveolar lavage, damp = damage/danger-associated molecular pattern, f-gp = f glycoprotein, gpi = glycosylphosphatidyl, gro = growth related oncogene, hmgb-1 = high mobility group box-1 protein, icam = intracellular adhesion molecule, ifn = interferon, il = interleukin, irf = ifn regulatory transcription factor, lam = lipoarabinomannan, lbp = lipopolysaccharide binding protein, lps = lipopolysaccharide, lta = lipoteichoic acid, mcp = monocyte chemoattractant protein, myd88 = myeloid diff erentiation primary-response protein 88, nf = nuclear factor, nk = natural killer, nod = nucleotide-binding oligomerization domain containing, pafr = platelet activating factor resceptor, pamp = pathogen-associated molecular pattern, rip = receptorinteracting protein kinase, rsv = respiratory syncytial virus, sp = surfactant protein, tlr = toll-like receptors, tnf = tumour necrosis factor, trif = tir-domain-containing-adaptor-protein-inducing-interferon-β toll-like receptors: function and roles in lung disease cd14 and innate recognition of bacteria polymorphisms in the cd14 gene associated with pulmonary function in farmers crystal structure of cd14 and its implications for lipopolysaccharide signaling cd14, a receptor for complexes of lipopolysaccharide (lps) and lps binding protein relationship between soluble cd14, lipopolysaccharide binding protein, and the alveolar infl ammatory response in patients with acute respiratory distress syndrome innate immune sensing and its roots: the story of endotoxin van der poll t: pulmonary lipopolysaccharide (lps)-binding protein inhibits the lps-induced lung infl ammation in vivo lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharidebinding protein and soluble cd14 modulatory eff ects of scd14 and lbp on lps-host cell interactions the structural basis of lipopolysaccharide recognition by the tlr4-md-2 complex pathogen recognition and innate immunity cd14 is required for myd88-independent lps signaling pattern recognition receptors tlr4 and cd14 mediate response to respiratory syncytial virus augusto: la interactions between lps and lung surfactant proteins surfactant protein-d regulates soluble cd14 through matrix metalloproteinase-12 cd14 is a pattern recognition receptor lipoteichoic acid (lta) of streptococcus pneumoniae and staphylococcus aureus activates immune cells via toll-like receptor (tlr)-2, lipopolysaccharide-binding protein (lbp), and cd14, whereas tlr-4 and md-2 are not involved peptidoglycan recognition in innate immunity double-stranded rna-mediated tlr3 activation is enhanced by cd14 lipopolysaccharide binding protein and cd14 interaction induces tumor necrosis factor-alpha generation and neutrophil sequestration in lungs after intratracheal endotoxin eff ect of toll-like receptor 4 blockade on pulmonary infl ammation caused by mechanical ventilation and bacterial endotoxin eff ect of cd14 blockade on endotoxin-induced acute lung injury in mice distinct roles of pattern recognition receptors cd14 and toll-like receptor 4 in acute lung anas et al. critical care diff erential roles of cd14 and tolllike receptors 4 and 2 in murine acinetobacter pneumonia cd14 is an essential mediator of lps induced airway disease the role of toll-like receptor 4 in environmental airway injury in mice lipoteichoic acid-induced lung infl ammation depends on tlr2 and the concerted action of tlr4 and the platelet-activating factor receptor role played by toll-like receptors 2 and 4 in lipoteichoic acid-induced lung infl ammation and coagulation the myd88-dependent, but not the myd88-independent, pathway of tlr4 signaling is important in clearing nontypeable haemophilus infl uenzae from the mouse lung toll-like receptor 4 mediates innate immune responses to haemophilus infl uenzae infection in mouse lung eff ect of cd14 blockade in rabbits with escherichia coli pneumonia and sepsis tlr-4 pathway mediates the infl ammatory response but not bacterial elimination in e. coli pneumonia toll/il-1 receptor domaincontaining adaptor inducing ifn-beta (trif)-mediated signaling contributes to innate immune responses in the lung during escherichia coli pneumonia myeloid diff erentiation protein-2-dependent and -independent neutrophil accumulation during escherichia coli pneumonia control of pseudomonas aeruginosa in the lung requires the recognition of either lipopolysaccharide or fl agellin burkholderia cepaciainduced il-8 gene expression in an alveolar epithelial cell line: signaling through cd14 and mitogen-activated protein kinase role of toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice toll-like receptor 2 impairs host defense in gram-negative sepsis caused by burkholderia pseudomallei (melioidosis) cd14 impairs host defense against gram-negative sepsis caused by 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cd14 plays a limited role during infl uenza a virus infection in vivo the authors declare that they have no competing interests. key: cord-003376-2qi4aibx authors: van de groep, kirsten; nierkens, stefan; cremer, olaf l.; peelen, linda m.; klein klouwenberg, peter m. c.; schultz, marcus j.; hack, c. erik; van der poll, tom; bonten, marc j. m.; ong, david s. y. title: effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study date: 2018-12-18 journal: crit care doi: 10.1186/s13054-018-2261-0 sha: doc_id: 3376 cord_uid: 2qi4aibx background: cytomegalovirus (cmv) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. therefore, we studied the effects of cmv reactivation on the temporal course of host response biomarkers in patients with sepsis. methods: in this matched cohort study, each sepsis patient developing cmv reactivation between day 3 and 17 (cmv+) was compared with one cmv seropositive patient without reactivation (cmvs+) and one cmv seronegative patient (cmvs−). cmv serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. systemic interleukin-6 (il-6), il-8, il-18, interferon-gamma–induced protein-10 (ip-10), neutrophilic elastase, il-1 receptor antagonist (ra), and il-10 were measured at five time points by multiplex immunoassay. the effects of cmv reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models. results: among 64 cmv+ patients, 45 could be matched to cmvs+ or cmvs− controls or both. the two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. cmv+ patients had increased ip-10 on day 7 after viremia onset (symmetric percentage difference +44% versus −15% when compared with cmvs+ and +37% versus +4% when compared with cmvs−) and decreased il-1ra (−41% versus 0% and −49% versus +10%, respectively). however, multivariable analyses did not show an independent association between cmv reactivation and time trends of il-6, ip-10, il-10, or il-1ra. conclusion: cmv reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-cmv therapy. electronic supplementary material: the online version of this article (10.1186/s13054-018-2261-0) contains supplementary material, which is available to authorized users. cytomegalovirus (cmv) reactivation is observed in 14-41% of intensive care unit (icu) patients without known prior immune deficiency [1] [2] [3] and is associated with increased morbidity and mortality [4] [5] [6] . in a previous study, we estimated that the population-attributable fraction of icu mortality due to cmv reactivation was 23% in patients with acute respiratory distress syndrome (ards) [7] . in a subsequent study among patients with septic shock, we found an effect of cmv reactivation on icu mortality only in patients with concurrent epstein-barr virus reactivation [8] . although multiple studies point toward a causal relationship, definitive proof that cmv reactivation worsens clinical outcome is lacking, as most data are also compatible with a scenario in which cmv reactivation is merely a marker of immune suppression in this patient group. based on previous studies in icu patients, there is a clear pathophysiological link between inflammation and immune suppression on the one hand and the subsequent risk of cmv reactivation on the other [9] [10] [11] [12] [13] . markers reflecting impaired functioning of natural killer cells and cytotoxic t cells were predictive of cmv reactivation [10, 11] . furthermore, bacterial sepsis and corticosteroids have been identified as clinical risk factors for cmv reactivation [9, 12, 13] . however, less is known about the reverse association and thus the effects of cmv reactivation on the immune system. direct cytotoxic effects of cmv on organs have been observed primarily in immunocompromised hosts [14] but also in previously immunocompetent patients in the icu [15] . moreover, indirect immune-modulating effects are assumed to play a role in the pathogenicity of cmv [13, [16] [17] [18] . in vitro analysis revealed multiple mechanisms encoded within the genome of cmv that may contribute to a non-specific inhibition of both cellular and humoral immunity [19] . observational clinical studies yielded conflicting results comparing levels of multiple inflammatory markers in patients with and without cmv reactivation [1, 11, 20] . however, these studies analyzed biomarker responses only immediately upon icu admission and thus could not assess potential immunological effects due to the onset of cmv reactivation. nevertheless, cytokine levels were used as a primary (surrogate) endpoint in a recent placebo-controlled randomized control trial in which prophylactic antiviral treatment with ganciclovir failed to reduce interleukin-6 (il-6) levels [21] . hence, definite proof of immune-modulating effects induced by cmv remains to be demonstrated. naturally, such an effect can be demonstrated only after onset of cmv reactivation. therefore, this longitudinal study aimed to investigate whether the temporal course of seven host response biomarkers, including both pro-and anti-inflammatory cytokines, in previously immunocompetent icu patients with sepsis differs between patients with and without cmv reactivation. this matched cohort study was performed among patients who had been included in two previous studies conducted within the molecular diagnosis and risk stratification of sepsis (mars) cohort [7, 8] . for this study, we included sepsis patients who presented with either concomitant ards or septic shock to the mixed icus of two university medical centers in the netherlands between january 2011 and june 2014 and had remained in the icu beyond day 4. exclusion criteria were cmv seronegative patients with cmv viremia (thus a primary infection) during their icu stay and known immunodeficiency or anti-viral treatment in the week before icu admission. the institutional review boards of both study centers approved an opt-out method of informed consent (protocol number 10-056c). from this parent cohort, we selected patients with an onset of cmv reactivation between day 3 and 17 in the icu. these patients with viremia were matched to two control groups consisting of patients without viremia on any day of icu admission. first, we matched patients with reactivation in a 1:1 ratio to cmv seropositive patients without reactivation (further referred to as "primary comparison"). second, we matched patients with reactivation in a 1:1 ratio to cmv seronegative patients without cmv viremia (further referred to as "secondary comparison"). this secondary comparison was intended mainly to confirm results of the primary comparison; the rationale was that any finding suggestive for an effect of cmv reactivation should also become apparent when compared with seronegative patients who are not at risk for cmv reactivation. matching criteria to reduce confounding were length of stay until reactivation (determines t = 0), sequential organ failure assessment (sofa) score at t = 0 (± 2 points), age (± 10 years), sex, and high-dose corticosteroid use during 4 days prior to t = 0 (that is, more than 250 mg hydrocortisone or equivalent). patients were also matched on hospital and calendar day of icu admission (± 365 days) in order to reduce possible influences of variation in sample workup and biobank storage duration [22] . the optimal matching result was retrieved by selecting the largest sample size after 1000 random iterations of the matching procedure. leftover plasma, obtained daily as part of routine patient care, was stored at −80°c and used to determine cmv serostatus at icu admission. subsequently, cmv load in blood was measured weekly, and for intermediary days, on which quantitative polymerase chain reaction was not performed, we estimated viral loads by log-linear imputation (see electronic supplementary materials of [7] ). cmv viremia was defined as at least 100 international units (iu) per milliliter. this cutoff value was similar to the ones used in previous studies [7, 8] . results of cmv viral load measurements in plasma performed for this study were not made available to the treating physicians, and none of the included patients received anti-cmv treatment. to map the immune response, we measured a panel of host response biomarkers in samples derived from five time points: day of viremia onset (t = 0), 2 days prior (t = −2), and after viremia onset at day 3, 7, and 10 (sample availability depended on length of stay in the icu). a multiplex luminex immunoassay was performed by using edta plasma and included the following proteins: il-6, il-8, il-18, tumor necrosis factor-alpha (tnf-α), tnf-related apoptosis-inducing ligand (trail), interferon-gamma (ifn-γ), ifn-γ-induced protein-10 (ip-10), neutrophilic elastase, granzyme-b, il-1 receptor antagonist (ra), and il-10. based on the results of a pilot run using 82 samples obtained from 15 ards patients without sepsis at icu admission (whom were not included in this study), we excluded ifn-γ, tnf-α, trail, and granzyme-b from the final panel because the levels of these biomarkers were below the lower limit of detection in more than 70% of the samples. of note, in this pilot run, cmv reactivation was not associated with detectability of the four excluded biomarkers. measurements of biomarkers were performed by using an in-house developed and validated multiplex immunoassay (iso9001 certified) based on luminex technology (xmap, luminex, austin, tx, usa). the assay was performed as described previously [23] . in short, thawed edta plasma samples (60 μl) were diluted 1:1 in high performance elisa (hpe) buffer (sanquin, the netherlands) and centrifuged through filtration columns to remove debris. then non-specific heterophilic immunoglobulins were pre-absorbed from all samples with heteroblock (omega biologicals, bozeman, mt, usa). next, samples were incubated with antibody-conjugated magplex microspheres for 1-h at room temperature with continuous shaking and this was followed by 1-h incubation with biotinylated antibodies and 10-min incubation with phycoerythrin-conjugated streptavidin diluted in hpe buffer. acquisition was performed with the flexmap 3d system (bio-rad laboratories, hercules, ca, usa) in combination with xponent software version 4.2 (luminex). data were analyzed by 5-parametric curve fitting using bio-plex manager software, version 6.1.1 (bio-rad laboratories). univariable analyses were performed to compare patients and disease characteristics for matched groups with and without cmv reactivation using chi-squared, wilcoxon rank sum, or fischer exact tests as appropriate. measured host response markers were natural log-transformed concentrations in picograms per milliliter for all analyses. symmetric percentage differences were calculated for each patient at the different time points. this delta percentage reflects the relative change from the measurement 2 days prior to cmv reactivation until the follow-up measurement [24] . we performed additional multivariable analyses by using generalized linear mixed models to assess the effect of cmv reactivation on the time course of each individual biomarker. in the mixed model analyses, we assessed whether baseline biomarker levels were comparable between matched groups (that is, coefficient for cmv reactivation) as well as the effect of cmv on the course of the biomarker levels over time (that is, coefficient for interaction term between time and cmv reactivation). a priori we chose to model the established immune markers il-6 and il-10. based on the observed divergence in the symmetric percentage differences over time between groups, we conducted the multivariable analyses also for the pro-inflammatory chemokine ip-10 and the anti-inflammatory cytokine il-1ra. since not all cmv reactivation patients were included in both comparisons, we performed separate mixed model analyses for the primary and secondary comparisons. thus, in total, eight models were built (for each of the four biomarkers in each of the two comparisons). for each model, sofa score at t = 0 (that is, the day of reactivation) and age were included as confounders since we used a range (instead of an exact value) as matching criteria for these co-variables. for the fixed part of th emodels a polynomial term for time was evaluted (that is, quadratic time effect). furthermore, a random intercept and a rondom slowe were evaluted for each model. restricted maximum likelihood estimation (reml) was used to generate unbiased variance estimates for the final models [25] . different ways to model the time course for each host response marker were compared by using the likelihood ratio test and akaike's information criterion. to take multiple testing into account and reduce the risk of spurious findings, we performed all statistical testing against a p value of 0.01 and used a confidence interval of 99%. bonferroni adjustment was deemed inappropriate and too conservative as the different measurements performed over time within a single patient and hence the tests were highly correlated with each other. analyses were performed by using either sas enterprise guide 7.1 (sas institute, cary, nc, usa) or r version 3.3.2 (r foundation for statistical computing, 2015; used packages "lme4", "lmetest"). forty-five (70%) of 63 eligible patients with cmv reactivation during icu day 3-17 could be included after matching (fig. 1) . twenty-eight patients were matched to a seropositive patient as well as a seronegative, nine to only seropositive, and eight to only seronegative, respectively. this resulted in a study population of 118 unique patients, divided into a primary comparison (that is, 37 with cmv reactivation matched to 37 cmv seropositive without reactivation) and a secondary comparison (that is, 36 with cmv reactivation matched to 36 cmv seronegative). patient and disease characteristics at icu admission were comparable between matched groups and are presented in table 1 . in the patients with cmv reactivation, median peak level of cmv dna load was 404 iu/ml (interquartile range (iqr) 214-1370). median length of stay in the icu until reactivation was 9 days (iqr 6-11), which was influenced by the used inclusion criterion (that is, viremia onset between day 3 and 17 in the icu). of the 118 unique sepsis patients included, 81 (69%) presented to the icu with septic shock and 80 (68%) patients had ards during the first week of icu admission. in the primary comparison, the median icu length of stay was 16 days (iqr 10-21) for patients with cmv reactivation versus 14 days (iqr [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] for subjects without reactivation (p = 0.90). this was 16 days (iqr 11-21) versus 19 days (iqr [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] in the secondary comparison (p = 0.21), respectively. hospital mortality was 57% for patients with cmv reactivation and 46% for the matched patients without reactivation in the primary comparison (p = 0.35). in the secondary comparison, this was 58% versus 47% (p = 0.35), respectively. baseline levels of measured host response markers were comparable between patients with and without reactivation, both at t = −2 (that is, 2 days prior to viremia onset) and at t = 0 (that is, day of reactivation onset) ( table 2 ). in general, this remained the case for each marker up to 10 days after cmv reactivation; the exceptions were median il-10 levels (which were significantly higher on day 10) and median il-6 levels (which were significantly lower on day 7) in patients with cmv reactivation compared with controls (additional file 1: table s1 ). however, these differences were not consistent across both primary and secondary comparison. time trends of various markers within patients were described by symmetric percentage differences relative to their levels 2 days prior to cmv viremia onset (fig. 2 for primary comparison, additional file 1: figure s1 for secondary comparison). for ip-10 and il-1ra, differences in time trends were observed between patients with and without reactivation in both comparisons. patients with cmv reactivation had a more pronounced increase of ip-10 (median percentage difference of 44% versus −15%) and decrease of il-1ra (median percentage difference of −41% versus 0%) on day 7 after viremia onset compared with cmv seropositive patients without reactivation. for the secondary comparison, with cmv seronegative patients, similar differences in trends were observed for ip-10 (+37% versus +4%) and il-1ra (−49% versus +10%), respectively. of importance, sample size decreased over time because of death or icu discharge with a minimum of 11 per patient group after 10 days (additional file 1 table s1 ). in the multivariable mixed model analyses, cmv reactivation did not significantly affect the baseline levels of il-6, ip-10, il-10, and il-1ra (table 3) . a significant decrease over time was observed in all patients for il-6 in both the primary and secondary comparison and for il-10 in the primary comparison only, respectively. however, cmv reactivation did not significantly affect the time trend of any of the four analyzed biomarkers. we performed an explorative study to compare time trends of host response biomarkers in patients with reactivation that were matched to non-reactivating control patients who were either seropositive or seronegative for cmv. although we initially observed differential trends of il-1ra and ip-10 in the crude analysis, these differences did not remain in the linear mixed model analysis the hypothesis of an immune-modulating effect of cmv is based on the observation of increased mortality and morbidity in patients with viremia without organ manifestation of cmv disease [13, 19] . proposed mechanisms of such indirect pathogenicity are autoantibody production, enhanced inflammation, vascular damage, and cmv-induced immunosuppression [17] . based on this hypothesis and an observed association between plasma markers and mortality in patients with ards [26] , il-6 was used as a surrogate endpoint in a recent randomized controlled trial that evaluated the safety of preventive antiviral treatment in icu patients [16] . our finding that cmv reactivation is not associated with modified il-6 dynamics questions the suitability of il-6 as an endpoint in clinical trials evaluating preventive therapy for cmv reactivation in icu patients. furthermore, time trends of other immunological biomarkers were not robustly affected by cmv reactivation. our study has several strengths. first, to our knowledge, this is the first study with serial measurements of the immune response following (instead of prior to) cmv reactivation. second, our study design included two matched control groups. because of the used matched cohort design, we could include only 45 out of 63 patients with cmv reactivation but this loss was compensated by the ability to include controls that were more comparable to those patients. sepsis patients in the icu are known to be very heterogeneous [27, 28] ; thus, the matching reduced in theory both confounding and unwanted variation by extraneous factors. third, by using mixed model analyses, we accounted for correlation of measurements performed within one patient by the use of random effects, which increased the statistical power to identify differences between patient groups. moreover, this type of analysis takes into account the considerable loss to follow-up of patients and allowed us to estimate an average trend over time based on available data. our study also has some limitations. first, this was an explorative study evaluating multiple host response biomarkers. we chose a lower p value threshold of significance in order to decrease the risk of spurious findings due to multiple testing, but false-negative findings remain an accessory risk to keep in mind also when considering our study sample size. unfortunately, a formal sample size calculation for this kind of statistical analysis was not possible. nevertheless, we postulate that possible immunomodulating effects of cmv reactivation il-18 6.5 (5.9-6.9) 6.4 (5.9-6.6) 0.46 6.3 (5.9-6.7) 6.4 (5.9-6.7) 0.77 ip-10 6.5 (6.0-7.0) 6.3 (5.9-6.8) 0. seem at most to be rather limited in these patients because no large differences in biomarker levels between matched groups were observed. second, we analyzed host response biomarkers as standalone markers, which is probably a simplification of the complex immune response. however, large sample sizes are required to perform more advanced network analyses, and the integration of time series in such analyses, to our knowledge, has not been conducted before. we also measured only the plasma concentrations. since cmv pneumonitis could be an important mediator of the pathological effect of cmv reactivation in critically ill patients, bronchoalveolar lavage samples may be additionally informative but were not available [16, 29] . finally, we did not evaluate all potentially relevant biomarkers for cmv reactivation; thus, future studies are needed before an immunomodulating effect of cmv can be ruled out with certainty as an important pathological mechanism in previously immunocompetent icu patients. this study could not demonstrate an independent immunomodulating effect of cmv reactivation in patients with sepsis. this finding does not lend support for the use of immunological markers as surrogate endpoints for clinical outcome in interventional studies of prophylactic or pre-emptive cmv therapy in icu patients. additional file 1: table s1 . absolute levels of host response markers during follow-up by cytomegalovirus (cmv) reactivation status. figure s1 . ethics approval and consent to participate all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional or national research committee (or both) and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. for this study, an opt-out informed consent method was approved. not applicable. cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers cytomegalovirus reactivation and associated outcome of critically 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162 circulating immune related proteins in healthy subjects statistics notes: percentage differences, symmetry, and natural logarithms using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury why have clinical trials in sepsis failed? unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates immunological insights into the pathogenesis of active cmv infection in non-immunosuppressed critically ill patients we thank the department of medical microbiology and the multiplex core facility of the laboratory for translational immunology for their logistical support and performance of measurements, the participating icus and research nurses of the two medical centers for their help in data acquisition, and all members of the molecular diagnosis and risk stratification of sepsis all authors declare that they have no conflicts of interest related to the subject matter. key: cord-257361-7q0vbvvd authors: lee, james s.; godard, aurélie title: critical care for covid-19 during a humanitarian crisis—lessons learnt from yemen date: 2020-09-23 journal: crit care doi: 10.1186/s13054-020-03281-y sha: doc_id: 257361 cord_uid: 7q0vbvvd nan on day 1, while assessing the site to plan patient flow, a newly recruited doctor approached and asked, "where do we get ppe? how does the centre work?" the response given, "i don't know yet, but we will figure this out together." patients had already arrived. in may 2020, médecins sans frontières/doctors without borders (msf) opened three covid-19 treatment centres (ctc) in sanaa and aden, yemen [1] . we report our experience from rapidly setting up ctcs with intensive care units (icu) . working in humanitarian crises presents numerous contextual and cultural issues [2] , but providing critical care in a war-torn country during a pandemic has further challenges. in the first week of opening the aden ctc, a surge of war-wounded resulted in a mass-casualty plan activation at the msf aden trauma hospital, which functioned as our covid-19 response support base. additionally, some hospitals were closed from fear of covid-19, resulting in the aden ctc becoming rapidly overwhelmed and a second ctc opening. resource constraints, high influx of patients, and societal pressures were encountered in all 3 ctcs, requiring that lessons learnt be applied in real-time. msf's three ctcs included wards and icus. invasive mechanical ventilation (imv) received global attention but is only the visible "tip of the iceberg" for covid-19 care. a full package of critical care includes, but not limited to, critical care trained staff, allied health and logistics staff, clinical mentoring for juniors, biomedical equipment, oxygen, medications, and a reliable supply chain. our icus emulated a closed-unit model with local nurses and generalist doctors supervised by an international intensivist and nurse. each icu had contextspecific resource constraints resulting in differences in the package of care related to equipment (ultrasound), investigations (laboratory, x-ray), oxygen supply, nutrition, medications, and staff (specialist doctors, nurses, physiotherapists, social workers, pharmacists, logisticians). due to limited icu beds, many critically ill patients remained in the ward where the maximal oxygen therapy was a non-rebreather mask (nrm) combined with a regular nasal cannula. this double oxygen set-up, in addition to prone positioning, successfully treated some patients, avoiding the need for ventilatory support. all three ctcs had rapid increases in admissions and community/contextual pressure to open immediately leaving no time for pre-opening training. local intensivists were not available and recruiting internationally was difficult, as the pandemic has increased the need for intensivists/icu nurses worldwide, many who are obliged to work in their home country. closure of airports/borders and security constraints limited the ability to move staff and supplies. this placed further pressure on local staff, many of whom had no or limited icu experience. routine icu care, such as ventilator settings, ventilator-associated pneumonia prevention bundles, infusion pump usage, and early mobility, amongst others, were unfamiliar. clinical protocols were developed and taught on-the-job. prone positioning had never been performed locally, but successfully taught in all 3 icus. teaching critical care concepts within a few days (which typically take years of training) was challenging enough, but further complexity was added by simultaneously managing patients with a new disease, where medical knowledge of covid-19 was evolving daily. the aim of msf's covid-19 response in yemen was to provide oxygen to the maximum number of patients possible, irrespective of ventilator capacity. our ctcs were new structures without centralized oxygen, but solutions developed. in the first days at one icu, each ventilator was attached to one oxygen cylinder, which meant the patient was deprived of oxygen when the cylinder was changed. malfunctioning regulators delivered too much pressure, which damaged the ventilator and/or did not accurately measure the amount of oxygen remaining; thus, staff did not know when the cylinder was empty until the ventilator detected a sudden drop in fio2. to overcome the above problems, a y-connection circuit with 2 cylinders was created, ensuring that a ventilated patient was never deprived of oxygen. providing critical care requires a steady supply of medications, but supply challenges were numerous. we were unable to rely on msf's usual mechanisms for international procurement. a shortage of analgesia/sedation/ neuromuscular blocking agents in addition to inconsistent oxygen supply forced us to adapt. when the medications for imv were unavailable, non-invasive ventilation (niv) was favoured-and sometimes the only option (high flow nasal cannula oxygen was unavailable). bilevel positive airway pressure was commonly used because many patients presented late with silent hypoxia and increased work of breathing, requiring inspiratory pressure support. initially, we did not have niv masks and used ambu-bag masks with a bandage wrap to secure them. this apparatus frequently had a poor mask seal, resulting in excessive oxygen use further straining our supply issues, but was life-saving in some cases. our protocol for niv in covid-19 incorporated a weaning schedule alternating niv with nrm by gradually decreasingincreasing the time on niv-nrm over days. this avoided intubation in some patients who survived to icu discharge after a mean 5.3 days of niv (range 2 to 9 days). overtime, imv medications became available locally and sometimes the quality was uncertain (e.g., ineffective atracurium likely due to a lack of cold chain storage), but there was no alternative option. a consistent supply was needed and contributed to successful application of imv. survivors of imv required a mean 19.3 ventilator days (range 8 to 33 days). patient outcomes for the first 6 weeks of operations for one icu are shown in fig. 1 , but the high crude mortality provides an incomplete picture of outcomes, as quality of care improved overtime. additionally, there were important secondary benefits from introducing critical care with imv. patients inside and outside of the icu benefited overtime due to an increase in knowledge and awareness from monitoring, increase in staff skills, fig. 1 confirmed covid-19 (by pcr or ct scan) admitted to one intensive care unit (icu) from 1 june 2020 to 12 july 2020 and ability to provide a higher level of care. multidisciplinary teamwork was strongly encouraged in the icu and this effect extended to the ward, where the icu team frequently assisted in patient care. in summary, providing critical care with imv for patients with covid-19 during a humanitarian crisis in a war-torn country such as yemen is feasible but requires implementation of a full package of care adapted to the context. catastrophe unfolding in aden's only covid-19 treatment centre caring for critically ill patients in humanitarian settings publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all field staff, local collaborators, patients, and families from all msf yemen field projects that we have had the pleasure of participating in. we thank dr. clair mills for her review of the manuscript and all departments from msf operational centre brussels and operational centre paris for their support. both authors equally contributed to the manuscript. both authors read and approved the final manuscript. authors' information jl is an intensivist and emergency care advisor for médecins sans frontières. ag is an intensivist and intensive care advisor for médecins sans frontières. availability of data and materials routine monitoring data was assessed as part of routine field operations. data sharing is not applicable to this article as no datasets were generated or analysed for this article.ethics approval and consent to participate not applicable. need for approval was waived by the medical director for médecins sans frontières. not applicable. the authors declare that they have no competing interests. received: 31 august 2020 accepted: 10 september 2020 key: cord-281663-c2okrt2b authors: sella, nicolò; zarantonello, francesco; andreatta, giulio; gagliardi, veronica; boscolo, annalisa; navalesi, paolo title: positive end-expiratory pressure titration in covid-19 acute respiratory failure: electrical impedance tomography vs. peep/fio(2) tables date: 2020-09-01 journal: crit care doi: 10.1186/s13054-020-03242-5 sha: doc_id: 281663 cord_uid: c2okrt2b nan to the editor, hypoxemic acute respiratory failure (harf) secondary to covid-19 presents with heterogeneous features depending on several determinants, such as the extent of intravascular microthrombosis, superinfections, and other complications [1, 2] . the easiest approach for setting positive end-expiratory pressure (peep) and inspiratory oxygen fraction (fio 2 ) is using peep/fio 2 tables [3, 4] . however, because the magnitude of lung recruitability is variable, personalizing peep would be desirable [1] . electrical impedance tomography (eit) offers this opportunity by bedside estimating both alveolar collapse and lung overdistension throughout a decremental peep trial [5] . this investigation (ethics committee approval: ref: 4853/ao/20-aop2012) aims to assess the agreement between eit-based peep values and those recommended by the higher and lower peep/fio 2 tables [6] in a series of consecutive intubated covid-19 harf patients, admitted to intensive care unit at our institution. written informed consent was obtained from all patients. we performed 15 decremental peep trials through a dedicated device (pulmovista500, dr ger-medical, germany) and subsequently analyzed pulmonary perfusion distribution [5] . five patients were evaluated in a prone position. eit optimal peep (peep eit ) was defined as the best compromise between lung collapse and overdistension [5] . all patients were deeply sedated without spontaneous breathing efforts and ventilated in volume control mode with lung-protective settings [3] . peep eit was compared with peep from higher and lower peep/ fio 2 tables [6] . data, expressed as median and interquartile ranges or 95% confidence interval (ci), were analyzed with the mann-whitney test for comparisons and spearman rank test for correlations, considering p values < 0.05 significant. the bland-alman analysis was also performed. patients had received invasive ventilation for 12.0 (10.0-14.5) days. patients' age was 63 (56-78) years, while body mass index (bmi) was 26.2 (25.4-30.9) kg/ m 2 . pulmonary shunt and dead space, as assessed by eit [5] , were 4% (2-6%) and 27% (23-36%), respectively. (fig. 1) . no correlation was found between peep eit and fio 2 (p = 0.789) (fig. 2) [4] . these differences are partly explained by the different criteria for peep eit selection, which in that study was set above the value indicated by the built-in algorithm corresponding to the least lung collapse and overdistension [4] . also, compared to our study, they enrolled more obese patients, as indicated by the higher bmi [30.0 (27.0-34.0) kg/m 2 ] [4] . not reported in that study [4] , our patients showed increased d-dimer and high fraction of pulmonary dead space, while shunt fraction and procalcitonin were nearly normal, suggesting predominant lung vascular disruption. in conclusion, we confirm the rationale for individualized peep setting in covid-19 patients intubated for fig. 1 bland-altman plot, evaluating the agreement between peep eit and the peep values proposed by the higher (a) and lower (b) peep/fio 2 tables from the alveoli trial [6] . x-axis: average of paired measurements. y-axis: difference between paired measurements. the blue line and blue shaded area: bias and 95% confidence interval of the bias between peep eit and the peep values suggested by peep/fio 2 tables. red lines: upper and lower limits of agreement between methods harf. whether eit is the best technique for this purpose and the overall influence of personalizing peep on clinical outcome remain to be determined. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. covid-19-associated acute respiratory distress syndrome: is a different approach to management warranted? different hypercoagulable profiles in patients with covid-19 admitted to the internal medicine ward and the intensive care unit regional covid-19 network for coordination of sars-cov-2 outbreak in veneto electrical impedance tomography for positive end-expiratory pressure titration in covid-19-related acute respiratory distress syndrome chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the translational eit development study group higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome key: cord-000161-hxjxczyr authors: rello, jordi; pop-vicas, aurora title: clinical review: primary influenza viral pneumonia date: 2009-12-21 journal: crit care doi: 10.1186/cc8183 sha: doc_id: 161 cord_uid: hxjxczyr primary influenza pneumonia has a high mortality rate during pandemics, not only in immunocompromised individuals and patients with underlying comorbid conditions, but also in young healthy adults. clinicians should maintain a high index of suspicion for this diagnosis in patients presenting with influenza-like symptoms that progress quickly (2 to 5 days) to respiratory distress and extensive pulmonary involvement. the sensitivity of rapid diagnostic techniques in identifying infections with the pandemic 2009 h1n1v influenza strain is currently suboptimal. the most reliable real-time reverse transcriptase-polymerase chain reaction molecular testing is available in limited clinical settings. despite 6 months of pandemic circulation, most novel h1n1v pandemic strains remain susceptible to oseltamivir. ensuring an appropriate oxygenation and ventilation strategy, as well as prompt initiation of antiviral therapy, is essential in management. as the novel swine-origin influenza a (h1n1)v global pandemic is under way, the medical community has already experienced an increase in hospitalizations from influenzarelated complications in many geographic regions. primary viral pneumonia is recognized as the most severe pulmonary manifestation of influenza. while uncommon during seasonal epidemics, the syndrome has been well documented during the h2n2 pandemic of 1957-1958 and is thought to be responsible for much of the mortality associated with the young healthy adult population during the 1918 h1n1 pandemic [1] . this paper reviews the clinical aspects of influenza and primary influenza pneumonia that may be of most interest to the practicing physician in the 2009 pandemic environment. seasonal influenza epidemics occur each year as a result of minor changes in the antigenic characteristics of the hemagglutinin and neuraminidase glycoproteins of the influenza viruses (antigenic drift) [2] . the morbidity and mortality associated with seasonal influenza outbreaks are significant, especially in older patients, who incur more than 90% of the influenza-related mortality each year [3] . factors contributing to their increased vulnerability include a decline in cellmediated and humoral immune responses, a reduction in lung compliance and respiratory muscle strength, a diminished cough reflex associated with normal aging, the frequent presence of multiple comorbid conditions, nutritional deficiencies, and in the case of residents of long-term care facilities, greater exposure risk due to close living quarters and shared caregivers [4, 5] . influenza pandemics occur less frequently, as a result of major changes in the surface glycoproteins of the virus (antigenic shift). the emerging novel influenza strain then easily spreads into an immunologically susceptible population. consequently, pandemics are characterized by a shift in mortality toward the otherwise young and healthy 18to 35-year-old adults, with relative sparing of older patients, as evidenced by epidemiological analyses of the 1918 influenza a pandemic [6] . this is likely due to the persistence of immunological memory in older patients after previous exposures to h1-type viruses similar to the pandemic strain [7, 8] . the virulence of the pandemic strain may also play a role, as demonstrated by recent experiments with the highly fatal 1918 influenza strain [9] . preliminary data from the 2009 h1n1 pandemic suggest a similar shift in age-related mortality. an analysis of 532 cases of 2009 pandemic h1n1 influenza a in the us, for example, has revealed that 60% of the cases occurred in patients not older than 18 years of age and that only 5% occurred in patients older than 50 years [10] . in the cohorts recently tested, the modest extent of immunological memory in older patients was confirmed by the presence of serum crossreactive antibodies to the pandemic h1n1 influenza a strain found in 33% of the adults older than 60 years of age versus 6% to 9% of the adults 18 to 64 years of age and none of the children [11] . influenza attack rates during seasonal epidemics vary between 10% and 20% but can be much higher during pandemics. for example, an analysis of the pandemic 2009 h1n1 influenza a outbreak in la gloria, veracruz, found clinical attack rates of 29% in adults older than 15 years and 61% in children younger than 15 years of age [12] . however, these rates may be different in geographic areas of low population density. groups at high risk for severe disease and complications secondary to 2009 pandemic h1n1 influenza a include patients with underlying pulmonary (asthma) and cardiac comorbid conditions, some immunosuppressive states, pregnancy and post-partum states, diabetes mellitus, obesity [13, 14] , and, in children, prior neurological disabilities [15] . severe primary h1n1 influenza pneumonia can also affect young adults without any underlying comorbidities [14] . person-to-person transmission occurs primarily through droplet spread via small particle-sized aerosols generated by coughing, sneezing, or talking [16] . airborne transmission should be considered in those patients exposed to aerosolgenerating techniques, such as intubation or mechanical ventilation. the incubation period is usually 24 to 48 hours. in the absence of antiviral treatment, viral shedding starts within 24 hours before the onset of symptoms and continues for approximately 5 days in healthy adults [17] . viral shedding can last longer in children, patients with extensive comorbidities, older patients, patients who undergo mechanical ventilation, and immunocompromised hosts [18] [19] [20] . the infectious period can be significantly reduced by the use of antiviral medications within the first 48 to 96 hours of illness [20] . after inhalation, the virus is deposited onto the respiratory tract epithelium, where it attaches to ciliated columnar epithelial cells via its surface hemagglutinin. local host defenses, such as mucociliary clearance, or secretion of specific secretory iga antibodies can remove some of the virus particles. however, if mucociliary clearance is impaired (as in smokers [21] or older patients [22] ) or secretory antiinfluenza iga antibodies are absent (as in no antecedent exposure to the virus), infection continues unabated [23] . respiratory epithelial cells are invaded, and viral replication occurs. newer viruses then infect larger numbers of epithelial cells, shut off the synthesis of critical proteins, and ultimately lead to host cell death [24] . in patients with uncomplicated influenza, bronchoscopy typically reveals diffuse inflammation and edema of the larynx, trachea, and bronchi, and biopsy may show cellular infiltration with lymphocytes and histocytes and desquamation of the ciliated columnar epithelium [25] . in patients with severe influenza infections that progress to primary viral pneumonia, the involvement of the respiratory tree is extensive, with necrotizing tracheobronchitis, ulceration and sloughing of the bronchial mucosa [26] , hyperemic alveolar capillaries with intra-alveolar hemorrhage, infiltration of alveolar spaces with fluid, fibrin, and cellular exudates, and lining of the alveoli with acellular hyaline membranes [1] . autopsies from patients with primary influenza pneumonia confirmed bilateral severe hemorrhagic pneumonitis with interstitial inflammation, diffuse alveolar damage, and heavy viral loads observed in the periphery of the lungs. the clinical features of uncomplicated influenza are virtually indistinguishable from those of other respiratory viral infections. influenza is classically characterized by an abrupt onset of headache, high-grade fever, chills, dry cough, pharyngeal irritation, myalgias, malaise, and anorexia. the fever lasts an average of 3 days (range of 2 to 8 days). the cough, initially nonproductive and nonpurulent, may persist for weeks. bronchial hyper-reactivity and small-airway dysfunction are often present in influenza virus infection. in the presence of asthma or structural lung disease, wheezing may be a prominent manifestation [24] . vomiting and diarrhea, while rare in seasonal influenza, have been frequently reported in infections with the 2009 pandemic influenza a h1n1v strain [10] , particularly in children. the clinical presentation of influenza in the immunocompromised host may be more subtle and manifest only as coryza; similarly, the classic fever symptom may be absent in the older patient, who may present only with lethargy, confusion, anorexia, and cough [27] . influenza pneumonia and respiratory complications in patients with th1 defects, such as hiv infection, are uncommon. pneumonia and the acute respiratory distress syndrome (ards) account for the majority of severe morbidity and mortality that accompany pandemic influenza infection [14] . pneumonia may occur as a continuum of the acute influenza syndrome when caused by the virus alone (primary pneumonia) or as a mixed viral and bacterial infection after a delay of a few days (secondary pneumonia) [28] . identifying patients who are more likely to develop severe complications from influenza pneumonia requires a high clinical vigilance. commonly used pneumonia severity assessment tools, such as the pneumonia severity index [29] or curb65 [30] , are not useful in deciding which patients to hospitalize in the context of primary influenza pneumonia since these tools have not been developed and validated during a pandemic scenario. thus, careful triage in the emergency department and early identification of young patients with decreased oxygen saturation, respiratory rate above 25, concomitant diarrhea, or hypotension are crucial. elevated lactate dehydrogenase, creatine phosphokinase, and creatinine at hospital admission may also serve as prognostic indicators of severe disease [14] . c-reactive protein and procalcitonin are increased during this acute lung injury stage of early fibroproliferation. the most ominous cases are those infections that progress rapidly to ards and multilobar alveolar opacification. these patients usually present with gradually increasing dyspnea and severe hypoxemia after an antecedent of 2 to 5 days of typical influenza symptoms [14] . the cough is usually productive of thin, often bloody, sputum with few cells. hypoxemia increases progressively to the point of respiratory failure requiring intubation and mechanical ventilation, often after only one day of hospitalization [14] . the radiological appearance of primary influenza pneumonia can be difficult to distinguish on chest x-ray from pulmonary edema, given the presence of perihiliar congestion and hazy opacification, at least in the lower lobes (figure 1a,b) . pleural effusions may also be present. computed tomography scans ( figure 2) can add further diagnostic insight and may be useful to differentiate primary viral pneumonia from bronchiolitis and interstitial pneumonias, which occur frequently in children and young adults but have a benign outcome. concomitant myopericarditis should be excluded by echocardiography. concurrent pulmonary emboli, as suggested by early case reports from hospitalized patients with pandemic influenza a h1n1v 2009 in the us [13] , may further contribute to clinical deterioration in some patients. however, the occurrence of concomitant pulmonary emboli has not been reproduced in other geographic regions so far. bacterial co-infection, though uncommonly reported in the early stages of the 2009 h1n1 pandemic, may be more prevalent than initially thought. a recent analysis of lung specimens from 77 fatal cases of pandemic h1n1v 2009 infection found a prevalence of concurrent bacterial pneumonia in 29% of these patients [31] . the most common coinfecting bacterial pathogens were pneumococcus, staphylococcus aureus, and streptococcus pyogenes, with a median duration of illness of 6 days [31] . the real-time reverse transcriptase-polymerase chain reaction (rrt-pcr) swine flu panel for detection of pandemic h1n1 influenza, developed by the centers for disease control and prevention (atlanta, ga, usa) and distributed to many laboratories in us and worldwide, is a reliable and timely method of diagnosing the pandemic strain [32, 33] . the viral culture, while the gold standard in influenza diagnostics, takes several days before the results are known [24] . the direct fluorescent antigen influenza test was recently reported to have a sensitivity of 93% compared with the rrt-pcr [34] , but the test requires considerable technical expertise in addition to a fluorescent microscope. the commonly used point-of-care rapid influenza tests provide results in less than 1 hour but are of only modest sensitivity for seasonal influenza viruses (63%) [35] and unacceptably insensitive for the detection of pandemic h1n1 influenza [35, 36] . thus, for the majority of clinicians practicing during the 2009-2010 influenza pandemic, the access to a reliable and timely diagnostic modality may still be limited. as such, it is chest x-rays of a patient with primary h1n1 (swine-origin influenza a) influenza pneumonia on day 1 (a) and day 6 (b) of hospitalization. reassuring to know that the patients presenting during influenza epidemics with both cough and fever within the first 48 hours of symptom onset are very likely to have actual influenza (79% positive predictive value) [37] . the majority of patients with primary influenza pneumonia require ventilatory support. mortality is high but can be decreased with an optimal protective ventilatory strategy (tidal volume of not more than 6 ml per kilogram of predicted body weight, with a plateau airway pressure goal of not more than 30 cm h 2 o), as shown in acute respiratory distress syndrome network clinical trials; this strategy is therefore recommended in acute lung injury [38, 39] . maintaining an adequate fluid balance is also important for survival in acute lung injury. the hemodynamic status should be optimized by appropriate repletion of intravascular volume deficits during the early systemic inflammatory stage [40] . once acute lung injury has become established, a conservative fluid management protocol, which was associated with beneficial effects in clinical trials, should be considered [41, 42] . in severe refractory cases of primary influenza pneumonia, some patients require venovenous extracorporeal membrane oxygenation support and continuous renal replacement for acute renal failure. antiviral treatment should be initiated as soon as possible, particularly in patients at high risk of complications. the majority of treatment benefits are derived when antivirals are initiated within the first 48 hours from onset of symptoms. unfortunately, most patients with primary viral pneumonia receive oseltamivir after 3 to 8 days of influenza onset [14] . however, the experience with seasonal influenza suggests that a reduction in mortality for hospitalized patients has been documented even when oseltamivir was initiated after the first 48 hours following illness onset [43] . thus, being out of the ideal therapeutic window should not be a reason to withhold antiviral treatment at any stage of active disease. both neuraminidase inhibitors (oseltamivir and zanamivir) are active against the novel h1n1v 2009 pandemic influenza a strain. the recommended adult dose for oseltamivir, considered the first-line therapy for h1n1 influenza infection, is 75 mg orally twice a day for a total of 5 days [44] . dose adjustment may be required in the presence of reduced creatinine clearance, but the dosage should be maintained for patients undergoing continuous venovenous hemodialysis. a recent world health organization treatment guideline for pharmacological management of 2009 pandemic h1n1v influenza a recommends the consideration of higher doses of oseltamivir (150 mg twice a day) and longer duration of treatment for patients with severe influenza pneumonia or clinical deterioration [44] . since hospitalized patients can shed influenza virus for prolonged periods of time, extending antiviral treatment beyond the first 5 days of treatment in cases of persistent influenza symptoms may be necessary. however, clear guidelines for these circumstances have not been established, and clinical trials examining the appropriate treatment dose and duration for severe h1n1 influenza in various patient populations are acutely needed. development of oseltamivir resistance in novel h1n1 influenza, though still exceedingly rare, has been reported from several countries [45] . it should be suspected in patients who remain symptomatic or have evidence of viral shedding despite a full treatment course of oseltamivir. immunosuppression and prior exposure to oseltamivir, such as receipt of prolonged post-exposure prophylaxis, increase the risk for oseltamivir resistance [45] . zanamivir remains an effective therapeutic option for these cases. zanamavir is also indicated in the rare circumstance when an oral route for oseltamivir administration is not available for critically ill patients in the intensive care unit. the risk of bronchospam rarely associated with zanamivir, particularly in patients with underlying reactive airway disease, can be minimized by concurrent bronchodilator administration. adamantanes (amantadine and rimantadine) have no activity against the 2009 influenza a h1n1v pandemic strain. they are effective for seasonal h1n1 influenza strains, which are 100% resistant to oseltamivir. therefore, for patients presenting with primary influenza pneumonia in geographic regions where seasonal h1n1 strains are circulating in addition to the novel h1n1 pandemic strain, amantadine or computed tomography scan of the patient with primary h1n1 (swineorigin influenza a) influenza pneumonia whose chest x-rays appear in figure 1 . rimantadine should be added to oseltamivir [46] . rimantadine is also associated with immunomodulatory effects. patients presenting with severe influenza pneumonia who may have concurrent bacterial superinfection should also receive antibacterial agents effective against the most common etiologic pathogens, such as streptococcus pneumoniae, streptococcus pyogenes, and staphylococcus aureus, including methicillin-resistant staphylococcus aureus, according to published guidelines in the management of communityacquired pneumonia [47] . corticosteroids remain controversial in persistent ards and are not routinely recommended [48] . further research is required to clarify their impact on outcome. whether other adjunctive immunomodulatory therapies such as statins, chloroquine, and fibrates could prove useful in the context of an influenza pandemic [49] remains to be determined. primary influenza pneumonia caused by the 2009 pandemic influenza a h1n1v strain, though rare, carries a high mortality. the rapid progression from initial typical influenza symptoms to extensive pulmonary involvement, with acute lung injury, can occur both in patients with underlying respiratory or cardiac morbidities and in young healthy adults, especially if obese or pregnant. prompt initiation of effective antiviral treatment, appropriate oxygenation and ventilation support, and antibacterial treatment in the case of concurrent bacterial pneumonia are critical for survival. the most reliable and timely diagnostic method for 2009 pandemic influenza a h1n1v infection is the rrt-pcr developed by the centers for disease control and 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guidelines for the management of communityacquired pneumonia in immunocompetent adults ancukiewicz m; national heart, lung, and blood institute acute respiratory distress syndrome (ards) clinical trials network: efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome confronting an influenza pandemic with inexpensive generic agents: can it be done? the patient whose radiological images appear in figures 1 and 2 has given written consent for their publication. the authors declare that they have no competing interests.this article is part of a review series on influenza, edited by steven opal.other articles in the series can be found online at http://ccforum.com/series/influenza key: cord-027526-ohcu28rk authors: zhou, xiaoyang; yao, shengmi; dong, pingping; chen, bixin; xu, zhaojun; wang, hua title: preventive use of respiratory support after scheduled extubation in critically ill medical patients—a network meta-analysis of randomized controlled trials date: 2020-06-22 journal: crit care doi: 10.1186/s13054-020-03090-3 sha: doc_id: 27526 cord_uid: ohcu28rk background: respiratory support has been increasingly used after extubation for the prevention of re-intubation and improvement of prognosis in critically ill medical patients. however, the optimal respiratory support method is still under debate. this network meta-analysis (nma) aims to evaluate the comparative effectiveness of various respiratory support methods used for preventive purposes after scheduled extubation in critically ill medical patients. methods: a systematic database search was performed from inception to december 19, 2019, for randomized controlled trials (rcts) that compared a preventive use of different respiratory support methods, including conventional oxygen therapy (cot), noninvasive ventilation (niv), high-flow oxygen therapy (hfot), and combinational use of hfot and niv (hfot+niv), after planned extubation in adult critically ill medical patients. study selection, data extraction, and quality assessments were performed in duplicate. the primary outcomes included re-intubation rate and short-term mortality. results: seventeen rcts comprising 3341 participants with 4 comparisons were included. compared with cot, niv significantly reduced the re-intubation rate [risk ratio (rr) 0.55, 95% confidence interval (ci) 0.39 to 0.77; moderate quality of evidence] and short-term mortality (rr 0.66, 95% ci 0.48 to 0.91; moderate quality of evidence). compared to cot, hfot had a beneficial effect on the re-intubation rate (rr 0.55, 95% ci 0.35 to 0.86; moderate quality of evidence) but no effect on short-term mortality (rr 0.79, 95% ci 0.56 to 1.12; low quality of evidence). no significant difference in the re-intubation rate or short-term mortality was found among niv, hfot, and hfot+niv. the treatment rankings based on the surface under the cumulative ranking curve (sucra) from best to worst for re-intubation rate were hfot+niv (95.1%), niv (53.4%), hfot (51.2%), and cot (0.3%), and the rankings for short-term mortality were niv (91.0%), hfot (54.3%), hfot+niv (43.7%), and cot (11.1%). sensitivity analyses of trials with a high risk of extubation failure for the primary outcomes indicated that the sucra rankings were comparable to those of the primary analysis. conclusions: after scheduled extubation, the preventive use of niv is probably the most effective respiratory support method for comprehensively preventing re-intubation and short-term death in critically ill medical patients, especially those with a high risk of extubation failure. invasive mechanical ventilation (imv) is universally recognized as a first-line therapy for rescuing acute respiratory failure. although it is a life-saving treatment in nature, prolonged imv is always accompanied by an increased risk of ventilator-associated pneumonia and lung injury [1, 2] and neurocognitive sequelae associated with prolonged sedation [3, 4] , thus resulting in a longer duration of intensive care unit (icu) stay and increased mortality [5, 6] . therefore, it is essential for mechanically ventilated patients to receive daily assessments of weaning readiness [6] and timely extubation when they meet the criteria of weaning from imv. however, approximately 10-20% of patients will experience extubation failure and require re-intubation within 24-72 h after scheduled extubation [7] [8] [9] [10] , and extubation failure is associated with poor outcomes and increased mortality [8] . it is therefore essential to receive prophylactic respiratory support for post-extubated patients. conventional oxygen therapy (cot) is the most frequently administered respiratory support method after extubation. cot can only deliver a maximum flow of oxygen (o 2 ) of 15 l/min using the venturi mask or reservoir mask [11] , and the delivered fraction of inspired oxygen (fio 2 ) is unstable because the fio 2 also depends on the inspiratory flow, respiration rate, and tidal volume of patients in addition to the o 2 flow [12] . hence, apart from improving oxygenation, cot seems to have no or minimal effects on changes in lung aeration, hemodynamics, or neuromuscular function, which are the main pathophysiological mechanisms that contributed to extubation failure [12] . in recent years, noninvasive ventilation (niv) and high-flow oxygen therapy (hfot) have been increasingly used as alternative respiratory support methods in post-extubated patients. both niv and hfot are anticipated to prevent extubation failure and improve prognosis by delivering more stable fio 2 [12, 13] , promoting alveolar recruitment and preventing alveolar collapse [14] [15] [16] , and reducing the work of breathing [17, 18] . nevertheless, the latest meta-analysis [19] of randomized controlled trials (rcts) suggested that compared to cot, preventive use of niv after extubation had no effect on the re-intubation rate or mortality in post-extubated patients. meanwhile, several recent metaanalyses [20] [21] [22] also revealed neutral effects of hfot used after planned extubation on the re-intubation rate or mortality compared with cot or niv. more recently, a multicenter rct [23] proposed a novel method that combined the use of hfot and niv (hfot+niv) and proved its superiority over hfot in the prevention of re-intubation in post-extubated patients. however, the method did not affect mortality. although the above studies are informative, the relative effectiveness throughout various respiratory support methods remains unknown. unlike conventional pairwise meta-analysis that only include head-to-head comparisons, network meta-analysis (nma) can compare multiple treatments simultaneously in a single analysis by combining direct and indirect evidence [24] and inform on the relative effect of indirectly compared treatments. therefore, we conducted an nma to evaluate the comparative effectiveness of various respiratory support methods used as a preventive strategy after planned extubation in critically ill medical patients. this nma was performed in accordance with the preferred reporting items for systematic reviews and meta-analyses (prisma) extension statement for reporting network meta-analyses [25] . the study protocol was registered at the international prospective register of systematic reviews (prospero registration number: crd42020164357). relevant studies regarding preventive use of various respiratory support methods, including cot, niv, hfot, and hfot+niv, after planned extubation in critically ill medical patients were searched systematically by two independent reviewers (xu z and chen b) from database inception through december 19, 2019, in pubmed, embase, web of science, and cochrane central register of controlled trials. the detailed search strategy is presented in additional file 1. a manual search of reference lists from previous relevant studies and reviews was also conducted to further identify relevant literature. this nma had no restrictions on language or date of publications. after filtering duplicate records, two reviewers (xu z and chen b) independently screened the title and abstract for eligibility. the full text of records deemed eligible during preliminary screening was reviewed to determine whether these studies met the inclusion or exclusion criteria. the reasons for the exclusion of irrelevant studies are recorded in additional file 1 (table s1 ). no restrictions were applied on study period, primary disease leading to imv, ventilation mode in niv, or risk of extubation failure. a third reviewer participated in the discussion to adjudicate disagreements. the inclusion criteria included the following: (1) participants: adult critically ill medical patients (age ≥ 18 years) admitted to the icu who received imv > 12 h, successfully passed the spontaneous breathing trial (sbt), and were ready for extubation; (2) interventions and comparisons: one of the following respiratory support methods compared with one another: cot, niv, hfot, and hfot+niv. all of these methods were used after planned extubation for preventive purposes; (3) outcomes: the primary outcomes were re-intubation rate and short-term mortality, and the secondary outcomes included post-extubation respiratory failure, length of icu stay and in-hospital stay, and comfort score. studies reporting on at least one of the above outcomes were included. the short-term mortality was predefined as death within 30 days after randomization irrespective of the cause of death; and (4) study design: prospective rcts. the exclusion criteria included the following: (1) non-rcts, including reviews, retrospective studies, cohort studies, and crossover studies; (2) studies conducted in post-surgical patients; (3) studies enrolled patients who underwent an unplanned extubation; (4) studies in which respiratory support was used for therapeutic or facilitative purpose [12] ; (5) studies did not report any outcomes of interest; and (6) conference abstracts without full-text manuscripts. two reviewers (yao s and dong p) independently reviewed the complete text of each included study and extracted data using a standardized form. the abstracted data included the name of the first author, publication year, sample size, details of the population enrolled, primary diagnosis leading to imv, characteristics of interventions, study period, acute physiology and chronic health evaluation (apache) ii score, and atrial partial pressure of carbon dioxide (paco 2 ) at end of sbt. data on primary and secondary outcomes were also recorded in detail. if a study reported various mortalities, the longest follow-up short-term mortality was used for analysis. data on the occurrence of re-intubation and respiratory failure within 72 h after extubation was preferred, and it would, if unavailable, be substituted by data on occurrence during icu admission. we also used the paco 2 measured during sbt or at extubation instead of that measured at the end of sbt when it was unavailable. the disagreement was resolved by a joint review of the full text to reach consensus. the criteria for diagnosing post-extubation respiratory failure were defined by the authors in the included trials. according to the previous studies [23, [26] [27] [28] , we predefined "high risk" of extubation failure as the presence of at least one among the following factors: (1) age > 65 years; (2) heart failure or chronic obstructive pulmonary disease (copd); (4) apache ii score > 12 at extubation; (5) body mass index > 30 kg/m 2 ; (6) airway patency problems, including high risk of developing laryngeal edema or inability to deal with respiratory secretions; (7) 2 or more comorbidities; (8) more than one sbt failure; and (9) imv > 7 days. two independent reviewers (yao s and dong p) evaluated the quality of each included trials using the cochrane risk of bias tool [29] . each trial was judged as low, unclear, or high risk with respect to adequate sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. we resolved disagreements by a discussion with a third reviewer to reach consensus. the random effects nma was performed using a frequentist framework to calculate risk ratios (rr) for dichotomous outcomes, mean differences (md) for continuous outcomes, and corresponding 95% confidence intervals (ci). the conventional pairwise metaanalyses were also conducted for each comparison using a random effects model. all statistical analyses were performed using the netmeta package in stata/se 15.0 (stata-corp, college station, tx, usa). two-sided p value less than 0.05 was considered statistically significant. homogeneity and consistency assumptions underlie the validity of evidence from nma [30] . to evaluate heterogeneity across studies within each direct comparison, we visually inspected the forest plots and quantified using the q test and the i 2 statistic [31] . inconsistency between direct and indirect estimates in the entire network for each outcome was assessed locally with a loop-specific approach and globally with design-bytreatment interaction model [32] . we also ranked the treatment effects of various respiratory support methods according to the probabilities of leading to the best results based on the surface under the cumulative ranking curve (sucra) for each outcome [33] . the value of scura ranges from 0 to 100%, the higher the value, the better the effectiveness of the method [33] . given that the risk of extubation failure and hypercapnia (paco 2 > 45 mmhg) at the end of sbt might affect the relative effectiveness of various respiratory support methods [34] , we performed two sensitivity analyses to evaluate the robustness of the nma results for the primary outcomes by excluding studies with low or unclear risk of extubation failure or studies that enrolled patients with hypercapnia at the end of sbt. we assessed the quality of evidence from direct comparisons, indirect comparisons, and nma estimates for each outcome using the modified grading of recommendation, assessment, development and evaluation (grade) tool for nma [35, 36] . the contribution matrix was constructed to evaluate the information contribution of direct evidence to entire nma estimates [36] . because only one loop (niv-cot-hfot) was connected in this nma, we assigned the quality of the indirect comparison with the lower quality rating in the two contributing direct comparisons within this loop. additionally, the higher confidence in the direct and indirect estimates was preferred as the quality rating of overall nma estimates. the quality of evidence would be rated down for the presence of risk of bias, imprecision, publication bias, indirectness, intransitivity, or incoherence between direct and indirect estimates [36] . we initially identified 3466 citations through the electronic database search. an additional 64 records were identified from the manual search of the references in previous publications. after excluding 334 duplicates and 3134 irrelevant citations, we reviewed the full text of the remaining 62 records. finally, a total of 17 eligible rcts [23, [26] [27] [28] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] , representing 3341 patients, were included in this nma. the prisma flowchart for study inclusion is shown in fig. 1 . of the 17 included rcts [23, [26] [27] [28] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] , 10 [23, 26-28, 38, 41, 43-46] were multicenter, and 7 [37, 39, 40, 42, [47] [48] [49] were single-center. all included rcts were published in the last 15 years, and the number of participants ranged from 38 to 614. participants in 5 trials [23, [26] [27] [28] 41] were at high risk of extubation failure, and participants in 1 trial [45] were at low risk. the specified definition of risk of extubation failure was unavailable in 11 trials [37-40, 42-44, 46-49] . among these trials, however, 9 trials [37-40, 42, 44, 47-49] fulfilled the predefined criteria of a high risk of extubation failure in our nma and were therefore classified as high risk, and the risk in the remaining 2 trials [43, 46] was unclear. niv was compared with cot in 9 trials [26, [37] [38] [39] [40] [41] [42] [43] [44] . four trials compared hfot with cot [28, [45] [46] [47] . three trials compared niv with hfot [27, 48, 49] , and 1 trial [23] compared the combinational use of hfot and niv (hfot+niv) with hfot alone. in all trials that involved niv [23, 26, 27, 37-44, 48, 49] , niv was used with bilevel positive airway pressure mode. the paco 2 level at the end of sbt was less than 45 mmhg in 11 trials [23, 26-28, 40-42, 45-47, 49] , greater than 45 mmhg in 4 trials [38, 39, 44, 48] , and unavailable in 2 trials [37, 43] . details regarding the characteristics and outcomes of each included study are described in additional file 1 (table s2 and s3) . the quality assessment is presented in detail in figs. 2 and 3. all trials were assessed to be at low or unclear risk of bias in terms of adequate sequence generation and allocation concealment except for one trial [37] in which randomization was performed based on the admission number. of note, all trials were judged as having a high risk of bias in blinding of participants and personnel because it was clinically impracticable due to virtual practice issues. apart from one trial [38] that had a high bias in detection, all other trials had a low or unclear risk of bias in detection, attrition, and reporting. additionally, three trials [28, 46, 49] had a high risk of other bias associated with the funding source. we downgraded the quality of evidence for several direct comparisons due to imprecision, limitations of risk of bias, or statistical heterogeneity. we had no significant concerns on intransitivity. although no statistical evidence of incoherency was found in the network for any outcomes, we downgraded the quality of evidence for the length of icu stay and length of in-hospital stay in two comparisons due to the presence of problematic incoherence that was evaluated by visually inspecting the direct and indirect estimates. the summary of evidence grading is presented in table 1 . all included rcts [23, [26] [27] [28] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] involving 3341 patients reported re-intubation rates. no statistically significant heterogeneity was noted among the included trials within each comparison ( table 1 ). the inconsistency test at the global and local levels indicated no significant inconsistency (fig. 4, fig. s1 in additional file 1). the quality of evidence for nma estimates was rated as moderate (table 1) . compared with cot, niv and hfot were similarly effective in reducing the reintubation rate (rr 0.55, 95% ci 0.39 to 0.77 and rr 0.55, 95% ci 0.35 to 0.86, respectively) (fig. 4) . indirect evidence showed that compared to niv or hfot, hfot+niv likely decreased the re-intubation rate ( table 2 ) despite the lack of statistical significance. thus, hfot+niv ranked best according to the sucra statistic followed by niv, hfot, and cot (table 3) . sixteen rcts [23, 26-28, 37-46, 48, 49] enrolling 3281 patients reported short-term mortality. we found no heterogeneity across the included trials, and no significant inconsistency existed in this network (table 1 , fig. s2 in additional file 1). nma estimates provided moderate to low-quality evidence and indicated that compared to cot, niv decreased the risk of short-term death (rr 0.66, 95% ci 0.48 to 0.91) (fig. 5 , table 1 ). hfot had no beneficial effect on the short-term mortality compared with cot (rr 0.79, 95% ci 0.56 to 1.12). we found no difference in short-term mortality among niv, hfot, and hfot+niv (table 2) . niv ranked first among the four respiratory support methods (table 3) . although hfot+niv ranked highest for prevention of re-intubation, indirect evidence suggested that compared to niv, hfot+niv likely increased short-term mortality ( table 2 ). in summary, niv is probably the most effective method for comprehensively preventing re-intubation and short-term death (fig. 6) . the network geometry and weight contribution matrix for the primary outcomes are shown in fig. s3 -s6 (see additional file 1). two sensitivity analyses were performed for the primary outcomes by exclusively using 14 trials that enrolled patients with a high risk of extubation failure or 11 trials that enrolled patients with paco 2 < 45 mmhg at the end of sbt. the results suggested that the comparative effectiveness of various methods remained similar, and the sucra rankings were comparable to those of the primary analysis (additional file 1: table s4 and s5, fig. s7 -s10). eleven trials [23, 26-28, 37, 38, 43-46, 48] reported post-extubation respiratory failure. heterogeneity was statistically significant across trials in the comparison of niv and cot ( table 1 ). the consistent assumption in this network was acceptable (fig. s11 in additional file 1). the network estimates were ranked as moderate to low quality. both niv and hfot were superior to cot in preventing post-extubation respiratory failure (table 1 , fig. s12 in additional file 1). although hfot+niv had the highest scura value, its 95% ci was wide and contained the null effect when compared with niv or hfot (table 2) . therefore, the treatment ranking should be interpreted with caution. fifteen trials [23, 26-28, 37-42, 44-46, 48, 49] reported the length of icu stay. substantial heterogeneity was noted across trials within the comparison of niv and cot (table 1) . a problematic incoherence was found by visually inspecting the direct and indirect estimates despite no statistical significance (additional file 1: fig. s13 and s14). no evidence revealed the superiority of one particular respiratory support method because all the confidence intervals were very wide and included the null value (table 1) . thus, the rank order should be interpreted cautiously. length of in-hospital stay was reported in 8 trials [23, 26-28, 38, 39, 41, 45] . we found a suspicious inconsistency in this network through visual inspection of the direct and indirect estimates (additional file 1: fig. s15 and s16). the network estimates provided low-to very low-quality evidence of no difference among cot, niv, hfot, and hfot+niv in terms of length of inhospital stay (tables 1 and 2 ). however, hfot might reduce the length of in-hospital stay compared with cot (table 1) . hfot ranked best among the four respiratory support methods (table 3) . only 3 rcts reported the comfort score, of which 2 compared hfot with cot [46, 47] , and 1 compared hfot with niv [48] . therefore, we did not perform an nma for this outcome. according to the results from pairwise meta-analysis (table 1) , the comfort score of hfot was lower than that of cot or niv. the network geometry and weight contribution matrix for each secondary outcome are available in the supplementary material (additional file 1: fig. s17-s22 ). this nma of 17 rcts comprising 3341 participants evaluated the relative effectiveness of four preventive respiratory support methods in critically ill medical patients. the findings suggested the superiority of niv over cot in terms of re-intubation, short-term mortality, and post-extubation respiratory failure. compared to cot, hfot had beneficial effects on the re-intubation rate and post-extubation respiratory failure but not short-term mortality. there were similar treatment effects on the primary and secondary outcomes among niv, hfot, and hfot+niv. although hfot+niv ranked best for reducing the risk of re-intubation, it exhibited the potential to increase short-term mortality compared with niv. therefore, to comprehensively prevent re-intubation and short-term death, prophylactic use of niv after scheduled extubation is probably the most effective respiratory support method in critically ill medical patients, especially those with a high risk of extubation failure. respiratory support has been widely applied to prevent post-extubation respiratory failure, treat respiratory failure that developed after extubation, or facilitate early weaning from imv in patients who have failed sbt [12] . currently, routine use of cot remains the mainstay of preventive respiratory support in post-extubated patients. since the low-flow oxygen delivered by cot is insufficient to generate positive airway pressure, cot may not guarantee adequate gas exchange to meet the demand of critically ill patients, especially those who were intubated for medical diseases, such as heart failure and copd. several rcts have proven that preventive use of niv or hfot after planned extubation was an effective alternative approach [26, 37, 38, 41, 42, [44] [45] [46] . however, the most recent pairwise meta-analysis by maitra et al. [19] concluded that niv was not superior to cot in terms of prevention of re-intubation or death. interestingly, in addition to trials that used niv as a preventive strategy after planned extubation, the meta-analysis by maitra et al. [19] also included trials in which niv was applied as a facilitative or therapeutic strategy and trials in which patients received unplanned extubation. moreover, at least two studies [37, 40] were missed in their meta-analysis [19] . thus, substantial heterogeneity was identified across the included trials in their study [19] , and their evidence had a low quality. regarding the comparison of hfot and cot, the two latest meta-analyses [20, 22] drew contradictory conclusions. the meta-analysis by xu et al. [22] found a beneficial effect of hfot on re-intubation. however, the meta-analysis by zhu et al. [20] revealed no effects on re-intubation or mortality with the use of hfot. unfortunately, the two meta-analyses included a heterogeneous population that comprised post-surgical patients and critically ill medical patients. moreover, the study by zhu et al. [20] pooled results from rcts and crossover studies. these factors might contribute to the above conflicting results. in contrast, a relatively homogeneous population of critically ill medical patients who received preventive respiratory support after planned extubation was recruited in our nma. network estimates suggested the benefits of niv on the reintubation rate and short-term mortality and the benefit of hfot on the re-intubation rate compared with cot. these findings raised the question of why the benefits of hfot on re-intubation could not be translated into survival benefits, but niv could. it might be explained by the following: first, niv could provide a higher positive airway pressure than hfot. the high positive airway pressure delivered by niv increases the intrathoracic pressure, which is analogous to imv; reduces the left ventricular preload and afterload; and improves the cardiac performance [12] ; these features might translate into a better prognosis in medical patients with cardiac failure. in addition, copd is another one primary disease leading to icu admission in most of the included trials in our study. due to the generation of higher positive airway pressure, niv may be more effective than hfot in facilitating decarboxylation in copd patients. this may be another one reason for interpreting the survival benefits of niv. finally, hfot is more comfortable compared with cot or niv [46] [47] [48] . for patients treated with noninvasive respiratory support that would fail, apparent improvement in patients comfort could mask deterioration to some extent [27] because prolonged noninvasive respiratory support no. number, rcts randomized controlled trials, cma conventional meta-analysis, nma network meta-analysis, niv noninvasive ventilation, hfot high-flow oxygen therapy, cot conventional oxygen therapy, icu intensive care unit, rr risk ratio, md mean difference, ci confidence interval, ne not estimable a p < 0.05 1 quality of evidence for direct estimate rated down by one level for serious risk of bias because of the high risk of unblinding of participants and personnel in all included trials 2 quality of evidence for direct estimate rated down by one level for serious imprecision because 95% ci include values favoring either treatment 3 quality of evidence for direct estimate rated down by one level for substantial heterogeneity 4 quality of evidence for direct estimate rated down by two levels for very serious imprecision because 95% ci are very wide and include values favoring either treatment 5 quality of evidence will be not downgraded for intransitivity in the indirect comparisons 6 quality of evidence for indirect estimate rated down by one level for serious risk of bias 7 quality of evidence for indirect estimate rated down by one level for serious imprecision 8 not estimable because no loop can be constructed for the two treatments in the evidence network 9 quality of evidence for indirect estimate rated down by one level for serious incoherence 10 quality of evidence for indirect estimate rated down by two levels for very serious imprecision 11 quality of evidence for network estimate rated down by one level for serious risk of bias 12 quality of evidence for network estimate rated down by one level for serious imprecision 13 quality of evidence for network estimate rated down by one level for potential serious incoherence fig. 4 forest plot of network meta-analysis for re-intubation rate. niv noninvasive ventilation, hfot high-flow oxygen therapy, cot conventional oxygen therapy, ci confidence interval resulting from comfort and tolerance could improve oxygenation ostensibly and thus might disguise signs of respiratory distress for an extended period [45] and ultimately lead to delayed re-intubation and increased mortality. this view is supported by the results of the study by kang et al. [50] . this study suggested that the failure of hfot might delay intubation and increase mortality. there is limited information about the comparison of hfot and niv in post-extubated patients. theoretically, preventive hfot might be noninferior to niv in post-extubated patients because hfot had some distinctive advantages over niv, including increased comfort [46] [47] [48] 51] , easier clearance of secretions [52] , and reduced risk of adverse effects [51, 53] . a multicenter rct [27] found similar effects on the re-intubation rate and icu mortality between hfot and niv. our nma also further confirmed the similar effectiveness of niv and hfot on the re-intubation rate and short-term mortality, which was consistent with the results of previous meta-analyses [21, 22] . combinational use of hfot and niv seems to be a promising method in postextubated patients because the addition of hfot to niv could, at least theoretically, further improve gas exchange and decrease the work of breathing. the high-wean study [23] indicated that re-intubation rate and post-extubation respiratory failure were reduced with hfot+niv compared with hfot alone. our nma also suggested that hfot+niv ranked first for the prevention of re-intubation rate and post-extubation respiratory failure. however, only one study has compared hfot+niv with other methods to date, and its direct estimate suggested that the 95% ci contained the null effect. one should thus be cautious in the interpretation of these findings. the risk of extubation failure and paco 2 level at the end of sbt might be the effect modifiers in this nma. therefore, we conducted sensitivity analyses for the primary outcomes. our evidence was in favor of the preventive use of niv after planned extubation in high-risk critically ill medical patients, which was consistent with the conditional recommendation from the european respiratory society/american thoracic society clinical practice guidelines [34] . sensitivity analysis also indicated that niv remains the most effective method in nonhypercapnic critically ill medical patients. however, an observational study by gong et al. [54] found a conflicting result that prophylactic niv could not reduce re-intubation or hospital mortality in copd patients with paco 2 < 45 mmhg. it is noteworthy that in our nma, most trials that enrolled nonhypercapnic patients had a high risk of extubation failure. in addition, highcot conventional oxygen therapy, niv noninvasive ventilation, hfot high-flow oxygen therapy, icu intensive care unit risk factors were not limited to copd; they also comprised other factors, which might be one of the causes of the above conflicting results. several strengths in this nma should be mentioned. first, to our knowledge, this is the first nma to evaluate the comparative efficacies of various respiratory support methods in post-extubated critically ill patients. nma allows the comparison of multiple treatments simultaneously in a single analysis and improves the precision by combining direct and indirect estimates. second, a more homogeneous population was enrolled in this nma. to improve the transitivity across comparisons and reduce the heterogeneity across included trials, we set strict inclusion criteria that only critically ill medical patients who were treated with preventive respiratory support after planned extubation could be included. third, we performed sensitivity analyses to eliminate the influence of two potential effect modifiers on the nma results and confirmed the robustness of the nma results. other strengths included a comprehensive literature search and application of grade methodology to assess the quality of evidence. this nma had some limitations. first, we did not construct a comparison-adjusted funnel plot to assess the presence of small-study effects due to limited studies in each direct comparison. therefore, the possible overestimation of effect size in studies with a small sample size should be considered when interpreting the results. second, although it is difficult to identify the effect modifiers in an nma, we performed two sensitivity analyses to assess the robustness of the nma results. however, there were also other differences among the included studies that potentially influenced the nma results, including sample size, duration of respiratory support, and primary disease lead to imv. unfortunately, we did not perform sensitivity analysis for these factors given the limited information in the included studies. third, the adverse complications were not analyzed in this nma because the definition of adverse complications was largely different among included trials. thus, we had no insight into the safety of various respiratory support approaches. fourth, the pooled results of this nma might have a potential bias given the lack of blindness in all included trials. finally, we redefined forest plot of network meta-analysis for short-term mortality. niv noninvasive ventilation, hfot high-flow oxygen therapy, cot conventional oxygen therapy, ci confidence interval high risk of extubation failure according to the previously published studies given that no consistent definition of "high risk" is available to date. as a consequence, this limitation may impact the certainty of the sensitivity analysis results. in critically ill medical patients, especially those who are at high risk of extubation failure, preventive use of niv after scheduled extubation is probably the most effective respiratory support method for comprehensively preventing re-intubation and short-term death. this network meta-analysis showed a promising result for hfot+niv to prevent re-intubation. however, sufficient evidence regarding head-to-head comparisons of hfot+niv and other methods is still lacking. more high-quality studies comparing hfot+niv to other modalities of respiratory support are needed in the future. fig. 6 clustered ranking plot based on cluster analysis of sucra values for the two primary outcomes. treatment lying in the upper right corner is more effective in preventing re-intubation and short-term 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and increase mortality high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure sequential application of oxygen therapy via high-flow nasal cannula and noninvasive ventilation in acute respiratory failure: an observational pilot study noninvasive ventilation not all copd patients benefit from prophylactic noninvasive ventilation after scheduled extubation: an exploratory study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. zhou x designed the study, performed the data analysis, and drafted the manuscript. wang h participated in the conception and design of the study, helped to perform the quality assessment and study selection, and revised supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03090-3. key: cord-276856-88d3vzbs authors: petersen, lonnie g.; friend, james; merritt, sidney title: single ventilator for multiple patients during covid19 surge: matching and balancing patients date: 2020-06-18 journal: crit care doi: 10.1186/s13054-020-03041-y sha: doc_id: 276856 cord_uid: 88d3vzbs nan with a potential covid19-induced ventilator shortage, supporting multiple patients on a single ventilator seems a simple solution to maximize resources. described by neyman et al. [1] , this practice has anecdotally been used in the 2017 las vegas mass shooting and more recently in italy and new york during the covid-19 pandemic. however, a recent consensus statement from relevant medical associations discouraged the practice based on safety concerns [2] . beyond cross-contamination and increased dead space, matching patients to ensure appropriate individual ventilation peak pressures (p peak ), tidal volumes (v tidal ), and positive endexpiratory pressures (peep) is a concern, especially given the dynamic clinical presentation of the covid19 patients with complicated acute respiratory distress syndrome (ards). the central question remains: what does it mean to match patients? how much can they differ before we are no longer saving two lives but risking both? to illustrate the effect of progressive mismatching, we ventilated two mechanical lungs (ttl3, michigan instruments) on a ventilator (840, puritan bennett™) using pressure control mode and ards-compatible settings (p peak = 20-30 cmh 2 o; r = 20 bpm; f total = 24 l/min; i = 1.5 s; peep = 8 cmh 2 o) [3] . while keeping patient b at constant pulmonary compliance (0.03 l/ cmh 2 o), we let patient a progressively deteriorate in compliance from 0.06 to 0.01 l/cmh 2 o, finally creating a maximum mismatch between patients (see fig. 1 ). one-way valves on both inspiratory and expiratory limbs ensured unidirectional flow, which both reduces functional dead space and the risk of crosscontamination between patient a and b, and seemingly also facilitated stable ventilation of b as a deteriorated. importantly though, simultaneous and opposite changes in compliance made it possible to fatally hypo-ventilate one patient and hyper-ventilate the other without triggering alarms. as ventilator alarms are triggered only by changes in the sum of the pressure/volume of both patients on the circuit, we recommend a narrow alarm range (e.g., v tidal ± 200 ml; f total ± 1 l; p peak ± 5 cmh 2 o). the one-way valves on each expiratory limb prevent backflow but introduce a risk of competing exhalation: a slightly earlier or more forceful expiration from a can (partly) impair b and worsen breath staggering, particularly at higher respiration rates. frequent or constant monitoring of patients and shuffling when a mismatch arises is recommended. asthma or copd may increase the rate of fatal mismatch, making the method even more unpredictable. finally, each class of ventilators requires a specific set up; if the method is considered, use the calm before the patient surge to familiarize, and ameliorate the many risks associated with sharing a ventilator. a single ventilator for multiple simulated patients to meet disaster surge american association of critical-care nurses (aacn), and american college of chest physicians (chest) ventilator sharing protocol: dual-patient ventilation with a single mechanical ventilator for use during critical ventilator shortages. columbia university college of physicians & surgeons springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors acknowledge ucsd from deans, chairs, and staff for allowing work directed to meet the medical emergency. all authors contributed equally to the data collection, analysis, and interpretation. all authors edited the letter and approved the final version prior to submission. the author(s) read and approved the final manuscript. no funding was applied for this work. the datasets used and analyzed during the current study are available from the corresponding author on reasonable request. the authors declare that they have no competing interests financial or otherwise. key: cord-003513-hmdikgf5 authors: cillóniz, catia; dominedò, cristina; torres, antoni title: multidrug resistant gram-negative bacteria in community-acquired pneumonia date: 2019-03-09 journal: crit care doi: 10.1186/s13054-019-2371-3 sha: doc_id: 3513 cord_uid: hmdikgf5 this article is one of ten reviews selected from the annual update in intensive care and emergency medicine 2019. other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2019. further information about the annual update in intensive care and emergency medicine is available from http://www.springer.com/series/8901. we are currently living through an antibiotic resistance crisis, mainly because antibiotics tend to lose their efficacy over time due to the emergence and dissemination of resistance among bacterial pathogens, principally caused by the overuse and inappropriate use of antibiotics, as well as the extensive use of antibiotics in agriculture and the food industry. the global point prevalence survey (global-pps), an international network set up to measure antimicrobial prescription and resistance in the hospital setting, recently published its findings [5] . pneumonia was the most common illness to receive antibiotic therapy worldwide, accounting for 19% of patients treated. the most frequently prescribed antibiotics for community-acquired infections were penicillins with a β-lactamase inhibitor (29%); amoxicillin with a β-lactamase inhibitor accounted for 16% and piperacillin with a β-lactamase inhibitor accounted for 8%. third-generation cephalosporins were the second most commonly prescribed antibiotics for community-acquired infections (mainly ceftriaxone, 16%), followed by fluoroquinolones (14%). antibiotic resistance is a natural phenomenon in bacteria that cannot be stopped; however various measures can be taken in order to reduce the rate of its development and devise more effective strategies to control its spread [6] . because cap caused by mdr gram-negative bacteria is an important clinical concern, we review the main findings concerning the epidemiology, diagnosis and clinical impact of cap. the pathogen: why is it difficult to treat? p. aeruginosa is an opportunistic gram-negative, non-fermentative bacterium that inhabits the soil and surfaces in aqueous environments. its high intrinsic antibiotic resistance, broad metabolic versatility and adaptability make it especially difficult to treat. several studies have shown that the physical characteristics (phenotype) of p. aeruginosa isolates vary between those derived from chronic infections, such as cystic fibrosis, and those from acute infections, such as pneumonia [7] . common chromosomal mutations in the muca gene can convert a non-mucous phenotype into a mucous phenotype. the adaptation of p. aeruginosa, which includes complex physiological changes, confers a selective advantage since it can better survive in different habitats [8] . p. aeruginosa has intrinsic, adaptive and acquired mechanisms of resistance, the main ones including the presence of β-lactamases, alterations in membrane permeability due to the presence of ejection pumps, and mutations of transmembrane porins. furthermore, the capacity to form biofilms (intricate, highly organized bacterial communities, embedded in a matrix composed of exopolysaccharides, dna and proteins that is attached to a surface and hinders antimicrobial action) favors the persistence of p. aeruginosa and makes it more difficult to treat, due to the inherent protection that biofilms provide [8] (table 1) . a large number of intrinsic p. aeruginosa virulence factors are required to establish infection [7] . moreover, the differential presence or expression of some of these virulence factors may determine major inter-strain variability in virulence and thus potentially have a major impact on disease severity and mortality [8] . in conclusion, the pathogenesis of p. aeruginosa cap is very complex, in addition to the broad antimicrobial resistance that limits antibiotic therapy; the virulence of p. aeruginosa is certainly a major driver of pneumonia severity and outcome, as well as the different phenotypes described. the capacity to form biofilms provides the bacteria with a further possibility to escape the effects of antibiotics, turning it into a superbug. prevalence: what is the prevalence? the reported prevalence of cap caused by p. aeruginosa is controversial, largely due to data being limited to single-center studies and because of differences in the study populations [9] (table 2) . recently, a multinational point-prevalence study analyzed data from 3193 cap patients in 222 hospitals in 54 countries [10] . the study showed a low prevalence of cap caused by p. aeruginosa (4.2%), which corresponded to only 11.3% of patients with culture-positive pneumonia. the prevalences of antibiotic-resistant and mdr p. aeruginosa were also low (2 and 1% respectively). interestingly, the study reported the prevalence of p. aeruginosa in cap in different continents: 3.8% in europe, 4.3% in north america, 5.2% in asia, 4.9% in south america, 5.5% in africa and 3.1% in oceania. the prevalence of antibiotic-resistant p. aeruginosa in cap was 1.6% in europe, 2.5% in north america, 2.2% in asia, 3.0% in south america, and 3.9% in africa; there were no reported cases of p. aeruginosa antibiotic resistance in oceania. finally, the prevalence of mdr p. aeruginosa in cap was 0.9% in europe, 1.2% in north america, 0.5% in asia, 2% in south america, and 2.3% in africa; there were no cases of mdr p. aeruginosa in oceania. similarly, a spanish study of clinical outcomes and risk factors for cap caused by mdr and non-mdr p. aeruginosa reported a prevalence of mdr p. aeruginosa of 1.1% in a prospective cohort study of 2023 culture-positive cap patients [11] . the authors also reported that p. aeruginosa was an individual risk factor associated with mortality in the study population. a study by ferrer et al. [12] of 664 severe cap cases requiring mechanical ventilation showed that 336 patients had a final microbiological diagnosis; p. aeruginosa was reported in 7% (n = 25) of cases (4% in the non-invasive mechanical ventilation group and 5% in the invasive mechanical ventilation group). antibiotic therapy for p. aeruginosa is totally different from the standard antimicrobial therapy used to treat common cap pathogens. current recommendations provided by international guidelines stratify therapy on the basis of pseudomonas risk factors [1, 13] . risk factors for p. aeruginosa include structural lung disease (bronchiectasis, chronic obstructive pulmonary disease [copd]), nursing home residence, c-reactive protein (crp) < 12.35 mg/dl, prior use of oral steroids, antibiotic therapy within the previous 90 days, and malnutrition [1, 11] . chronic p. aeruginosa colonization in patients with bronchiectasis and copd can be an important preliminary step to pneumonia. non-cystic fibrosis bronchiectasis and copd account for 2-55% and for 20-46% of cap cases, respectively. these two structural lung conditions facilitate chronic colonization by p. aeruginosa, mainly due to failure to eradicate the bacterium during acute infections. as mentioned earlier, p. aeruginosa can transform from a non-mucous phenotype to a mucous phenotype which can then adapt to the lung environment and grow as a biofilm. interestingly, a recent case-control study [14] identified risk factors for pneumonia due to p. aeruginosa susceptible to all routinely tested antipseudomonal β-lactams (apbl-s) and resistant to at least one antipseudomonal β-lactam (apbl-r). the authors identified bronchiectasis, interstitial lung disease, prior airway colonization with p. aeruginosa and recent exposure to an antipseudomonal β-lactam as risk factors for apbl-s p. aeruginosa in adults with acute bacterial pneumonia. in the last few years, cases of p. aeruginosa infection in previously healthy individuals have been reported; in the majority, heavy exposure to aerosols of contaminated water has been identified [15] . p. aeruginosa can establish polymicrobial interactions, mainly with staphylococcus aureus and candida albicans that may affect disease management. the relationship between s. aureus and p. aeruginosa is competitive in nature. the association of c. albicans with p. aeruginosa or s. aureus enhances disease severity in several ways. in vivo studies in rats have shown that pre-colonization of lung tissue by c. albicans increases the rate of pneumonia caused by p. aeruginosa. this microbial interaction should be taken into account in patients with copd or non-cystic fibrosis bronchiectasis who are frequently colonized with p. aeruginosa and s. aureus [16] . according to a recent study, prior antibiotic treatment is a risk factor for p. aeruginosa, especially for mdr p. aeruginosa [11] . it has been demonstrated that low levels of antibiotics contribute to strain diversification in p. aeruginosa; sub-inhibitory and sub-therapeutic antibiotic concentrations induce alterations that effect changes in gene expression, horizontal gene transfer and mutagenesis, which can promote and spread antibiotic resistance. given that p. aeruginosa cap has been related to poor clinical outcomes, largely because of inappropriate empiric antibiotic treatment, it is recommended to use empiric anti-pseudomonal cover in all cases of highly suspected mdr p. aeruginosa cap. risk stratification should take into account the local ecology (prevalence of the pathogen in a specific area) and the patient's risk factors, especially in cases of severe cap that are associated with higher mortality rates (20-50%) [1] . the pathogen: how important is a. baumanii in cap? a. baumannii is an aerobic gram-negative coccobacillus. in 2017, the world health organization (who) included it in the list of "priority pathogens", a group of bacteria that poses the greatest threat to human health and for which new antibiotics are urgently needed [17] . in recent years, isolates of a. baumannii have been recovered from multiple extra-hospital sources, such as vegetables, water treatment plants, fish and shrimp farms, apart from its known natural habitat (soil and humid environments). this broad source of the bacteria may explain the occurrence of community-acquired infections [18] . a. baumannii has a natural resistance to desiccation due to morphological changes that justify its viability for months. infections caused by a. baumannii may be very difficult to treat due to the ability of the bacterium to evade the host immunity and to form biofilm. furthermore, a. baumannii has several resistance mechanisms, including β-lactamases, multidrug efflux pumps, aminoglycoside-modifying enzymes, permeability defects and modifications of target sites [19] ( table 1) . the majority of a. baumannii isolates from cap have a lower antibiotic resistance than isolates from nosocomial infections. despite this lower rate of antibiotic resistance, severe cap is the most frequent clinical presentation of a. baumannii pneumonia. caution should be taken when choosing the empirical antibiotic therapy. although use of a ß-lactam plus a macrolide or a fluoroquinolone is the current international guideline recommendation for severe cap [1] , these drug combinations do not completely cover a. baumannii, mostly because of its frequent resistance to ceftriaxone [20] . several studies have reported isolates of mdr a. baumannii in community-dwelling patients and in nursing-home patients. recently, a prospective cohort study of 651 newly admitted patients in six nursing facilities in the usa reported that 95% of patients were admitted for post-acute care; 57% of patients were colonized with mdr pathogens at enrollment. prolonged hospitalization (> 14 days), functional disability, antibiotic use, or device use were the main risk factors for colonization at enrollment. the rate per 1000 patient-days of acquiring a new resistant gram-negative bacillus was 13.6%. mdr colonization at discharge for resistant gram-negative bacilli was 34% [21] . in a study from west china [22] , investigating the antimicrobial susceptibility of 32 isolates of a. baumannii causing cap, the authors reported that 30% of the isolates were resistant to the majority of the antibiotics; the resistant rates to imipenem and meropenem were 19 and 9%, respectively. an important finding of this study is that approximately 80% of the patients had had a previous hospital admission. an mdr a. baumannii was recently isolated in a previously healthy patient with cap from hong kong. the patient was treated with intravenous colistin and oral monocycline and recovered fully [23] . this case is not isolated and more and more reports of cases of cap caused by mdr a. baumannii are being published. in conclusion, although a. baumannii is not a frequent cause of cap, the capacity to rapidly develop resistance mechanisms to antibiotics and the fulminant clinical presentation (with a mortality rate around 50%) make this pathogen an important health problem, especially in tropical and subtropical areas. prevalence: what is the prevalence? during the last 10 years, a. baumannii has been described as a rare cause of cap but with clinical relevance. the great majority of cap cases caused by a. baumannii occurs in countries with tropical or sub-tropical climates. a. baumannii is an emerging pathogen in the regions of asia-pacific, with a higher prevalence in hong kong, singapore, taiwan, south korea and australia [24, 25] . cap cases caused by a. baumannii are very rare in europe and usa. a recent usa case report of severe cap and review of the literature found that 19 cases of cap caused by a. baumannii have been reported in the usa to date [26] . unlike nosocomial pneumonia caused by a. baumannii, cap cases caused by a. baumannii have a seasonal presentation, with the highest prevalence during the warm and humid months of the year [25] . the clinical presentation of a. baumannii cap is fulminant with acute onset of fever, dyspnea and rapid progression to respiratory failure and shock. a. baumannii cap is associated with a mortality rate ranging from 40 to 60% especially in cases presenting with bacteremia and shock. the main risk factors related to this infection are alcoholism, diabetes mellitus and chronic lung disease [24] . it is known that alcohol abuse impacts on the innate and adaptive immune response. a study published in 2013 described the impact of alcohol on macrophage-like cell antimicrobial functions in a. baumannii infections [27] . the authors demonstrated that alcohol plays an important role in inhibiting nitric oxide (no) production which is essential to eradicate bacteria exposed to macrophages after phagocytosis. alteration of intra-and extra-cellular no production promotes microbial survival, facilitating intracellular replication. furthermore, macrophages exposed to alcohol have lower production of pro-inflammatory tumor necrosis factor (tnf)-α, interleukin (il)-1β, and il-12 and increased levels of il-6. this imbalance in the production of cytokines affects the differentiation of naïve t cells into th1 cells because of low il-12 production, and the production of interferon (ifn)-γ from t and natural killer (nk) cells. moreover, it is known that low levels of tnf-α and il-1β are associated with septic shock and the risk of bacterial infections [27] . a related study recently published by kamoshida et al. [28] described for the first time the ability of a. baumannii to inhibit the formation of neutrophil extracellular traps (nets), thus suppressing neutrophil adhesion. it is well known that the main role of nets is to prevent microbial dissemination and to eradicate pathogens. the ability of a. baumannii to escape the immune response may explain the fulminant clinical presentation of cap caused by this pathogen. an australian study suggested that microaspiration of pharyngeal a. baumannii may be responsible for cap in alcoholic patients [29] . in this study, 10% of community residents attending the emergency department in the wet-season (march-april) with non-respiratory diseases, no episode of previous hospitalization and a history of alcohol abuse (alcohol intake > 6 standard drinks/day) had a. baumannii in their throat [29] . the susceptibility to pneumonia in patients with diabetes can be ascribed to several factors. patients with diabetes have an increased risk of hyperglycemia (which reduces the mobilization of polymorphonuclear leukocytes, chemotaxis and phagocytic activity), increased risk of aspiration, impaired immunological defenses, and deterioration in lung function and chronic complications, such as neuropathy [30] . patients with underlying chronic lung disease, such as copd or bronchiectasis, also show reduced innate defense mechanisms. generally, these patients are smokers, passive smokers or ex-smokers and the frequent use of inhaled corticosteroids make them more vulnerable to infections such as pneumonia [10, 11, 27] . in conclusion, because of its possible fulminating course, cap caused by a. baumannii should be suspected in patients with specific risk factors and a severe presentation of pneumonia. early recognition and prompt initiation of broad empirical antibiotic coverage are mandatory to limit the high mortality related to this infection. the pathogen: what is so special about k. pneumoniae in cap? k. pneumoniae is a gram-negative capsulate bacterium responsible for severe pneumonia especially in immunocompromised patients. in the last two decades, there has been an increase in antibiotic resistance in k. pneumoniae isolates globally. the emergency of mdr and hypervirulent k. pneumoniae strains has been reported in immunocompromised patients and in healthy persons [31] . the main mechanisms of antibiotic resistance in k. pneumoniae are the expression of extended spectrum β-lactamases (esbls), which confers resistance against penicillins, cephalosprins and monobactams, and the expression of carbapenemases, which confers resistance against all β-lactams including carbapenems (table 1) . interestingly, hypervirulent k. pneumoniae strains produce a hypercapsule, also known as being hypermucoviscous. the capsule, a polysaccharide matrix that coats the cell, is necessary for k. pneumoniae virulence and is arguably the most thoroughly studied virulence factor of k. pneumoniae [31] . although antimicrobial resistance in hypervirulent k. pneumoniae is generally lower than in non-hypervirulent k. pneumoniae strains, cases with more resistant strains of hypervirulent k. pneumoniae have recently been reported [32] . k. pneumoniae has the ability to avoid phagocytosis. a recent experimental study found that the capsule is dispensable for intracellular klebsiella survival if bacteria are not opsonized. k. pneumoniae survives the killing by macrophages by manipulating phagosome maturation, which may contribute to klebsiella pathogenesis [33] . in conclusion, cap caused by mdr and hypervirulent k. pneumoniae represents a great challenge in terms of treatment and management, especially in asian countries, where the majority of cases are reported. a recent 5-year study in a french icu [34] described 59 infections caused by k. pneumoniae; 26 (44%) of them were community-onset infections. interestingly, the authors reported 12 hypervirulent k. pneumoniae strains in the group of community-onset infections, 6 (50%) of which were isolated from patients with cap. the authors observed that hypervirulent k. pneumoniae cases had higher rates of organ failure compared with non-hypervirulent cases. however, mortality rates were similar in the two groups. in a study performed in cambodia [35] , 2315 patients with acute lower respiratory infections were enrolled, including 587 (25%) whose bacterial etiology could be assigned. k. pneumoniae was identified in 8% (n = 47) of the microbiologically-confirmed cases. esbl-producing strains were found in 8 (17%) patients. the main risk factors related to k. pneumoniae infection were female sex and diabetes mellitus. the overall mortality rate due to k. pneumoniae infection was 38%. approximately 1-7% of cases of cap are caused by k. pneumoniae, with 5-36% of these being mdr strains [2, 36] . interestingly, in asian countries (taiwan, cambodia, shanghai) k. pneumoniae is described as a frequent pathogen causing bacteremia [37, 38] . although reports of cases from europe and usa are generally rare, an increasing incidence from these regions has been registered in recent years [34, 39] . the recognized risk factors for k. pneumoniae cap are female sex, diabetes mellitus and alcoholism. mdr k. pneumoniae can be recognized as a virulent pathogen causing severe cap, frequently associated with septic shock, respiratory failure and bacteremia. morbidity and mortality rates are high especially in asian countries were the pathogen is reported in younger patients with no chronic conditions. this pattern may be explained by the virulence of the strains (especially hypervirulent k. pneumoniae) and the high rate of antibiotic consumption in these regions [35, 40] . the pathogen: what is so special about s. maltophilia in cap? s. maltophilia is a motile, aerobic, non-fermentative gram-negative bacillus with the ability to survive on any humid surface, form biofilm and colonize humid surfaces. it is an emerging opportunistic pathogen with multidrug resistance, which particularly affects immunocompromised patients (i.e., with malignances, post-organ transplantation) worldwide [41, 42] . s. maltophilia is intrinsically resistant to carbapenems and frequently carries genetic elements that provide resistance to other β-lactams, fluoroquinolones, aminoglycosides and tetracyclines. s. maltophilia has the ability to acquire genes involved in antibiotic resistance from other bacterial species. the most relevant mechanisms of antibiotic resistance include β-lactamase (l1 and l2) production, multidrug efflux pumps (which confer resistance to macrolides, quinolones, aminoglucosydes, polymyxins), antibiotic-modifying enzymes, mutations of bacterial topoisomerase and gyrase genes and reduction in outer membrane permeability [42] (table 1) . although s. maltophilia has been reported in patients with cystic fibrosis, it can affect healthy individuals through contaminated wounds or infected catheters [43, 44] . transmission of s. maltophilia may occur through direct contact with contaminated source such as contaminated water or medical devices [42] . in conclusion, cap caused by s. maltophilia is associated with high mortality rates. hemorrhagic pneumonia is one of the most severe forms of s. maltophilia infection [45] . it is associated with poor outcome despite appropriate antibiotic therapy. there is limited information on the worldwide prevalence of community-acquired s. maltophilia pneumonia. the majority of data comes from case reports [46] . s. maltophilia has been reported as an important cause of cap in patients with hematologic diseases, with a prevalence of bacteremia ranging between 2 and 7%. the mortality rate is approximately 35% (ranging between 30 and 40%) in this special population. the majority of patients affected by this pathogen have previous chronic comorbidities, such as copd, cystic fibrosis, malignancy (especially hematologic diseases), human immunodeficiency virus (hiv)-infection (acquired immunodeficiency syndrome [aids]) or other immunodeficiencies. patients with prior antimicrobial therapy, prolonged hospitalization, indwelling catheters, mechanically ventilated and receiving corticosteroids have an increased risk of s. maltophilia cap [42, 46] . diagnosis: is it possible to predict gram-negative mdr pathogens in cap? the reference microbiological diagnostic tools for bacteria causing respiratory tract infections remain the gram stain and semi-quantitative conventional cultures from direct respiratory samples. bacterial identification is currently based on matrix-assisted latex laser desorption/ionization time-of-flight mass spectrometry (mal-di-tof ms) and susceptibility testing. as a consequence of the time needed for microbiological diagnosis, many patients initially receive inappropriate antibiotic treatment, which may increase morbidity and mortality. molecular techniques based on multiplex pcr have also been developed in recent years in order to simultaneously identify and quantify multiple respiratory pathogens from different types of samples in a single procedure [47] . however, the main challenge for the rapid diagnosis of respiratory infections is the early detection of the antibiotic resistance profile of the various bacteria. the biggest obstacle in the use of molecular techniques for detecting resistance is the discrepancy between genotype and phenotype, the continuous discovery of new resistance mechanisms and, as a result, the potential presence of unknown mechanisms, which may lead to false negative results using molecular techniques [47] . recognizing patients at risk of colonization with mdr gram-negative bacteria, such as patients with bronchiectasis or copd (frequently colonized by p. aeruginosa), is essential, since several studies have reported the association between previous colonization and risk of pneumonia [48, 49] . currently, there is no specific score to predict mdr gram-negative pathogens in cap. however, several scoring systems have been proposed to identify patients with risk factors for developing cap caused by mdr pathogens. the aliberti score [2] takes into account different variables and gives a specific score to each of them: chronic renal failure (5 points), prior hospitalization (4 points), nursing home residence (3 points) and other variables (0.5 points each). cap patients with an aliberti score ≥ 3 points have a reported prevalence of mdr of 38%, whereas cap patients with an aliberti score of ≤0.5 have a reported prevalence of mdr of 8%. the pes (p. aeruginosa, enterobacteriaceae esbl-positive, methicillinresistant s. aureus [mrsa]) score includes 1 point each for age 40-65 years and male sex; 2 points each for age > 65 years, previous antibiotic use, chronic respiratory disorder, and impaired consciousness; 3 points for chronic renal failure; and minus 1 point if fever is present initially. the risk of mdr pathogens is higher with 5 points or more [50] . unfortunately, studies validating the aliberti and pes score do not include immunocompromised patients. the ability of these scores to identify risk factors for cap by mdr pathogens in this population is still unclear. an important study by shindo et al. [51] investigated the main risk factors for mdr pathogens in 1413 patients with cap. six risk factors were identified: prior hospitalization, immunosuppression, previous antibiotic use, use of gastric acid-suppressive agents, tube feeding and non-ambulatory status. unlike the aliberti and pes studies, shindo's study included immunocompromised patients. interestingly, the authors analyzed risk factors for gram-positive (mrsa) and gram-negative pathogens separately. the authors observed that the risk of mdr gram-negative pathogens did not increase in the presence of ≥3 risk factors; conversely, for gram-positive (mrsa) pathogens, the risk increased in the presence of ≥2 risk factors, especially if one of the risk factors was specific for mrsa, such as previous colonization or previous hospitalization. therapy: how is it possible to treat these pathogens? since antibiotic treatment for p. aeruginosa is completely different from standard therapy to cover the most common pathogens in cap, current international guidelines for severe cap stratify therapy recommendations on the basis of p. aeruginosa risk factors [1] . mdr p. aeruginosa should be covered only in cases that are strongly suspected because of concurrent risk factors. it is important to underline that prior antibiotic therapy has been reported as the only risk factor for mdr p. aeruginosa in cap patients [11] . empirical antibiotic treatment based on the evaluation of the patient's risk factors is also of pivotal importance in the management of a. baumannii cap. because cap caused by a. baumannii has a fulminant clinical presentation with a high mortality rate (approximately 50%), greater attention should be paid in elderly patients with multi-comorbidities, and patients with alcohol abuse, chronic lung disease and prior antibiotic therapy, especially in asian countries where this pathogen is frequently reported. early appropriate antimicrobial therapy is critical. recommended empirical antibiotic therapy for a. baumannii cap includes anti-pseudomonal penicillins, aminoglycoside, ciprofloxacin, and imipenem. tigecycline, colistin, ceftazidime, doxycycline, minocycline, piperacillin/tazobactam, tobramycin, rifampin, fosfomycin and levofloxacin are active against variable percentages of strains. the treatment should include an association of two or more of these antibiotics according to the antibiogram of the isolated pathogen. moreover some countries, notably asia [52] and australia [53] , have implemented specific antibiotic recommendations in cases of severe cap in order to cover pathogens such as a. baumannii. in cap caused by k. pneumoniae, depending on the clinical severity and the risk of infection by a strain with resistance mechanisms (production of esbls, cefaminases or carbapenemases), a 3rd generation cephalosporin (cefotaxime or ceftriaxone) or a fluoroquinolone (ciprofloxacin or levofloxacin) should be used. another possibility, in case of infection by carbapenemase-producing or carbapenem-resistant strains (due to loss of porin and hyperproduction of amp-c), is the use of associations of two or three of the following antibiotics: colistin, tigecycline, fosfomycin (if the strain is sensitive), an aminoglycoside (amikacin or gentamicin) and meropenem (if the minimum inhibitory concentration [mic] = 16 mg/l), administered in high doses and by continuous perfusion. hypervirulent strains (serotypes k1 and k2) are usually more sensitive to antibiotics, but production of k. pneumoniae-type carbapenemase has also been observed. for the antibiotic treatment of s. maltophilia pneumonia, trimethoprim-sulfamethoxazole (tmp-smx) is still considered the drug of choice despite increasing resistance. it is preferably used in association with another antibiotic depending on the severity of the pneumonia and the sensitivity of the pathogen. other alternative antibiotics include β-lactams (i.e., ceftazidime), fluoroquinolones (i.e., levofloxacin, moxifloxacin), minocycline or tigecycline. in vitro, the following associations are often synergistic: cotrimoxazole with colistin, tigecycline, ceftazidime and rifampicin; colistin with tigecycline, ceftazidime and rifampin; ceftazidime with levofloxacin, moxifloxacin and aztreonam. figure 1 proposes an algorithm for the empiric antibiotic therapy of cap in patients with risks factors for mdr pathogens. correct identification of cap patients suspected of being infected with mdr gram-negative pathogens is crucial. specific risk factors, local ecology and resistance patterns should always be considered in order to determine the adequate empirical antibiotic therapy. early hemodynamic and respiratory support is critical in these patients since the majority of cases of pneumonia may become fulminant systemic disease with both respiratory failure and multiple organ dysfunction. the collaboration of a multidisciplinary team (critical care specialists, pneumologist, infectious disease specialists, microbiologists) improves management of the most severe cases. the role of the microbiology laboratory, in particular, is of pivotal importance to determine the antimicrobial susceptibility pattern of the pathogen causing cap, so that appropriate antibiotic therapy can be initiated as soon as possible, avoiding excessive use of broad spectrum antimicrobials, which increase the selection of resistant pathogens. 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hemorrhagic pneumonia caused by stenotrophomonas maltophilia in the treatment of hematologic diseases communityacquired stenotrophomonas maltophilia infections: a systematic review laboratory diagnosis of pneumonia in the molecular age multidrug-resistant pathogens in patients with pneumonia coming from the community epidemiology and predictors of multidrug-resistant community-acquired and health careassociated pneumonia risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia diagnosis and treatment of communityacquired pneumonia in adults: 2016 clinical practice guidelines by the chinese thoracic society, chinese medical association therapeutic guidelines antibiotic version 15. in: australian clinical practice guidelines. canberra: national health and medical research council dr. cillóniz is the recipient of a postdoctoral grant (strategic plan for research and innovation in health-peris 2016-2020). availability of data and materials not applicable. authors' contributions cc, cd and at conceived, provided expertise, wrote the raft and contributed to revising the manuscript. all authors read and approved the final manuscript.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-003701-i70ztypg authors: chow, eric j.; doyle, joshua d.; uyeki, timothy m. title: influenza virus-related critical illness: prevention, diagnosis, treatment date: 2019-06-12 journal: crit care doi: 10.1186/s13054-019-2491-9 sha: doc_id: 3701 cord_uid: i70ztypg annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the united states (u.s.) and worldwide. in temperate climate countries, including the u.s., influenza activity peaks during the winter months. annual influenza vaccination is recommended for all persons in the u.s. aged 6 months and older, and among those at increased risk for influenza-related complications in other parts of the world (e.g. young children, elderly). observational studies have reported effectiveness of influenza vaccination to reduce the risks of severe disease requiring hospitalization, intensive care unit admission, and death. a diagnosis of influenza should be considered in critically ill patients admitted with complications such as exacerbation of underlying chronic comorbidities, community-acquired pneumonia, and respiratory failure during influenza season. molecular tests are recommended for influenza testing of respiratory specimens in hospitalized patients. antigen detection assays are not recommended in critically ill patients because of lower sensitivity; negative results of these tests should not be used to make clinical decisions, and respiratory specimens should be tested for influenza by molecular assays. because critically ill patients with lower respiratory tract disease may have cleared influenza virus in the upper respiratory tract, but have prolonged influenza viral replication in the lower respiratory tract, an endotracheal aspirate (preferentially) or bronchoalveolar lavage fluid specimen (if collected for other diagnostic purposes) should be tested by molecular assay for detection of influenza viruses. observational studies have reported that antiviral treatment of critically ill adult influenza patients with a neuraminidase inhibitor is associated with survival benefit. since earlier initiation of antiviral treatment is associated with the greatest clinical benefit, standard-dose oseltamivir (75 mg twice daily in adults) for enteric administration is recommended as soon as possible as it is well absorbed in critically ill patients. based upon observational data that suggest harms, adjunctive corticosteroid treatment is currently not recommended for children or adults hospitalized with influenza, including critically ill patients, unless clinically indicated for another reason, such as treatment of asthma or copd exacerbation, or septic shock. a number of pharmaceutical agents are in development for treatment of severe influenza. annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the united states (u.s.) and worldwide [1] [2] [3] . in temperate climate countries, including the u.s., influenza activity peaks during the winter months whereas in tropical regions influenza activity may be more variable [4] [5] [6] . most persons with symptomatic influenza virus infection have self-limited uncomplicated upper respiratory tract illness. one study estimated that during 2010-2016, approximately 8.3% of the u.s. population experienced symptomatic influenza each year [7] . however, complications may result in severe illness, including fatal outcomes. during 2010-2018, an estimated 4.3-23 million medical visits, 140,000-960,000 hospitalizations, and 12, 000-79,000 deaths were associated with influenza each year in the u.s. [8] . another study estimated that 18, 000-96,000 influenza-related intensive care unit (icu) admissions occur annually in the u.s. [9] . there are an estimated 291,000-646,000 respiratory deaths attributed to seasonal influenza each year worldwide [2] . here, we review strategies for prevention, diagnosis, and treatment of influenza virus infections in the icu (table 1) . influenza vaccination is the primary method for preventing influenza and reducing the risk of severe outcomes. in the u.s., the advisory committee on immunization practices (acip) recommends annual influenza vaccination for all persons aged 6 months and older and prioritizes those at higher risk for influenza complications [10] . high-risk groups include adults aged > 65 years [11, 12] , children aged < 5 years (particularly those aged < 2 years) [13, 14] , pregnant women (up to 2 weeks postpartum) [15] [16] [17] [18] , persons with certain chronic medical conditions, native americans/alaska natives, 1 and residents of nursing homes and other long-term care facilities (table 2) . studies have specifically highlighted that those with chronic pulmonary, cardiovascular, renal, hepatic, neurologic, hematologic or metabolic disorders, immunocompromised persons, children and adolescents receiving aspirin-or salicylate-containing medications and who might be at risk for experiencing reye syndrome with influenza virus infection, and those who are extremely obese (bmi > 40) are at increased risk for influenza-related complications [10, [19] [20] [21] [22] [23] . many studies evaluated risk factors for severe influenza during the 2009 h1n1 influenza pandemic. adult icu patients with influenza a(h1n1)pdm09 virus infection were primarily non-elderly, were obese [24] [25] [26] [27] [28] , and had higher odds of death, invasive mechanical ventilation, acute respiratory distress syndrome (ards), septic shock, and multi-lobar pneumonia when compared with seasonal influenza patients [24, 29] . in children, independent risk factors for influenza a(h1n1)pdm09-related mortality included chronic neurologic condition or immune compromise, acute myocarditis or encephalitis, and early presumed mrsa co-infection of the lung [30] . female gender was also identified as a risk factor; however, there was no gender difference in overall mortality. bacterial coinfection was identified in approximately one third of fatal influenza a(h1n1)pdm09 cases in the largest autopsy case series [31] . bacterial co-infections in the interpandemic period are also common in critically ill influenza patients [32] . one study identified past or current tobacco use as a risk factor associated with icu admission [33] . a recent multicenter cohort study reported that mortality was higher in immunosuppressed patients with influenza a(h1n1)pdm09 than in immunocompetent patients [34] . severity of influenza seasons varies from yearto-year based on the predominant influenza viruses, and between seasonal and pandemic influenza [35, 36] . one study reported that patients with influenza a(h1n1) pdm09 had higher odds of severe disease than patients with either influenza a(h3n2) or influenza b virus infections [37] . however, influenza b virus infection has been shown to increase the odds of in-hospital mortality in children compared with influenza a virus infection [38] . influenza vaccination is recommended each fall for all persons aged > 6 months in the u.s. and should continue • there are an estimated 291,000-646,000 seasonal influenza-associated respiratory deaths every year worldwide. • annual influenza vaccination is the primary method of preventing influenza and influenza-related complications, especially in high-risk persons. • influenza molecular diagnostic testing is recommended for all patients requiring hospitalization with suspected influenza. • influenza antiviral treatment should be started as soon as possible in hospitalized patients with suspected influenza, including critically ill patients, and should not be delayed while awaiting results of influenza diagnostic tests. • enterically administered oseltamivir is recommended for influenza patients except for those with contraindications (e.g., gastric stasis, ileus, malabsorption). • repeat virologic testing in lower respiratory tract specimens may be required to determine therapeutic endpoints in ventilated patients with influenza • corticosteroids are not recommended for the routine treatment of influenza except when indicated for treatment of underlying medical conditions (e.g., copd or asthma exacerbation) or septic shock. [39] , and reducing in-hospital mortality and icu admissions for those aged 18-49 years and > 65 years compared to unvaccinated individuals [40] . one study reported that duration of icu hospitalization was reduced a half-day in patients aged 50-64 years who had received influenza vaccination compared with unvaccinated patients [41] . a study across all age groups in spain reported influenza ve of 58% in reducing the risk of severe influenza requiring hospitalization [42] . a southern hemisphere study reported influenza ve of 82% in reducing influenza-associated icu admissions among adults [43] while a study in spain showed an adjusted influenza ve of 23% in preventing icu admission and death [44] . despite the benefits of influenza vaccination, there continues to be low vaccine coverage among adults admitted to the icu who often have a high prevalence of high-risk comorbidities [45, 46] . in children, low influenza vaccination coverage has also been reported among those admitted to pediatric icus, even among those with underlying high-risk conditions [47] . full influenza vaccination was shown to result in a 74% reduction in pediatric icu admissions compared to unvaccinated or partially vaccinated influenza patients [47] . furthermore, one study showed that influenza ve was 65% in reducing the risk of mortality in children aged 6 months to 17 years in the u.s. [48] . these data further emphasize the benefits of influenza vaccination in reducing severe influenza complications, especially in high-risk persons. persons with uncomplicated influenza typically experience acute onset of respiratory symptoms (cough, rhinorrhea, congestion), myalgias, and headache with or without fever. during influenza season, clinicians should also consider influenza when there is only fever present or in patients who are afebrile and have respiratory symptoms [49] . complications of influenza vary by age, underlying comorbidities or high-risk conditions such as pregnancy, and immune function; elderly and immunocompromised persons may not always manifest fever. critically ill patients may be admitted with respiratory or multi-organ failure, exacerbation of an underlying condition such as chronic lung disease [50, 51] , heart failure [52] , or other extrapulmonary complications including stroke, encephalopathy, or encephalitis [30, 49, 53] . influenza testing is recommended for all patients requiring hospitalization with suspected influenza, including those admitted to the icu during influenza season with acute respiratory illness and community-acquired pneumonia, without a clear alternative diagnosis. furthermore, all individuals requiring critical care outside of influenza season should be tested for influenza if there is a possible epidemiological link to an individual with recent influenza, such as travel to areas with influenza activity or exposure to an institutional influenza outbreak. special consideration should be given to elderly and immunocompromised patients, as influenza virus infection may not present with typical acute respiratory illness signs and symptoms (e.g., absence of fever). the infectious diseases society of america (idsa) 2018 influenza clinical practice guidelines also recommend influenza testing for patients at high risk of complications such as exacerbation of chronic cardiopulmonary disease [49] . diagnosis of influenza should be made as soon as possible in critically ill patients, and initiation of antiviral treatment should not be delayed while awaiting results of diagnostic tests. studies have reported an increase in mortality of icu patients with influenza a(h1n1)pdm09 virus infection when diagnosis was delayed [54] , and shorter hospital length of stay when antiviral treatment was initiated within 6 h of admission [55] . several kinds of influenza diagnostic tests are available in clinical settings with variable sensitivities and specificities, including antigen detection assays, and molecular assays (nucleic acid detection) using respiratory tract specimens (table 3) . within each of these testing categories, there is a wide range of available tests with varying diagnostic accuracy, and understanding the limitations of each diagnostic tool will allow the clinician to properly interpret their results. most studies of influenza diagnostic accuracy have been conducted on specimens from patients with uncomplicated influenza, and few have assessed the performance of influenza tests in critically ill patients. the idsa guidelines recommend molecular influenza assays for testing respiratory specimens from all hospitalized patients with suspected influenza because of their high sensitivity, specificity, and time to results (15 min to several hours) [49] . the use of rapid influenza molecular diagnostic testing can result in better outcomes for patients and reduce the amount of resources required to care for patients in the emergency room [57] . serology and viral culture are not recommended for clinical decision making, because timely results will not be available to inform clinical management. serology requires collection of appropriately paired acute and convalescent sera performed at specialized public health reference laboratories, and results based upon a single serum specimen are not interpretable [49] . although viral culture can confirm the presence of infectious virus with very high sensitivity and specificity, it must be performed at public health laboratories and requires 3-10 days to yield results. a recent meta-analysis reported that influenza antigen detection tests that produce rapid results had very high specificities (> 98%), but sensitivities were highly variable compared with rt-pcr [58] . rapid influenza diagnostic tests (ridts) without an analyzer device had only moderate sensitivity (53-54%), ridts that utilize an analyzer device (digital immunoassays) had moderately high sensitivity (77-80%), and rapid influenza molecular assays (nucleic acid detection) had high sensitivity (92-95%) [58] . low sensitivity of ridts for detecting influenza virus in icu patients has been reported [59] . recently, a systematic analysis of rapid influenza molecular tests from 29 studies reported pooled sensitivity and specificity of 87.9% and 97.4%, respectively [60] . therefore, antigen detection assays, such as rapid influenza diagnostic tests and immunofluorescence assays, are not recommended for hospitalized patients with suspected influenza because of their lower sensitivities, unless molecular assays are not available [49] . negative results for influenza based on tests with low sensitivity (e.g., ridts, immunofluorescence assays) should not be used to make clinical decisions. instead, negative test results should be followed up with reverse transcription polymerase chain reaction (rt-pcr) or other influenza molecular assays to confirm results, and antiviral treatment should continue until results are available. preferred respiratory specimens for influenza testing in hospitalized patients without lower respiratory tract disease include nasopharyngeal, mid-turbinate nasal, or combined nasal-throat swabs. collection of lower respiratory tract specimens should be considered in hospitalized patients with suspected influenza if upper respiratory tract specimens are negative and a positive test would result in a change of clinical management [61] , because viral replication in the lower respiratory tract may be ongoing and prolonged after virus is no longer detectable in the upper respiratory tract [24, 25] . influenza a(h1n1)pdm09 virus in particular has been shown to have affinity for infecting the lower respiratory tract [24, 31] . in hospitalized patients receiving invasive mechanical ventilation in whom influenza is suspected, but not yet diagnosed, influenza testing should be performed on endotracheal aspirate specimens instead of those collected from the upper respiratory tract [61] . molecular testing, including rt-pcr for influenza viruses can also be performed on bronchoalveolar lavage (bal) fluid if collected for the testing of other pathogens. blood, plasma, serum, cerebrospinal fluid, urine, and stool samples have very low diagnostic yield and are not recommended for influenza testing [49] . diagnostic test results on specimens collected from non-respiratory sites should not be used for clinical decision making even for patients with extra-pulmonary complications of influenza. novel influenza a viruses are typically of animal origin, differ antigenically and genetically from currently circulating seasonal influenza a viruses (including h1n1pdm09 and h3n2 subtypes) and have infected at least one person. novel influenza a viruses can cause a wide clinical spectrum of illness, ranging from asymptomatic infection, uncomplicated illness, to fulminant pneumonia, ards, and multi-organ failure [62] and human infection with a novel influenza a virus is of public health concern. in the u.s., human infection with a novel influenza a virus is nationally reportable to the centers for disease control and prevention; globally, treatment of severe influenza presents multiple challenges. the mainstay of therapy for patients with influenza is initiation of antiviral medication as soon as possible after illness onset [49] . currently available fdaapproved antiviral medications include neuraminidase inhibitors (nais) (e.g., oral oseltamivir, inhaled zanamivir, and intravenous peramivir); cap-dependent endonuclease inhibitor (baloxavir marboxil); and adamantanes (e.g., amantadine and rimantadine) ( table 4 ). nais and baloxavir have activity against both influenza a and b viruses. adamantanes only have activity against influenza a viruses and are not recommended for treatment of influenza due to widespread resistance among currently circulating strains of seasonal influenza a viruses. notably, fda-approved antiviral medications for treatment of influenza are approved for early treatment of uncomplicated influenza in outpatients based upon randomized placebo-controlled clinical trials conducted among previously healthy outpatients. meta-analyses of randomized placebo-controlled clinical trials of early oseltamivir treatment of influenza in pediatric and adult outpatients have reported clinical benefit in reducing duration of illness and risk for some complications associated with influenza [65, 66] . no completed randomized, placebo-controlled trials of antiviral treatment have been conducted in hospitalized influenza patients to establish the efficacy of oseltamivir or other nais. a number of observational studies have reported clinical benefit of neuraminidase inhibitors in hospitalized patients, including reduction in duration of hospitalization and risk of death, including in icu patients [67] [68] [69] [70] [71] [72] [73] [74] . additionally, a systematic review of published reviews/meta-analyses reported survival benefit of nai treatment in hospitalized patients [75] , although another meta-analysis of observational studies did not [69] . in particular, a large pooled individual patient-level meta-analysis of observational studies from 38 countries identified a 38% reduction in risk of mortality in critically ill adults and those aged ≥ 16 years old when comparing early nai treatment (< 48 h) with later treatment (> 48 h), and a 69% reduction in mortality risk between influenza patients receiving early nai treatment and those who did not receive nais [72] . the mortality risk reduction of nai treatment at any time versus no treatment was 28% for critically ill patients aged ≥ 16 years old; while a similar reduction in mortality was identified in critically ill children aged < 16 years, the result was not statistically significant [72] and was likely underpowered because death is less common in hospitalized children with influenza than in adults. although studies have shown the greatest clinical benefit when antivirals are started within 2 days of illness onset, some observational studies have shown clinical benefit of neuraminidase inhibitors when started up to 5 days following symptom onset [15, 55, 76, 77] . the large metaanalysis mentioned above also identified a significantly reduced mortality risk reduction (35%) in critically ill patients aged ≥ 16 years old who received nai treatment > 48 h after symptom onset compared with those who did not [72] . a cohort study of early versus late oseltamivir treatment reported a significant reduction in mortality and median duration of icu hospitalization in severely ill patients with influenza a(h3n2), but not a(h1n1pdm09) or b virus infection in greece [78] . one french study reported delays in initiation of oseltamivir treatment prescribed to hospitalized influenza patients and suggested empiric administration of oseltamivir treatment in the emergency department for patients being admitted with lower respiratory tract disease during influenza season [79] . overall, based upon available observational data to date in hospitalized patients with influenza, including icu patients, initiation of neuraminidase inhibitor antiviral treatment is recommended as soon as possible for hospitalized patients with suspected or confirmed influenza. data on optimal dosing and duration of therapy with neuraminidase inhibitors are limited in critically ill influenza patients. enterically administered oseltamivir is the preferred treatment for most hospitalized patients, given the lack of data for intravenous peramivir in this population. the use of inhaled zanamivir is not recommended in in critically ill patients due to the lack of data in hospitalized patients and the risk of bronchospasm in patients with underlying lung disease. studies indicate that oseltamivir administered orally or via oro/naso-gastric tube is well absorbed in critically ill patients and reaches plasma levels comparable to those in ambulatory patients [80] . similarly, several observational studies indicate that enteric oseltamivir reaches comparable plasma concentrations to non-critically ill patients in those receiving extracorporeal membrane oxygenation (ecmo) and renal replacement therapy [80] [81] [82] [83] [84] [85] [86] [87] , although dosing should be reduced in patients with significant renal impairment. there is scant evidence that increased nai dosing (e.g., twice daily dosing) in critically ill patients provides additional clinical benefit than standard dosing [80, [88] [89] [90] [91] [92] . of note, studies also suggest that increased oseltamivir dosing does not provide additional clinical benefit in obese adults, including extreme obesity (bmi > 40) [93, 94] . duration of therapy can be difficult to define, as prolonged influenza viral replication and shedding from the both upper and lower respiratory tract can occur in critically ill patients [95, 96] . for this reason, it may be beneficial to continue antiviral therapy beyond 5 days, and repeat virologic testing may be beneficial in determining appropriate therapeutic endpoints [97] . continuing antiviral treatment in critically ill patients until virus is not detectable in the lower respiratory tract may also help reduce the pro-inflammatory dysregulated cytokine response triggered by influenza virus infection and reduce nosocomial influenza virus transmission to healthcare personnel in the icu. consultation with a specialist with training in infectious diseases for the potential emergence of antiviral resistant virus infection should be considered for icu patients with evidence of persistent influenza viral replication after nai treatment, particularly in severely immunocompromised patients [49, 98] . for patients who cannot tolerate or absorb enteric oseltamivir due to gastric stasis, malabsorption, or other gastrointestinal processes, intravenous peramivir may be an alternative [99, 100] ; however, studies have not identified an advantage for intravenous peramivir in comparison with enteric oseltamivir [101] . notably, a randomized trial conducted in three influenza seasons found similar clinical outcomes between iv peramivir and enteric oseltamivir in hospitalized adult influenza patients [102] ; a separate trial did not identify significant additional clinical benefit of peramivir in combination with standard-of-care therapy (which often included an nai) [103] . a more recent, multicenter randomized controlled trial also found similar clinical benefit between enteric oseltamivir and intravenous peramivir in hospitalized influenza patients [104] . in 2018, a novel antiviral agent, baloxavir marboxil, was fda-approved for early treatment of uncomplicated influenza in outpatients aged ≥ 12 years old. baloxavir acts via inhibition of the influenza virus cap-dependent endonuclease, a different mechanism than the neuraminidase inhibitors, and can treat nai-resistant influenza virus infections. randomized controlled trials of single-dose oral baloxavir showed similar clinical benefit to 5 days of twice-daily oral oseltamivir [105] . however, because these studies were limited to patients with uncomplicated influenza, the role of baloxavir monotherapy or in combination with an nai for treatment of hospitalized influenza patients is unclear. specifically, optimal dosing, duration of therapy, and appropriate endpoints have yet to be determined for baloxavir treatment of hospitalized influenza patients. in the outpatient rct, patients treated with single-dose baloxavir showed significant reduction in influenza viral levels in the upper respiratory tract at 24 h compared with those receiving placebo or oral oseltamivir [105] . however, it is unknown whether this reduction in influenza viral shedding correlates with reduced transmissibility. a potential concern for the use of baloxavir in critically ill patients is the rapid development of resistance observed during the outpatient clinical trials [106] . a trial to assess the efficacy and safety of baloxavir in combination with oseltamivir versus oseltamivir monotherapy in hospitalized influenza patients is currently enrolling participants [107] . there are no completed randomized clinical trials of adjunctive corticosteroid treatment in influenza patients. a trial of corticosteroid therapy was planned during the 2009 h1n1 pandemic, but was halted due to limited number of enrolees [108] . one observational study in china during the 2009 h1n1 pandemic reported that administration of parenteral glucocorticoids within 72 h of illness onset tripled the risk of developing critical illness or death from influenza a(h1n1)pdm09 virus infection [109] . a re-analysis of prospectively collected data on 1846 influenza patients admitted with primary influenza pneumonia to 148 icus in spain during 2009-2014 using propensity scoring matching reported that corticosteroid use was significantly associated with icu mortality [110] . meta-analyses of observational studies have concluded that that corticosteroid treatment of hospitalized influenza patients does not result in better outcomes and may be associated with adverse outcomes including increased mortality [111] [112] [113] . similarly, a retrospective observational study conducted on critically ill children during the 2009 h1n1 pandemic found that high-dose (equivalent to 2 mg/kg per day of methylprednisolone) corticosteroid treatment was associated with mortality in the icu, although a causative relationship was not determined [30] . a selection of individual observational studies in critically ill children and adults have also reported potential association between corticosteroid treatment and adverse influenza outcomes [30, 114, 115] . a recent cochrane review of available observational studies suggested increased mortality when adjunctive corticosteroid therapy is used for influenza patients; however, the available evidence was of low quality and the authors suggest interpreting these results with caution [116] . multiple studies have reported that corticosteroid treatment is associated with prolonged influenza viral shedding in hospitalized patients [117] [118] [119] , including in sporadic human infections with avian influenza a(h7n9) virus in china [120] , and increased rates of secondary bacterial and fungal co-infections [121, 122] , which may lead to adverse clinical outcomes. however, there is some evidence to suggest that the increased risk attributed to corticosteroid treatment is a result of bias in observational studies. a large, retrospective study of critically ill adults in canada found an increased risk of mortality in patients receiving corticosteroids; however, after adjusting for time-dependent differences between groups, no significant differences in mortality were observed with corticosteroid treatment [123] . moreover, potential differences between low-dose and medium-/ high-dose corticosteroid treatment are not well understood. one observational study of hospitalized patients with viral pneumonia due to avian influenza a(h7n9) virus infection in china reported that high-dose, but not low or moderate-dose corticosteroids, was associated with increased 30-day and 60-day mortality [124] . currently, on the basis of available observational data to date, adjunctive corticosteroid treatment is not recommended for children or adults hospitalized with influenza, including critically ill patients, unless clinically indicated for another reason, such as treatment of asthma or copd exacerbation or septic shock [49] . further studies are required to understand the clinical benefit or harms associated with corticosteroid treatment of critically ill influenza patients. although neuraminidase inhibitors (oseltamivir) are currently recommended for antiviral treatment of influenza in hospitalized patients based on observational studies, including in critically ill patients, there are a number of novel strategies and products for treating influenza in various stages of development. one approach under investigation is triple-combination antiviral drug (tcad) therapy, which combines amantadine, ribavirin, and oseltamivir for treatment of influenza in critically ill and high-risk patients. unfortunately, studies to date have not shown a benefit of tcad over oseltamivir monotherapy [125] [126] [127] . several novel antiviral compounds are in various stages of investigation, including small-molecule polymerase inhibitors such as pimodivir [128] and favipiravir [129] . a number of monoclonal and polyclonal antibodies, targeted against a variety of influenza viral proteins, are also in development [130] [131] [132] [133] . similarly, convalescent plasma has shown potential benefit in the treatment of severe influenza, and further trials are underway [134] [135] [136] . another area of intense interest is the modification of the host antiviral response to influenza virus infection. there are ongoing preclinical and clinical studies of a variety of other immunomodulatory agents for treatment of influenza, including celecoxib [137] , statins, etanercept, pioglitazone, azithromycin [138] , and interferons [139] . influenza vaccination can reduce the risk of complications from influenza, including reducing illness severity and the risks of hospitalization, icu admission, and death. the elderly, young children, pregnant women, and those with underlying medical conditions are most at risk for severe complications of influenza. a diagnosis of influenza should be considered in critically ill patients admitted with complications such as exacerbation of underlying chronic comorbidities, community-acquired pneumonia, and respiratory failure during influenza season. influenza molecular assays are recommended for testing upper respiratory tract specimens in patients without signs of lower respiratory tract disease. however, because critically ill patients with lower respiratory tract disease may have cleared influenza virus in the upper respiratory tract, but have prolonged influenza viral replication in the lower respiratory tract, an endotracheal aspirate (preferentially) or bronchoalveolar lavage fluid specimen (if collected for other diagnostic purposes) should be tested by molecular assay. antiviral treatment with standard-dose oseltamivir delivered orally or enterally by oro or naso-gastric tube is recommended as soon as possible for patients with suspected influenza without waiting for testing results. corticosteroids should not be routinely administered for treatment of influenza and should only be given for other indications (e.g., exacerbation of asthma or chronic obstructive pulmonary disease, or septic shock), because of the risk for prolongation of influenza viral shedding and ventilator-associated pneumonia in critically ill influenza patients with respiratory failure. future directions for treatment of influenza in critically ill patients include novel antiviral compounds, combination antiviral treatment with drugs with different mechanisms of action, immunomodulatory agents, and strategies for multimodality, combination antiviral, and host-directed immunomodulatory therapies. endnotes 1 these risk factors are included in the u.s. cdc's advisory committee on immunization practices recommendations for influenza vaccination. this may also apply to indigenous people from other countries, 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disease control and prevention. key: cord-281191-n9gerpwy authors: herridge, margaret s title: autopsy in critical illness: is it obsolete? date: 2003-09-26 journal: crit care doi: nan sha: doc_id: 281191 cord_uid: n9gerpwy the autopsy continues to have important implications for patient management in critical illness. it is not obsolete. autopsy data help us to track shifts in disease prevalence over time and to heighten surveillance for serious diagnoses that are commonly missed. these data help us to identify important contributors to death that may be remediated through quality assurance and control programs. in discrete patient subsets, information from autopsies may reinforce the degree of certainty surrounding end-of-life decision-making. in the present issue of critical care, perkins and colleagues revisit the role of autopsy in critically ill patients [1] . these authors evaluated 38 of 49 available autopsy reports in a population of 636 patients (6%). they found that premortem and postmortem findings were in complete agreement in less than one-half of these cases and that major missed diagnoses that might impact on treatment and outcome were present in 39% of the cases reviewed. the most frequently missed diagnoses included myocardial infarction, carcinoma and pulmonary embolism. autopsy series continue to appear in the medical literature and they continue to have an important clinical impact. the present commentary will outline the limitations and contributions of autopsy data. it will include a brief discussion of selection bias in autopsy studies, the important role autopsy plays in tracking disease prevalence over time, its characterization of newly emerging diseases, its contribution to education and quality control programs, and its role in clinical decision-making. autopsy studies are case series and they usually represent a small proportion of the total number of patient deaths recorded in the study period. most often, the reader is not given the total number of patient deaths, so the proportion of patients undergoing autopsy and how representative that study sample might be is never known. the perkins and colleagues' study, however, gives the reader very complete information [1] . they indicate that 7.7% of their deaths had postmortem examinations and that their study sample represented 6% of the total deaths. this proportion is small and it is not valid to conclude that these results represent the larger patient population. the authors point this out themselves. that is not to say that these observations are uninformative, but it does mean that most autopsy study data suffer from selection bias and this has to be considered when one discusses study results and their implications. findings on autopsy may reflect systematic shifts in the prevalence of disease states over time and may serve to highlight the limitations of current medical imaging and other diagnostic procedures. in 1983, goldman and colleagues analyzed 100 randomly selected autopsies from each of the academic years 1960, 1970 and 1980 at one university teaching hospital [2] . in each of these three decades, approximately 10% of autopsies revealed a diagnosis that might have lead to a change in therapy or outcome had it been known prior to the patient's death. in the 1980 autopsy series, there were fewer cases of renal disease and pulmonary embolism but a dramatic increase in systemic bacterial, viral and fungal infections. renal disease became a less prevalent cause of death because of the introduction of long-term renal replacement therapy. pulmonary embolus was better diagnosed by improved imaging modalities, and infectious complications increased because newer chemotherapy practices resulted in a greater population of immunocompromised patients. autopsy findings helped to highlight shifts in clinical practice and to inform the clinician of new sequelae of emerging treatments. autopsy studies are essential to characterize newly emerging diseases. the recent severe acute respiratory syndrome (sars) epidemic illustrates this point. it was hypothesized that the corona virus-induced pneumonia was associated with acute lung injury but pathological information was required to confirm this. autopsy data suggest that lung injury in sars patients is diffuse alveolar damage and is histopathologically consistent with that of the acute respiratory distress syndrome (ards) [3] . major discrepancies noted from autopsy studies may have important implications for our own education and for that of our housestaff. fernandez-segoviano and colleagues [4] evaluated 100 consecutive autopsies from patients in a multidisciplinary intensive care unit and noted a discrepancy rate of 22% between premortem and postmortem diagnosis. blosser and colleagues reported a discrepancy rate of 27% on 41 autopsies from medical intensive care unit patients [5] . each of these studies identified three major diagnoses that had been overlooked: acute myocardial infarction, pulmonary embolism and occult infection. the perkins and colleagues' study [1] reports similar findings. these observations are consistent across different patient populations, countries and investigators, and they should heighten our surveillance for these commonly missed diagnoses. autopsy findings may have important implications for quality control programs in the intensive care unit. mort and yeston observed a 41% discrepancy rate between premortem and postmortem diagnosis in patients admitted to a surgical intensive care unit from 1986 to 1992 [6] . they noted that the majority of discrepancies were due to undiagnosed infection and that one-half of these were fungal in origin and were found in transplant patients. as a result of this observation, these investigators initiated an enhanced infection control program at their institution. some investigators have suggested that autopsy data might be helpful in bedside clinical decision-making in specific patient groups. withdrawal of life-sustaining treatment is a frequent mode of death in critically ill bone marrow transplant patients, and end-of-life decision-making is based on clinical data. al-saidi and colleagues [7] determined the degree of concordance between premortem and postmortem diagnoses in this patient group in an attempt to enhance the level of certainty surrounding this practice. they reviewed 28 autopsies in critically ill bone marrow transplant patients and found that only 7% of discrepancies would have altered therapy and none would have altered outcome. these authors suggested that reliance on clinical data may be valid for withdrawal of life-sustaining treatment decision-making in view of the significant agreement between clinical diagnosis and postmortem findings. autopsy continues to have an important role in the management of the critically ill patient. it is an invaluable tool in the characterization of newly emerging diseases such as sars. as well, it is an important quality assurance measure that tracks changes in disease prevalence over time and identifies significant, and possibly remediable, contributors to icu death. in certain discrete patient groups, it may reinforce the degree of certainty surrounding end-of-life decision making. autopsy continues to provide unique and valuable data and it is not obsolete in critical illness. discrepancies between clinical and post mortem diagnoses in critically ill patients: an observational study the value of the autopsy in three medical eras lung pathology of fatal severe acute respiratory syndrome iruretagoyena jr: autopsy as quality assurance in the intensive care unit do autopsies of critically ill patients reveal important findings that were clinically undetected? the relationship of pre-mortem diagnoses and post mortem findings in a surgical intensive care unit relationship between premortem and postmortem diagnosis in critically ill bone marrow transplant patients none declared. key: cord-276904-lmqschxy authors: courcelle, romain; gaudry, stéphane; serck, nicolas; blonz, gauthier; lascarrou, jean-baptiste; grimaldi, david title: neuromuscular blocking agents (nmba) for covid-19 acute respiratory distress syndrome: a multicenter observational study date: 2020-07-19 journal: crit care doi: 10.1186/s13054-020-03164-2 sha: doc_id: 276904 cord_uid: lmqschxy nan the benefit of neuromuscular blocking agents (nmba) in acute respiratory distress syndrome (ards) is debated [1] [2] [3] . recent guidelines suggest use for most hypoxemic ards patients but no more than 48 h [3] . covid-19 ards appears different from classical ards [4] , and we aimed to describe the use of nmba and analyze their association with day 28 outcome, in a multicentric observational prospective study (21 icus from belgium and france). we enrolled consecutive patients with covid-19 moderate to severe ards (berlin definition) between 10 march and 15 april. the use of nmba was defined as administration within 24 h after intubation and its duration as the length of continuous paralysis until 24 h of infusion cessation. further administrations were not considered. main indications for paralysis were prone positioning and hypoxemia (p/f < 150 mmhg). we dichotomized a priori the nmba duration in less and more than 2 days. patients without nmba were considered to have 0 day of treatment. the primary endpoint was breathing without assistance at day 28. to account for difference between groups, we match the patients with short or long course of nmba using a propensity score with 0.01 margin. we compared the time to extubation using the kaplan-meier curve and log rank test. four hundred seven patients with day 28 follow-up were included (table 1) . among 342 patients (84%) who received nmba (median duration 5 [iqr 2-10] days), 241 received it for more than 2 days. these latter had higher plateau pressure and rate of prone position and were more frequently in french icus. after propensity score matching of 206 patients, the rate and time to breathing without assistance at day 28 did not significantly differ between groups (table 1 and fig. 1 ). this was also the case in the subgroup of more hypoxemic (p/f < 120 mmhg) patients (n = 76) and in those with the lowest compliance (< 37 ml/cmh 2 o). mechanical ventilation tended to be longer in survivors with long nmba administration. no other secondary outcomes appeared significantly different in this analysis. in this multicentric study, nmba were largely used for a longer duration than recommended. in a monocentric study, 60% of 267 mechanically ventilated covid-19 patients received paralysis [5] , whereas in the lungsafe study [6] , only 26% of ards patients receive nmba. the massive use of nmba in the context of shortage during covid-19 crisis may be questionable. after adjustment for confounders, we did not observe a difference in the proportion of extubation rate according to nmba length. the high compliance of covid-19 ards should protect them from barotrauma [4] , one of the protective effects of nmba [2] . however, respiratory drive appears high in these patients and patient self-induced lung injury (p-sili) may occur, which may explain why investigators administered nmba. we observed a low plateau pressure in our study but have no data about potential p-sili. one can be surprised to observe that matched on severity, time to extubation at day 28 was similar between patients with short or long course of nmba. our results indicate an equipoise regarding the duration of nmba, which should be tested in proper trials. our study has limitations. confounding and indication biases may exist despite adjustment, which decreased the study power. we did not collect the reason for nmba continuing; they may have been prolonged in patients with the worst evolution. finally, we did not gather the use of light sedation [1] and the occurrence of icu-acquired weakness and diaphragm paresis, suggested by the trend to higher length of ventilation in the survivors. in conclusion, we observed a large and prolonged use of nmba in covid-19 ards. after adjustment, a prolonged course of nmba was not associated with a lower rate of extubation at day 28. ethics approval and consent to participate this study was approved by appropriate regulatory committee in france (cnil 2217488) and in belgium (ec n°p2020/253) in accordance with the national regulation. each patient was informed about the study. in case of incompetency, the next of kin were informed. competing interests early neuromuscular blockade in the acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome formal guidelines: management of acute respiratory distress syndrome covid-19 pneumonia: ards or not? respiratory mechanics and gas exchange in covid-19 associated respiratory failure epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank jb mesland for the language revision of the manuscript. we would like to thank all the participants of the covadis study for their efforts in collecting the information used in this study: dr. nadia aissaoui, medecine intensive reanimation, hôpital européen georges pompidou, paris france. the authors declared no conflict of interest. received: 3 june 2020 accepted: 9 july 2020 responsible for the study concept and design: grimaldi d. and lascarroou jb.; analysis and interpretation of the data: grimaldi d., lascarrou jb., and courcelle r.; drafting of the manuscript: grimaldi d., courcelle r., and serck n.; interpretation of the data and critical revision of the manuscript for important intellectual content: grimaldi d., courcelle r., serck n. gaudry s., and lascarrou jb.; acquisition of the data: grimaldi d., blonz g., courcelle r., gaudry s., serck n., and lascarrou jb. the authors read and approved the final manuscript. this study was not funded.availability of data and materials d. grimaldi and jb. lascarrou had full access to all the data in the study and had final responsibility for the decision to submit for publication. the database will be public within 3 months after publication at https:// icucovadis.com fig. 1 cumulative proportion of patients breathing without assistance in the two neuromuscular blocker agents (nmba) groups using kaplan-meir curves. comparison with log rank test key: cord-290776-l6ajq6vp authors: frithiof, robert; bergqvist, anders; järhult, josef d.; lipcsey, miklos; hultström, michael title: presence of sars-cov-2 in urine is rare and not associated with acute kidney injury in critically ill covid-19 patients date: 2020-09-29 journal: crit care doi: 10.1186/s13054-020-03302-w sha: doc_id: 290776 cord_uid: l6ajq6vp nan patients infected with sars-cov-2 requiring intensive care due to coronavirus disease 2019 (covid-19) frequently develop acute kidney injury (aki) [1] , but the underlying mechanisms are poorly explored. sars-cov-2 has been found in both urine and the kidneys, where it has been suggested to cause proximal tubule damage [2] [3] [4] . direct renal infection of sars-cov-2 causing aki potentially leads to viral shedding in urine. however, to our knowledge, no study has been undertaken to investigate urinary levels of sars-cov-2 in patients with aki. in this report, sars-cov-2 rna levels were prospectively investigated in urine of patients with upper or lower airway swab test pcr-verified covid-19, admitted to a swedish intensive care unit (icu, n = 81). the presented data is part of a study approved by the national ethical review agency (2020-01623). informed consent was obtained from the patient or next of kin. the declaration of helsinki and its subsequent revisions were followed. nucleic acid was extracted from urine samples using nuclisens® emag® (biomerieux), and the amount of viral rna was quantitated by detection of sars-cov-2 e and n-genes using real-time rt-pcr according to previously described protocols [5, 6] . for quantitative assessment, the assay was calibrated against a synthetic rna standard from atcc and the detection limit was determined to 200 copies/ml. sars-cov-2 was found in urine of only 6 patients (7%). the median concentration was 1200 copies/ml (range 300-2800). urinary viral secretion was not associated with mortality or severity of disease as estimated by simplified acute physiology score 3 (saps3) on admission, length of stay in the icu, the need for invasive ventilation, or renal replacement therapy (table 1 ). based on changes in plasma creatinine, 51 (63%) patients developed aki during their icu stay. only 5 (10%) of those patients had detectable sars-cov-2 rna levels in the urine. this indicates that urinary secretion of sars-cov-2 is uncommon in covid-19-associated aki. furthermore, detection of sars-cov-2 rna in urine was not significantly associated with renal dysfunction and was most frequent in the mildest stage of aki (table 1 ). of interest is that positive samples in patients with aki were collected significantly further from onset and peak aki as compared to negative samples ( table 1) . limitations of the present study include that urine was not sampled repeatedly in the same patient. in case of varying viral secretion, this may have led to an underestimation of the number of patients being positive prior to or during the complete icu stay. furthermore, aki was determined based only on the change in plasma creatinine, not taking into account urine output. as aki stages are defined by the maximum change of either plasma creatinine or urine output, we may have underestimated the incidence of aki in this cohort. finally, the low concentration of viral rna in a limited number of patients prevents definitive conclusions regarding mechanisms of viral urinary secretion. a late onset of viral shedding in the urine may suggest a slowly developing glomerular filtration barrier dysfunction, but future studies are needed to investigate this in detail. here we show that urinary secretion of sars-cov-2 is scarce in critically ill covid-19 patients. in this cohort, sars-cov-2 rna was not more frequently detected in urine of patients that died or developed acute kidney injury. this suggests that determining viral presence in urine will not aid in predicting or grading renal dysfunction or severity of disease in covid-19. our findings do not support direct renal sars-cov-2 infection as an important mechanism of covid-19-induced aki, since renal infection likely would result in viral shedding in urine and thus a higher frequency of pcr positivity in urine of patients with aki. all authors participated in the conception and design of the study. ab performed the urinary analysis. all authors had access to the data and participated in the data collection and interpretation. rf drafted the manuscript, and all authors contributed to manuscript revision and gave approval of the final version. the study was funded by the scilifelab/kaw national covid-19 research program project grant to mh (kaw 2020.0182) and the swedish research council to rf (2014-02569 and 2014-07606). open access funding provided by uppsala university. data in the current study is available from the corresponding author on a reasonable request. the study was approved by the swedish national ethical review agency (epm; no. 2020-01623). informed consent was obtained from the patient or next of kin. not applicable. the authors declare that they have no competing interests. days between onset of aki and sample 2 (− 1-4), n = 46 6 (5-8), n = 5 0.01 days between peak p-creatinine and sample − 2 (− 7-3), n = 46 5 (4-5), n = 5 0.03 mortality rate of acute kidney injury in sars, mers, and covid-19 infection: a systematic review and meta-analysis unspecific post-mortem findings despite multiorgan viral spread in covid-19 patients secretion of severe acute respiratory syndrome coronavirus 2 in urine sars-cov-2 causes a specific dysfunction of the kidney proximal tubule detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr cdc 2019-novel coronavirus (2019-ncov) real-time rt-pcr diagnostic panel. centers for disease control and prevention division of viral diseases publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank research nurses joanna wessbergh and elin söderman and the biobank assistants erik danielsson and philip karlsson for their expertise in compiling the study. author details key: cord-287490-g1r9zew2 authors: despres, cyrielle; brunin, yannick; berthier, francis; pili-floury, sebastien; besch, guillaume title: prone positioning combined with high-flow nasal or conventional oxygen therapy in severe covid-19 patients date: 2020-05-26 journal: crit care doi: 10.1186/s13054-020-03001-6 sha: doc_id: 287490 cord_uid: g1r9zew2 nan prone positioning combined with high-flow nasal or conventional oxygen therapy in severe covid-19 patients cyrielle despres 1 , yannick brunin 1 , francis berthier 1 , sebastien pili-floury 1,2 and guillaume besch 1,2* dear editor, a massive outbreak of coronavirus disease 2019 (covid-19) occurred in france in march and april 2020. about 20% of covid-19 patients develop acute respiratory distress syndrome (ards), with mortality ranging from 20 to 50%. since the publication of the proseva study [1] , prone positioning (pp) has become a cornerstone of management of mechanically ventilated severe ards patients. recently, pp was reported to enhance oxygenation when combined with high-flow nasal cannula in severe non-covid-19 ards [2, 3] and to improve lung recruitability when combined with non-invasive ventilation in severe covid-19 ards [4] . we report the case of 6 severe covid-19 patients admitted to our critical care unit between march and april 2020, who had pp combined with either highflow nasal oxygen (hfno) or conventional oxygen therapy (cot). all patients had laboratory-confirmed sars-cov-2 infection, defined as a positive result of real-time reverse transcriptase-polymerase chain reaction (rt-pct) from nasal and pharyngeal swabs. ards was defined according to the berlin definition, with a ratio of p a o 2 to f i o 2 (p a o 2 /f i o 2 ) ≤ 300 mmhg. all patients presented rapid worsening of dyspnea and oxygenation, defined as s p o 2 ≤ 92% despite increasing oxygen supply to more than ≥ 5 l/min. all patients were spontaneously ventilated, and no patient had criteria that indicated the need for emergency intubation. all patients had predominant posterior lung condensation documented either on lung ultrasound or ct-scan. hfno or cot was prescribed to reach s p o 2 ≥ 94%. the clinical course of ards was closely followed using the rox index [5] . pp was proposed to patients who presented clinical worsening, as persistent hypoxia despite increasing oxygen delivery, or a decrease in the rox index. pp was maintained depending on patient clinical tolerance and could be repeated if necessary. relevant clinical, laboratory data and hfno or cot settings were obtained from medical records and are presented in table 1 . a total of 9 pp sessions was performed in 6 patients. pp was combined with hfno in 4 sessions and to cot in 5 sessions. the p a o 2 /f i o 2 ratio improved after 4 sessions, including 3 sessions combined with hfno and 1 session combined with cot. intubation was avoided in 3 patients. this is the first report of pp combined with either hfno or cot in severe covid-19 pneumonia. the proportion of patients with p a o 2 /f i o 2 ratio improvement after pp appeared to be higher with hfno compared to conventional oxygen therapy, suggesting the need for a high flow of oxygen to provide a significant oxygen response [6] . all patients described subjective enhancement of dyspnea after prone positioning, but this data was not quantified. the efficacy of pp combined with hfno therapy or non-invasive ventilation was recently reported in small cohorts of non-infectious and infectious non-covid-19 ards patients [2, 3] . interestingly, the proportion of patients with an improvement in p a o 2 /f i o 2 ratio and the rate of intubation avoided in these 2 studies were very close to that observed in the present series of 6 severe covid-19 patients. considering these observations, pp combined with either hfno or cot could be proposed in spontaneously breathing, severe covid-19 patients to avoid intubation. the indication for pp in non-intubated covid-19 pneumonia needs to be addressed in further studies. prone positioning in severe acute respiratory distress syndrome efficacy and safety of early prone positioning combined with hfnc or niv in moderate to severe ards: a multi-center prospective cohort study prone positioning combined with high-flow nasal cannula in severe noninfectious ards lung recruitability in sars-cov-2 associated acute respiratory distress syndrome: a single-center, observational study an index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy influence of positive end-expiratory pressure titration on the effects of pronation in acute respiratory distress syndrome: a comprehensive experimental study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank fiona ecarnot, ph.d., university hospital of besancon and university of franche-comte, besancon, france, for her assistance in preparing the manuscript. cyrielle despres, yannick brunin, francis berthier, sebastien pili-floury, and guillaume besch had substantial contributions to conception and design of the study, acquisition and interpretation of data, and drafting of the article manuscript. the author(s) read and approved the final manuscript. no funding to report.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors have no conflict of interest to disclose.received: 12 may 2020 accepted: 18 may 2020 key: cord-295585-dl29curs authors: hékimian, guillaume; lebreton, guillaume; bréchot, nicolas; luyt, charles-edouard; schmidt, matthieu; combes, alain title: severe pulmonary embolism in covid-19 patients: a call for increased awareness date: 2020-06-02 journal: crit care doi: 10.1186/s13054-020-02931-5 sha: doc_id: 295585 cord_uid: dl29curs nan coronavirus disease 2019 (covid-19) is associated with severe systemic inflammation and important elevation of fibrinogen and d-dimers that has been associated with a poor prognosis [1, 2] . this proinflammatory state might favor severe thromboembolic events and pulmonary embolism (pe). we retrospectively reviewed characteristics of patients with confirmed sars-cov-2 infection and acute pe who were admitted to our tertiary icu, which serves as an ecmo referral center for the greater paris. in accordance with the ethical standards of french legislation, only non-opposition of patient's surrogate for utilization of the deidentified data was obtained. the icu database was registered with the national data protection authority (cnil 1950673) . no analysis for statistical significance was performed given the descriptive nature of the study. from february 25, 2020, to april 6, 2020, 51 patients with confirmed sars-cov-2 infection were treated in our icu, of whom 8 (16%) had confirmed severe pe. patients' main characteristics are described in table 1 . four patients had pe while on vv-ecmo for severe ards. va-ecmo was initiated in 3 other patients with refractory shock due to right ventricular failure, and one patient died of refractory cardiac arrest before ecmo could be installed. pe was suspected in 6 patients because of acute cor pulmonale at echocardiographic evaluation (online supplementary data). pe diagnosis was confirmed by ct angiography (online supplementary data) in 7 patients and by autopsy in one patient. all except one had received anticoagulation before pe diagnosis. five patients had a very high level of fibrinogen, and all had important increase in d-dimers. as of april 6, 2020, 3 patients had died of multiple organ failure and 5 are still on mv and ecmo in the icu. we describe a series of 8 critically ill patients with massive pe following covid-19 infection. four of these patients developed pe while on vv-ecmo for severe ards, a condition that was not reported in the 156 patients included in the eolia trial [3] who received ecmo and in the 350 vv-ecmo patients of the life-gards international multicenter prospective cohort [4] . interestingly, 7 of the 8 patients had received preventive anticoagulation that did not prevent pe. in 6 of the 8 patients, doppler echocardiography showing acute right ventricle dilation prompted ct angiography that confirmed pe. massive pe in covid-19 patients may be the consequence of sepsis-induced disseminated intravascular coagulation or to a specific procoagulant state caused by inflammation or virus-induced endothelial dysfunction [5] . important elevation of d-dimers was indeed reported in these patients and was associated with subsequent ards and in-hospital mortality [5] . however, massive pe was not reported in previous series [1, 2] , although it may have been the unproven cause of death in some patients. our observation has potential major clinical implications. first, higher level of anticoagulation might be considered in patients with the most severe forms of the disease, those with high d-dimers and, contrarily to our previous recommendation, in patients supported by vv-ecmo [3] . second, routine doppler echocardiography should be performed daily to detect early signs of acute cor pulmonale in critically ill patients. lastly, pe should also be suspected in covid-19 patients with worsening hypoxemia or hypercapnia under mechanical ventilation. this case series has several limitations. it is a small single-center case series of critically ill patients, we did not compare clinical and biological characteristics of patients with or without pe, and pe incidence could not be accurately estimated. however, we think that physicians should be warned about the occurrence of severe and potentially fatal pe in covid-19 patients. clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study extracorporeal membrane oxygenation for severe acute respiratory distress syndrome mechanical ventilation management during extracorporeal membrane oxygenation for acute respiratory distress syndrome. an international multicenter prospective cohort abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank corinne frère 1 md, phd, and pascal leprince 3 md, phd, for their help during the preparation of the manuscript. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-02931-5. authors' contributions gh and ac analyzed the results and drafted the manuscript. all authors participated in the data collection and final manuscript preparation and agreed with the latest manuscript. availability of data and materials the datasets generated during the current study are available from the corresponding author on reasonable request. in accordance with french law and the ethical standards of our hospitals' institutional review board (committee for the protection of human subjects), informed consent was not obtained because this observational study did not modify existing diagnostic or therapeutic strategies. however, patients and/ or their relatives were informed about the anonymous data collection and were told that they could decline inclusion. this database is registered at the national commission for informatics and liberties (cnil registration no. 1950673). the authors declare that they have no competing interests. key: cord-256237-xiv9vxdp authors: suntharalingam, ganesh; cousins, jonathan; gattas, david; chapman, martin title: scanning the horizon: emerging hospital-wide technologies and their impact on critical care date: 2005-01-13 journal: crit care doi: 10.1186/cc3046 sha: doc_id: 256237 cord_uid: xiv9vxdp this commentary represents a selective survey of developments relevant to critical care. selected themes include advances in point-of-care diagnostic testing, glucose control, novel microbiological diagnostics and infection control measures, and developments in information technology that have implications for intensive care. the latter encompasses an early example of an artificially intelligent clinical decision support mechanism, the introduction of a national health care information technology programme (uk npfit) and its implications, and exotic threats to patient safety due to emergent behaviour in complex information systems. this series of articles provides regular surveillance of new technologies which may impact on critical care. several countries have developed national horizon scanning systems to identify and monitor new health technologies. there is variation in how these centres gather information, but a consistent set of high priority sources has been identified [1] . for the purposes of this article, the outputs of major health technology assessment centres, national regulatory authorities, and recognized scientific news sources (table 1) were systematically searched for developments relevant to acute and critical care. this was combined with a manual medical literature search, along key editorial themes subjectively selected for this issue. point-of-care testing is a major emerging theme throughout the health sector, encompassing both new diagnoses and monitoring of known diseases and their treatment. areas of research range from the potentially lucrative markets for outpatient, 'office'-based and patient self-testing, through to in-hospital diagnostics, which include both rapid access analysis of traditionally laboratory bound diagnostics and direct patient imaging. both aspects are particularly relevant to critical care clinicians, who rely on time sensitive diagnosis and treatment in a hyper-acute setting. an example of bedside imaging in cardiac assessment has already been cited in the first article of the present series [2] . sample analysis, meanwhile, is rapidly developing to encompass bedside biochemical markers, physiological homeostasis monitoring, and novel ultra-rapid forms of infectious disease diagnosis. b-type natriuretic peptide can be a rapid and effective marker of ventricular strain and heart failure [3] , and can now be measured using a point-of-care diagnostic panel (triage bnp test; biosite inc., san diego, ca, usa). similar current and forthcoming technologies include rapid access d-dimer assays for diagnosis of pulmonary embolism as part of a structured point-of-care algorithm [4] and unpublished early developments in stroke diagnostics. validation and clinical trials of these technologies have taken place primarily in the emergency department setting, but heart failure, cerebrovascular accident and pulmonary embolism are all of commentary scanning the horizon: emerging hospital-wide technologies and their impact on critical care added significance in the intensive care unit (icu) as both primary and acquired conditions. rapid bedside diagnosis of such conditions with minimal need for intrahospital transport may be of great potential benefit to intensivists. the importance of tight glucose control in sepsis is becoming well established [5] , although work continues on refining the target range, with a study of 4,000 patients now in progress (normoglycaemia in intensive care study, anzics, commencing 2004). the first major prospective study of tight glucose control in sepsis introduced a novel algorithm requiring frequent measurements [6] , which raised concerns over patient safety and resource utilization in general icus. point-of-care 'stick' glucose testing is already prevalent, but technology now exists for continuous in vivo glucose monitoring, which, although intended for ambulatory use, could improve accuracy in the acute setting. a subcutaneous interstitial glucose sensor system (continuous glucose monitoring system; medtronic minimed, inc., northridge, ca, usa) was tested against clamp controlled hypoglycaemic and hyperglycaemic excursions in volunteers [7] ; it was shown to be closely correlated with reference analyzer results (r 2 = 0.91; p < 0.001) and highly responsive (half-time 4.0 ± 1.0 min). similarly, another device (glucoday; a. menarini diagnostics, florence, italy), utilizing a 15-100 µl micropump and a biosensor coupled with microdialysis to give a claimed response time of 2 min, will reach european markets this year. such devices may be incorporated into manual algorithms, or they may potentially open the way to automated closed-loop glucose control. microbiological diagnosis within clinical laboratories has been advancing apace [8] . polymerase chain reaction technology is well established, but progressive refinements have made possible the rapid and near real-time diagnosis of current, novel, or newly relevant pathogens, including hiv and sars (severe acute respiratory syndrome). techniques initially aimed at viruses because of their manageable size can now also be applied to bacteria and can be used for broad, simultaneous screening of multiple pathogens (pneumoplex, prodesse, milwaukee, wi, usa). further refinements in microarrays and microfluidics are anticipated to bring handhand and point-of-care systems into use in the near future. point-of-care and rapid laboratory based technologies will soon be able to elicit not only pathogen identity but also patterns of drug resistance. developments include the use of adenylate kinase assay for accelerated laboratory based identification of drug-resistant bacteria, including methicillinresistant staphylococcus aureus and vancomycin-resistant enterococci (baclite, acolyte biomedica, salisbury, uk; http://www.acolytebiomedica.com/tech.htm). point-of-care testing within emergency and critical care areas is likely to develop rapidly in the next 5 years, but it will bring complications relating to quality control, medicolegal liability, certificated training for icu and other nonlaboratory staff, increased cost, and territoriality issues. finally, other bedside technologies that have recently been assessed include the use of handheld ultrasound devices to detect occult pneumothoraces, which have been shown to have a higher sensitivity than chest radiography (48.8% versus 20.9%) against a computed tomography standard [9] . preliminary investigations suggest that handheld infrared table 1 agencies and information scources scanned for health technology assessment related data (2004) the european agency for the evaluation of medicinal products (emea) http://www.emea.eu.int/ pupillometry may be of clinical use in detecting midline cerebral shift in head injury patients [10] . more procedure orientated assistance may become available from near-infrared technology, which has been piloted in a computerized bedside visualization device to aid venous cannulation [11] . applicability to central venous cannulation has not been explored. acquired bloodstream infection (bsi) in the icu is a serious complication. a study of icu patients in calgary [12] demonstrated crude death rates of 45% among patients with icuacquired bsi, as compared with 21% in those without (p < 0.0001). s aureus was isolated in 18% of cases in the study cited above. in this context, the development of an antistaphylococcal vaccine (staphvax; nabi pharmaceuticals, boca raton, fl, usa) represents a promising new health technology [13] . staphvax is currently in phase iii trials for end-stage renal disease, but phase ii trials are under way in postoperative and long hospital stay patients. health technology assessment encompasses the best use of current health care devices as well as emerging technologies. medical devices represent a prime infection hazard, and us centers for disease control and prevention guidelines [14] cover the safe use of intravascular devices to minimize acquired bsi. however more recent work demonstrates that the incidence of catheter-related bsi may be significantly reduced by adding a further deviceneedle-free, disinfectable connectors instead of three-way stopcocks -to the existing recommendations (0.7 infections/1000 days versus 5.0 infections/1000 days of catheter use; p < 0.03) [15] . clinical management of sepsis is normally outside the remit of this section of the journal. however, it is noteworthy that new mechanical technology has been applied to the direct treatment of sepsis rather than to cardiovascular or tissue perfusion monitoring. a recent european multicentre open randomized phase ii trial [16] investigated the use of the endotoxin adsorber system en500 (fresenius, bad homburg, germany) in 145 patients with severe sepsis or septic shock due to suspected gram-negative infection. the study demonstrated a trend toward reduced icu stay and more rapid reduction in lipopolysaccharide levels, but it failed to show any difference in outcome. certain developments in this sector are pertinent to critical care. isabel is a web-based, diagnostic decision support tool intended to provide diagnosis reminders and minimize missed diagnosis of critical disease processes. it is currently in use in several uk and overseas hospitals, with development supported by uk department of health funding followed by a commercial launch [17] . the methodology is novel; a commercial artificial intelligence inference engine (autonomy, cambridge, uk) is used to extract and structure information from standard paediatric textbooks, and to generate diagnostic reminders from this knowledge base in response to unstructured free text clinical information. the software has been under development for some time and was reviewed in this journal in 2002 [18] , but it is now being modified to encompass adult critical illness. a review of decision support systems by the uk national institute of clinical excellence is pending. there are political and medicolegal implications. the isabel project was initially set up on a charitable basis by the parents of a child who survived a prolonged stay in paediatric intensive care after a missed diagnosis of necrotizing fasciitis. although the system is as yet little known among adult intensivists, its technology is innovative and its proposed status as an 'online second opinion' may give it, together with similar expert systems, a powerful consumerist resonance with patients, carers and managers. the uk national institute of clinical excellence findings should be monitored with interest by critical care providers. more broadly, the uk health service is currently in the grip of a globally unprecedented large-scale national project for it (npfit) [19] . structured as a series of private finance initiatives, this ambitious programme will ultimately see in a host of regionally standardized patient information systems, image storage, and networked monitoring and audit systems, linked to a national electronic patient record 'spine'. there are already concerns about timescale, feasibility and funding. broader concern is growing about catastrophic and unpredictable 'emergent behaviour' in massively interconnected information technology (it) systems, which are rapidly becoming too complex to test or accurately model [20] . emergent behaviour in complex systems has already been explored in popular fictional media, in which predicted outcomes are spectacular but somewhat discouraging [21] ; however, even without quite such an apocalyptic scenario, we may well see a rising incidence of total system failures due to unpredictable nonlinear behaviour -that is, major collapses triggered by small unforeseen causes. in the light of recent north american power outages and destructive computer failures in the uk social service and tax systems, emergent behavour must now be considered a clear and present threat to our increasingly networked health services and their supporting infrastructure. levels of concern are such that the uk government is funding a £10 million research programme into it complexity and catastrophic failures. how much of this is relevant to critical care or to other countries? first, icus provide complex, time-sensitive care to highly dependent patients. they therefore require the successful convergence of multiple hospital systems, which makes them uniquely vulnerable to the consequences of system failures, whether in diagnostics, supplies, information flow, or indeed electrical power. second, the currently stated uk npfit vision is that all icu subsystems, including networked monitoring, telemetry and audit systems, will eventually be integrated into npfit, with control over equipment selection and data collection handed to the regional private sector consortia and to national audit bodies. clinician engagement and choice may not feature highly on the agenda, and there are clear concerns over the future of independent research and audit. finally, clinicians from other countries would be well advised to follow such developments because the uk is not unique in its desire to radically modernize and standardize health it, starting with a drive toward electronic patient records. in april 2004, president bush issued an executive order calling for us national implementation of electronic medical records within 10 years, from a current baseline of 19% implementation. in a series of presidential speeches he went on to further define health care objectives substantially similar to the uk npfit agenda [22] . therefore, this represents another area in which political and technological developments outside the icu may have a direct impact on clinical practice and patient safety, and intensivists are strongly recommended to consult early and engage with those driving their local and national health economy. a variety of emerging technologies are examined here. very few of these are designed or marketed to be specific to intensive care, and few are traditional 'devices' that can be physically handled or attached to a patient. however, critical care is a distillation of acute hospital practice, and any health care technology that has an impact on diagnosis, monitoring, and management of acute conditions will be of heightened importance in the clinical pressure cooker of intensive care. point-of-care testing, accelerated microbiological diagnostics, decision support systems and networked it systems are all key developments that will exert an impact on future critical care practice. use of the internet in scanning the horizon for new and emerging health technologies: a survey of agencies involved in horizon scanning innovations in technology for critical care medicine utility of btype natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting impact of a rapid rule-out protocol for pulmonary embolism on the rate of screening, missed cases, and pulmonary vascular imaging in an urban us emergency department surviving sepsis campaign guidelines for management of severe sepsis and septic shock bouillon r: intensive insulin therapy in critically ill patients determination of plasma glucose during rapid glucose excursions with a subcutaneous glucose sensor new microbiology tools for public health and their implications handheld thoracic sonography for detecting post-traumatic pneumothoraces: the extended focused assessment with sonography for trauma (efast) quantitative pupillometry, a new technology: normative data and preliminary observations in patients with acute head injury. technical note vein camera keeps injections on target. new scientist intensive-care-unit-acquired bloodstream infections in a regional critically ill population national horizon scanning centre: new and emerging technology briefing: staphvax for the prevention of staphylococcus aureus infections in end stage renal disease guidelines for the prevention of intravascular catheterrelated infections prevention of catheter-related bloodstream infection in critically ill patients using a disinfectable, needle-free connector: a randomized controlled trial open randomized phase ii trial of an extracorporeal endotoxin adsorber in suspected gram-negative sepsis national programme for it (npfit) in the nhs homepage sprawling systems teeter on it chaos terminator 3: rise of the machines. munich: intermedia films the white house: president bush touts benefits of health care information technology the author(s) declare that they have no competing interests. key: cord-291934-pm3ns6ge authors: jiang, ronglin; wang, kungen; mao, wei; zhu, wei; hu, weihang; huang, liquan title: chinese herbal experience for the 2019 novel coronavirus date: 2020-07-21 journal: crit care doi: 10.1186/s13054-020-03170-4 sha: doc_id: 291934 cord_uid: pm3ns6ge nan the novel coronavirus (covid-19) has spread rapidly and become a severe global threat, with a reported acute respiratory distress syndrome (ards) incidence up to 40% [1] . according to a large survey, more than 14% patients were transferred to the intensive care unit care (icu), and among those who received invasive mechanical ventilation, the mortality was as high as 88.1% [2] . here we presented the data from a single icu of tianyou hospital in wuhan, and according our experience, the overall mortality decreased in patients receiving chinese herb therapy. from january 11, 2020, to march 17, 2020, a total of 37 patients confirmed with covid-19 infection were admitted to icu (table 1) , of whom seven patients were transferred to other hospitals and were excluded from this analysis. the general treatment regimens included glucocorticoids, antibiotics, hydroxychloroquine, and arbidol; however, the overall mortality rate remains as high as 78.1%. chinese herb was applied in these patients since feb 17. thus, a total of nine patients received chinese herbal therapy during the whole disease course (admitted to icu after feb 17), five patients received chinese herbal therapy for a period of the whole disease course, and the rest fourteen patients had not received chinese herbal therapy. despite with limited sample size, the mortality rate decreased significantly after applying chinese herbal to these patients (4/9 vs. 5/5 vs. 14/16, p = 0.033), especially in patients who received chinese herbal therapy during the whole disease course. further, these patients were also divided into two groups according to whether they had used chinese herbal; a decreased trend of mortality was also observed (9/14 vs. 14/16, p = 0.134). we understand our finding is unstable due to the limited sample size and potential cofounders. however, in china, chinese herbal therapy has been fully applied to patients with covid-19 infection in the middle stage of this epidemic and the effect is positive. the following content is the risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-000522-d498qj2b authors: vincent, jean-louis; abraham, edward; annane, djillali; bernard, gordon; rivers, emanuel; van den berghe, greet title: reducing mortality in sepsis: new directions date: 2002-12-05 journal: crit care doi: 10.1186/cc1860 sha: doc_id: 522 cord_uid: d498qj2b considerable progress has been made in the past few years in the development of therapeutic interventions that can reduce mortality in sepsis. however, encouraging physicians to put the results of new studies into practice is not always simple. a roundtable was thus convened to provide guidance for clinicians on the integration and implementation of new interventions into the intensive care unit (icu). five topics were selected that have been shown in randomized, controlled trials to reduce mortality: limiting the tidal volume in acute lung injury or acute respiratory distress syndrome, early goal-directed therapy, use of drotrecogin alfa (activated), use of moderate doses of steroids, and tight control of blood sugar. one of the principal investigators for each study was invited to participate in the roundtable. the discussions and questions that followed the presentation of data by each panel member enabled a consensus recommendation to be derived regarding when each intervention should be used. each new intervention has a place in the management of patients with sepsis. furthermore, and importantly, the therapies are not mutually exclusive; many patients will need a combination of several approaches – an 'icu package'. the present article provides guidelines from experts in the field on optimal patient selection and timing for each intervention, and provides advice on how to integrate new therapies into icu practice, including protocol development, so that mortality rates from this disease process can be reduced. sepsis is the tenth most common cause of death in the us [1] . a recent us study reported that severe sepsis accounts for in excess of 215,000 deaths annually from a total population of approximately 750,000 patients-a mortality rate of approximately 29% (with published studies quoting a range of 28-50%) [2] . this persistent, high mortality rate is clearly unacceptable, given that it ranks sepsis above some of the higher profile causes of in-hospital death, including stroke (12-19% risk of death in the first 30 days) and acute myocardial infarction (ami) (8% risk of death in the first 30 days) [3] . moreover, the actual number of deaths associated with the condition may be even higher than current estimates suggest. many sepsis patients have at least one comorbidity and deaths are often attributed to these conditions rather than to sepsis [4] [5] [6] . unfamiliarity with the signs and symptoms of sepsis may further hinder accurate diagnosis. there are many possible reasons for this high mortality. sepsis is certainly a complex disease state; the pathophysiology is only now beginning to be unraveled, and it is complicated by heterogeneous presentation (possible signs of sepsis are presented in table 1 ). while none of these signs alone is specific for sepsis, the otherwise unexplained presence of these signs should signal the possibility of a septic response. many cases of sepsis are recognized late, and patients are often inappropriately treated before entering the intensive care unit (icu) by physicians unfamiliar with the signs and symptoms of the condition. furthermore, treatment may be initiated by any of a number of physicians (anesthetists, hematologists, intensivists, infectious disease specialists, pulmonologists, and emergency physicians). there are presently various defined supportive strategies for treating patients with sepsis, but improvements are needed to reduce the unacceptably high mortality rate. moreover, as with other areas of medicine, the application and integration of new but proven strategies for reducing morbidity and mortality into clinical practice has been slow. encouraging new data have recently been presented on new approaches to the management of patients with sepsis. many of these approaches attempt to modulate or interrupt the sepsis cascade and to address the cause of multiorgan dysfunction. although many of these approaches are in early phases of development (e.g. antibodies to tumor necrosis factor [tnf] alpha, bactericidal permeability increasing protein, high-flow hemofiltration to remove circulating inflam-matory mediators, platelet-activating factor acetyl hydrolase, and antielastases), other approaches are more advanced and are already beginning to impact on outcomes in the icu. at a roundtable discussion in london in june 2002, professor jean-louis vincent brought together five experts to discuss more effective implementation of five exciting new interventions in the icu setting to decrease the unacceptable burden of mortality in patients with severe sepsis. each of the roundtable panelists is a highly respected physician in the world of sepsis and critical care medicine. the interventions discussed encompassed low tidal volume in patients with acute lung injury (ali)/acute respiratory distress syndrome (ards) (edward abraham), early goal-directed therapy (egdt) (emanuel rivers), drotrecogin alfa (activated) (gordon bernard), moderate-dose corticosteroids (djillali annane), and tight control of blood sugar (greet van den berghe). the purpose of the roundtable discussion was to provide guidance for clinicians on the integration of new interventions into the icu to reduce the mortality in sepsis, on appropriate patient selection for these interventions, and on appropriate timing of these interventions. the present review reports the discussions and recommendations of the panel. the overall 30-day mortality in the icu is typically ~20% [8] . the 30-day mortality in the population with severe sepsis, defined as sepsis with organ dysfunction, is 30-50%. it is clear from this figure that severe sepsis contributes disproportionately to the overall 30-day mortality in the icu and compares unfavorably with some of the higher profile acute killers in hospital (e.g. stroke and ami) [3] . despite the general improvements in medicine overall, this mortality rate has remained essentially unchanged for the past 25 years. this has contributed to a feeling of pessimism among table 1 possible signs of sepsis (adapted from [ intensivists and other medical professionals regarding treatment prospects for severe sepsis, and a reluctance to rapidly incorporate new interventions into clinical practice [9] . although the sepsis mortality rates are unacceptable, they camouflage some significant developments that are and have been occurring for hospital patients, for the general icu population and, particularly, for those with severe sepsis. direct comparison of mortality rates among patients with identical acute pysiology and chronic health evaluation (apache) scores in the placebo arm of anti-tnf or anti-endotoxin studies published 10-15 years ago [10] [11] [12] with more recent studies [13, 14] , demonstrates that the mortality rate is much lower in more recent studies. interestingly, this decrease was apparent even before the five interventions discussed in the present article were published, reflecting improvements in the general supportive care of sepsis patients. indeed, the panel contends that mortality from septic shock has already been reduced. some patients who in the recent past would have died from severe sepsis or septic shock do not reach the icu now because they are well managed on the wards, in the emergency department, and even during preoperative and postoperative care. for example, those sepsis patients that receive prompt antibiotic therapy have a 10-15% lower mortality rate than those who receive antibiotic therapy later in their care [15] . progress is also being made in diagnosing sepsis: more patients are being tested to identify the source of infection and the pathogens involved, supportive care measures have been improved (e.g. hemodynamic support), and other measures have been put in place to reduce the incidence of nosocomial infections (e.g. reducing the need for pulmonary artery catheters by using echo techniques to assess cardiac function). there has also been a realization of the importance of specially trained intensive care physicians in the icu. it has been internationally recognized that changing the icu from an 'open format', whereby patients are cared for by their admitting physician, to a 'closed format', whereby patients are managed by appointed intensivists, reduces mortality rates [16] . although the mortality rate is beginning to decline, it still remains unacceptably high. furthermore, the number of patients with severe sepsis and septic shock is increasing; people are living longer, and there has been a rise in the number of immunocompromised patients due to aggressive cancer therapy and the increased prevalence of hiv. in-hospital ami-associated mortality rates averaged approximately 25-30% in the 1960s [3] . this clearly unacceptable mortality rate was addressed by the development of a number of new pharmacological and mechanical interventions together with improvements in supportive care. in the landmark second international study of infarct survival trial, published in 1988, 17,187 suspected ami patients were treated with either streptokinase or aspirin, with both drugs, or with neither. the mortality rate in the combination group of this trial was 8%, compared with 13.2% in those patients given neither streptokinase nor aspirin [17] . cardiologists have effectively implemented multiple pharmacologic and supportive care interventions to reduce mortality in ami from 25-30% to 8% and lower. not satisfied with this already remarkable figure, they are trying to reduce it further. physicians treating patients with sepsis are clearly faced with a very different situation to those treating patients with ami, and so direct comparisons are not possible. however, several factors have contributed to the success of ami therapy and possibly to the lack of such success in sepsis (table 2) . sepsis is undoubtedly complicated. however, many of the lessons that have been learned through effective application of therapies in other disease states can be applied to severe sepsis. furthermore, the encouraging data that are beginning to appear in the literature indicate that sepsis may not be as intractable to treat as once thought. the following sections provide salient information on five interventions that have shown a significant positive impact on mortality rates in sepsis, severe sepsis, septic shock, or sepsis-related diseases in recent clinical trials. the interventions were presented at the roundtable by one of the principal investigators of the key trial of the intervention. each section concludes with recommendations for the integration of the particular intervention into clinical practice. the traditional approach in patients with ali/ards is to ventilate using tidal volumes between 10 and 15 ml/kg body weight, almost twice the average tidal volume at rest (7-8 ml/kg body weight), and to maintain a low positive endexpiratory pressure (peep). the purpose of this approach is to achieve normal values for the ph and partial pressure of arterial carbon dioxide. however, this method leads to high inspiratory airway pressures and to excessive stretch of the aerated lung. in 1997, tremblay et al. examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a pre-existing inflammatory stimulus in sprague-dawley rats [18] . in both stimulated and nonstimulated groups, the presence of inflammatory mediators (tnf-α, il-1β, il-6, il-10, macrophage inflammatory protein 2, and ifn-γ) was highest in those rats ventilated with a large tidal volume and zero peep. furthermore, in a study by ranieri et al. in 1999 [19] , the concentration of inflammatory mediators 36 hours after randomization of the groups was significantly lower in the lung-protective strategy group (tidal volume, 7.6 ± 1.1 ml/kg) than in the control group (tidal volume, 11.1 ± 1.3 ml/kg) (p < 0.05). following on from the positive results in the tremblay et al. trial [18] , a small study (53 patients) was carried out by amato et al. in brazil [20] . the mortality rate was 38% in patients given 'protective' ventilation (peep above the lower inflection point on the static pressure-volume curve, tidal volume < 6 ml/kg ideal body weight, driving pressures < 20 cmh 2 o above the peep value, permissive hypercapnia, and preferential use of pressurelimited ventilatory modes) compared with 71% in patients on conventional ventilation (p < 0.001). this impressive reduction in mortality was tempered by the higher than normal mortality level in the control group, prompting the national institutes of health-funded acute respiratory distress syndrome network to set up a similar, larger (861 patients), prospective, multicenter, randomized trial in the us [21] . for a summary of the protocol used in this study, see appendix 1. the trial was stopped after the fourth interim analysis because the use of lower tidal volumes was found to be associated with a significantly reduced mortality (p = 0.005 for the difference in mortality between groups). the primary endpoints were mortality prior to hospital discharge with unassisted breathing and ventilator-free days (days alive, off mechanical ventilation, between enrollment and day 28). both of these endpoints were achieved (figs 1-3 ). in addition, patients receiving a tidal volume of 6 ml/kg ideal body weight had increased organ failure free days and lower il-6 levels. ali is seen in 25-42% of patients with sepsis [22] . although the approach has only been tested in patients with ali/ards, a tidal volume of 6 ml/kg ideal body weight is at the lower end of the range of physiologic ventilation. hence, this approach should be suitable for most patients in the icu setting. furthermore, as many patients with severe sepsis or septic shock progress to frank ali/ards, the panel believes that low tidal volume therapy is a valid option in these patients, and an option that may indeed prevent the development of ali/ards. although patient selection in the clinical trial specified both blood gas and lung infiltrate criteria, at least 90% of patients in the general icu setting meet the criteria for blood gas but table 2 a comparison of acute myocardial infarction (ami) and sepsis market issues significant publicity surrounding and general awareness lack of understanding among physicians and the of the condition; large trials general public diagnosis a relatively straightforward and relatively common complicated by a long list of signs and symptoms diagnosis (electrocardiogram, enzymes, troponin), and and few objective tools for validation one that can be made by generalists, not just cardiology specialists generally single organ disease (notable exception when often chronic or acute comorbidities complicated by cardiogenic shock) generalists have been taught to recognize the signs sepsis patients often come 'second hand' from a and symptoms of ami; initial treatment is usually specialist who may not be appropriately trained to provided by emergency physicians, who are trained diagnose, manage, and refer patients with sepsis to treat these patients mortality prior to hospital discharge in patients receiving a tidal volume of 6 and 12 ml/kg ideal body weight. acidosis is more likely to develop in patients with severe lung problems rather than in those exhibiting milder disease when tidal volumes are kept low. however, acidosis is seldom a clinical problem and rarely requires administration of bicarbonates. one of the issues with low tidal volume therapy is that the patients are often more uncomfortable, at least initially, when they are being ventilated with a tidal volume of 6 ml/kg ideal body weight. the patients tend to exhibit tachypnea and may become more agitated. sedation is generally required, but the ventilator setting can be maintained. of more concern is that icu staff may consider a respiration rate of 40/min to be a sign of something more serious and may attempt to terminate the intervention. education of staff is clearly essential. the strategy assessed in this trial not only includes ventilation with a low tidal volume, but also the provision of extrinsic peep. there may be some concern that an increased respiratory rate may result in intrinsic peep and hemodynamic problems (e.g. decreased cardiac filling, decreased cardiac output, and diminished blood pressure). the panel believes that auto peep was not an issue in the acute respiratory distress syndrome network study. in addition, in the groups with low tidal volume, at least 10% more oxygen was required to maintain the fraction of inspired oxygen (fio 2 ), suggesting that there was very little auto peep occurring. when mechanical ventilation is indicated for treatment of patients with ali/ards, the tidal volume should be limited tõ 6 ml/kg ideal body weight. goal-directed therapy represents an attempt to adjust the cardiac preload, afterload, and contractility to balance systemic oxygen delivery with oxygen demand. in patients with severe sepsis and septic shock, such an approach would seem eminently reasonable as part of general supportive measures to restore and maintain adequate cellular perfusion and to prevent organ dysfunction. in the setting of the icu, however, supranormal and normal approaches have met with little or no success [23, 24] . it is possible that, by the time these therapies are applied in the icu, any such intervention may have been too late. hence, the focus has shifted towards hemodynamic optimization in the early presentation of disease, such as in the emergency department. a prospective, randomized, predominantly blinded study was initiated by the early goal-directed therapy collaborative group to examine the results of hemodynamic interventions in the emergency department [25] . in this study, patients were randomly assigned to either 6 hours of egdt or to standard therapy prior to admission to the icu. baseline characteristics (including the adequacy and duration of antibiotic therapy) in the egdt and standard therapy groups were not significantly different. the vital signs, resuscitation endpoints, organ dysfunction scores, and coagulation-related variables were similar in these groups at baseline [25] . however, there were some important differences between the treatment groups (see table 3 ). available online http://ccforum.com/content/6/s3/s1 proportion of patients alive and off the ventilator having been ventilated with a tidal volume of 6 and 12 ml/kg ideal body weight. median number of ventilator-free days in patients receiving a tidal volume of 6 and 12 ml/kg ideal body weight. patients randomized to egdt received the same therapy but, in addition, were monitored for the endpoint of central venous oxygen saturation (scvo 2 ) > 70%. egdt patients were given more intravenous fluids (including blood transfusions) and more inotropic support (mostly dobutamine). for more information on the protocol used in this study, see appendix 2. key data are presented in table 4 . the in-hospital mortality was 30.5% in the group assigned to egdt and was 46.5% in the group assigned to standard therapy (p = 0.009), indicating that egdt provides significant benefits in improving outcomes in patients with severe sepsis and septic shock. during the interval from 7 to 72 hours, patients assigned to egdt exhibited a more significant improvement in mean scvo 2 (70.4 ± 10.7% versus 65.3 ± 11.4%), in lactate concentration (3.0 ± 4.4 mmol/l versus 3.9 ± 4.4 mmol/), in base deficit (2.0 ± 6.6 mmol/l versus 5.1 ± 6.7 mmol/l), and in ph (7.40 ± 0.12 versus 7.36 ± 0.12) than patients assigned to standard therapy (p ≤ 0.02 for all comparisons). during the same period, the mean apache ii scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to egdt than in those patients assigned to standard therapy (13.0 ± 6.3 versus 15.9 ± 6.4, p < 0.001). the protocol was based predominantly on guidelines published in 1999 by the society of critical care medicine [26] . however, these guidelines have not been universally followed in clinical practice since their publication. an increasing number of critically ill patients are presenting to, and being treated in, emergency departments [27, 28] . this is present-ing significant resource challenges in the emergency department environment. the inability to institute egdt may thus not be a conscious decision by the clinician not to follow the society of critical care medicine guidelines. emergency medicine in general may have to develop and formulate the cost-benefit analysis to support or implement such care in this environment in order to improve outcomes. there are sufficient evidence-based data to recommend that all patients with severe sepsis or septic shock should receive early and aggressive resuscitation based on this egdt protocol (see appendix 2) . it is important that the interventions are individualized to each patient. a negative or positive value indicates how the control group therapy compares with the treatment group. a p < 0.001, b p = 0.01, c p = 0.02, d p = 0.03, e p = 0.04. egdt, early goal-directed therapy. it is possible to identify patients with profound global myocardial dysfunction who are hence at risk of impaired perfusion. these patients, almost 15% of those in the egdt group, received dobutamine during the first 6 hours because myocardial suppression was diagnosed. once myocardial dysfunction is corrected (and compliance improved), these patients become more suitable for volume loading, so this group received almost 3.5 liters more fluids in the first 6 hours than the control patients. therefore, although vasopressor use was similar in the first 6 hours, patients in the egdt group were more aggressively weaned off these agents during this period, resulting in fewer patients in this group entering the icu on vasopressors than in the control group. the lack of aggressive volume loading in the control group led to greater use of vasopressors in patients over the subsequent 72 hours. in spite of more volume loading, the egdt group received less mechanical ventilation over the subsequent 72 hours than in the standard treatment group. why was cardiovascular collapse a significant cause of death in the control group? cryptic shock (shock with normal vital signs) is a frequent occurrence in early severe sepsis and septic shock. despite resuscitation to the goals for mean arterial blood pressure and cvp, almost 40% of control patients continued to exhibit global tissue hypoxia (decreased scvo 2 and increased lactate levels); in these patients, there was a twofold increase in hemodynamic deterioration, requiring more mechanical ventilation, pulmonary artery catheterization, and vasopressor use in the subsequent 72 hours. how do severe sepsis and septic shock differ hemodynamically in the early stages compared with that classically described in the icu? patients presenting with early sepsis and septic shock are characterized by hypovolemia (low cvp), normal to increased blood pressures, and decreased cardiac output (decreased central venous oxygen saturation and low cardiac index). this is in contrast to icu patients who are euvolemic, have high scvo 2 , and have elevated cardiac indices [29] . what are the most important ways in which egdt can improve outcomes? the key factors are early detection of high-risk patients in cryptic shock, early reversal of hemodynamic perturbations and global tissue hypoxia, prevention of acute cardiovascular collapse, and the possibility of preventing the inflammatory aspects of global tissue hypoxia that accompany the inflammation or infection. severe sepsis and septic shock patients should receive early aggressive therapy to restore and maintain oxygen availability to the cells. there should also be generous use of fluids and inotropic agents titrated by appropriate hemodynamic monitoring. background a large number of observational studies have shown that patients with sepsis have severe depletion of protein c [30, 31] . a number of studies have also shown the association of protein c depletion with high mortality in sepsis [32] [33] [34] . furthermore, baboon studies have demonstrated that treatment with activated protein c prevents death from live escherichia coli infusions [35, 36] . activated protein c exerts a number of actions. anticoagulant action includes the inactivation of coagulation factors va and viiia, and the inhibition of the formation of thrombin. profibrinolytic action allows the activity of tissue plasminogen activator (endogenous tissue plasminogen activator), by inactivating plasminogen activator inhibitor 1 and thrombin activatable fibrinolysis inhibitor. finally, anti-inflammatory action reduces il-6 (in vivo) and proinflammatory cytokines (in vitro). the specific mechanisms by which drotrecogin alfa (activated) exerts its effect on survival in patients with severe sepsis are not completely understood. the efficacy of drotrecogin alfa (activated) (recombinant human activated protein c) in reducing mortality in patients with severe sepsis was investigated in a large multicenter, blinded, placebo-controlled, randomized, phase iii clinical trial, the protein c worldwide evaluation in severe sepsis (prowess) trial [14] . all patients in the prowess trial received standard supportive care in addition to either drotrecogin alfa (activated) or placebo. for a summary of the protocol used in the prowess study, see appendix 3. the overall mortality in patients treated with drotrecogin alfa (activated) was 24.7% compared with 30.8% in patients receiving placebo, an absolute risk reduction of 6.1% (p = 0.006) (see fig. 4 ). the absolute risk reduction in patients with high risk of death defined by an apache ii score ≥ 25 was 12.8% (p < 0.001). the absolute risk reduction in patients with high risk of death defined by multiple organ failure was 7.4% (p = 0.006). no substantial differences in drotrecogin alfa (activated) treatment effects were observed in subgroups defined by gender, ethnic origin, or infectious agent. can drotrecogin alfa (activated) be used in patients on dialysis for pre-existing renal failure, a category that was specifically excluded in the prowess trial? no pharmacokinetic data were available on drotrecogin alfa (activated) in patients on chronic dialysis when the prowess trial began, so such patients were excluded from the trial. subsequent research has shown that the pharmacokinetics of drotrecogin alfa (activated) are not substantially changed in patients on chronic dialysis. the design of the prowess trial allowed a maximum of 48 hours between the onset of first organ dysfunction and the receipt of drotrecogin alfa (activated) (a 24-hour window was allowed for receipt of the drug following the first confirmation of first organ dysfunction, which in turn had to have been present for no more than 24 hours). the treatment effect of drotrecogin alfa (activated) was consistent across all time intervals from meeting the entry criteria to the receipt of the study drug. treatment with drotrecogin alfa (activated) thus does not appear to be as time critical as interventions such as tissue plasminogen activator in stroke or myocardial infarction. because most of the experience with drotrecogin alfa (activated) was based on organ failure times less than 48 hours, treatment should not be delayed when an appropriate candidate is identified. the time window employed in the prowess trial should allow a full history to be taken and other tests to be performed to determine the bleeding risk. as with all anticoagulants, drotrecogin alfa (activated) is associated with a risk of severe bleeding. during the infusion period in the prowess trial, the bleeding rates were 2.4% in the drotrecogin alfa (activated) group versus 1.0% in the placebo group (p = 0.024). the risk of bleeding was fairly constant across most subgroups. however, severe thrombocytopenia (< 30,000/mm 3 ) was commonly associated with serious bleeding and intracerebral hemorrhage. patients at high risk of death in the prowess trial were most likely to benefit from drotrecogin alfa (activated). in the prowess trial, the apache ii score was the most effective predictor of risk of death and likelihood of benefit from drotrecogin alfa (activated), particularly in those patients with an apache ii score ≥ 25. in the prowess trial, the number of organ dysfunctions was also an important indicator that supported an association between likelihood of benefit from drotrecogin alfa (activated) and risk of death. two or more organ dysfunctions identify a population that responds well to therapy, and is a practical measurement. the panel believes that acute respiratory failure or hypotension unresponsive to fluid challenge should suggest the use of drotrecogin alfa (activated). however, coagulopathy, a platelet count < 80,000/mm 3 , acidosis, or low urine output alone should not suggest its use. a very large international study of 11,500 patients will be started in late 2002 to investigate the efficacy of drotrecogin alfa (activated) in patients with a single organ failure and/or apache scores < 25. the decision on whether to administer the drug should ultimately depend on whether the patient meets the selection criteria. a patient presenting in the emergency room with acute respiratory failure or acute cardiovascular decompensation should receive appropriate treatment there. the drawback to treatment in the emergency room is that there may not be sufficient time in which to evaluate the patient's bleeding risks. delaying treatment for a few hours will enable more tests to be performed and a fuller history to be taken, both of which will provide a better indication of whether drotrecogin alfa (activated) is appropriate. the dose is always the same (24 µg/kg/hour), regardless of the type of organ failure or the degree of sepsis severity. in addition, the 96-hour window of treatment is always the same so that interruptions of treatment are made up at the end to maintain a total of 96 hours of treatment. twenty-eight-day survival in patients treated with drotrecogin alfa (activated) or placebo: all-cause mortality. do patients require any laboratory testing before they receive drotrecogin alfa (activated)? no laboratory testing was carried out in the prowess trial, and subgroup analysis identified no biochemical marker that conclusively indicates treatment. for example, treatment-associated reductions in mortality were observed in patients with normal protein c levels and in those with low protein c levels. clinical criteria are recommended for the initiation of therapy. aspirin (650 mg/day) was allowed in the prowess trial. patients on glycoprotein iib/iiia inhibitors were excluded because no data were available regarding drug interactions and pharmacokinetics. use of these types of agents is likely to increase the risk of bleeding with drotrecogin alfa (activated) therapy. the anticipated benefits must therefore be weighed against the potential risks. in the prowess trial, efforts were made to correct the international normalized ratio towards normal if it was greater than 3 at any time during infusion of drotrecogin alfa (activated). approximately one-third of patients in the prowess trial received steroids at the same time as drotrecogin alfa (activated). there was no interaction with steroid use, presumably because the mechanism of action of steroids is so different from that of activated protein c. hence, steroids should be used if they are needed, and if the patient qualifies for drotrecogin alfa (activated) the two should be used together. drotrecogin alfa (activated) should be considered for use in all adult patients with recent onset severe sepsis or septic shock, and a high risk of death. the value of steroids in the treatment of patients with severe sepsis and septic shock has been fiercely debated for some time. although a number of well-designed, randomized, controlled trials failed to show any benefits of steroid therapy in terms of improved survival in patients with severe sepsis (reviewed in [37, 38] ), with mortality increased in many as a result of an increased incidence of nosocomial infections, these trials were primarily investigating the efficacy of short courses of high-dose steroids. the question of whether lower doses of steroids may provide benefit in these patients has only recently been addressed. there is a relatively strong rationale for considering the use of steroids in patients with refractory septic shock. relative adrenal insufficiency is common in patients with refractory septic shock (50-75% of patients) [39] . in addition to such relative adrenal insufficiency and the blunted response to corticotrophin, a large body of evidence indicates that sepsis and refractory septic shock are characterized by peripheral tissue resistance to corticosteroids [40, 41] . in septic patients, this can be evidenced in a variety of ways. first, global cortisol binding, which carries cortisol from the adrenal glands to the tissues, decreases in patients with severe sepsis [42] . second, the number and binding affinity of glucocorticosteroid receptors may be reduced in patients with sepsis and severe sepsis [43] , leading to a decrease in the conversion of cortisone to its active form, cortisol, particularly by il-2 levels in the tissues. finally, data have been published demonstrating that moderate doses of steroids may restore cell sensitivity to vasopressors [44] . this may reduce the intensity of the inflammatory response and decrease organ dysfunction. low-dose steroid treatment is also well tolerated [40] . this body of evidence prompted the initiation of a phase iii randomized, controlled trial performed in 19 centers in france with 300 patients [45] . the aim of the trial was to determine whether moderate-dose corticosteroid therapy affected survival in patients with refractory septic shock and adrenal insufficiency. all patients had to be treated with vasopressor agents and mechanical ventilation. for a summary of the protocol used in this study, see appendix 4. patients were stratified according to their response to the adrenocorticotrophic hormone (acth) test. nonresponders were defined by an increment in cortisol levels < 9 µg/dl or < 250 nm/l after challenge with 250 µg cosyntropin. of the 300 patients included, there were 229 nonresponders to the corticotropin test (placebo, 115 patients; steroids, 114 patients). a significant survival benefit was demonstrated among nonresponders receiving moderate-dose corticosteroids. there were 73 deaths in the placebo group (63%) and 60 deaths in the steroid group (53%) (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; p = 0.023). no beneficial effects were observed in the subset of patients who were classified as responders. hence, in this paradigm, the acth test serves as a useful prognostic measure. since a beneficial effect was observed in the total population, however, the need for an acth test can be challenged and further studies are required. if an acth test is performed, corticosteroid administration can be started before results are received. moderate-dose corticosteroids should be administered to patients with established refractory septic shock. what is the optimal dose for this intervention? hydrocortisone should be given daily at a dose of 200-300 mg. fludrocortisone should be given daily at a dose of 50 µg. what is the optimal duration for this intervention? moderate doses of steroids should be given for 7 days. hydrocortisone can be administered as serial boluses or as a continuous infusion. it may be that rebound phenomena at treatment discontinuation are more frequent when hydrocortisone is given as a continuous infusion. in addition, in the phase iii randomized trial, hydrocortisone was given as serial boluses. the phase iii randomized trial has shown that the combination of hydrocortisone and fludrocortisone increased survival. in addition, sepsis is more frequently associated with a mineralocorticoid deficiency than a glucocorticoid deficiency. hence, fludrocortisone should be added to hydrocortisone. administration of moderate-dose corticosteroids should be considered in cases of refractory septic shock, particularly in those with relative adrenal insufficiency. it is recommended that an acth test be carried out before starting the intervention. hyperglycemia, caused by insulin resistance in the liver and muscle, is a common finding in icu patients. it can be considered an adaptive response, providing glucose for the brain, red cells, and wound healing, and is generally only treated when blood glucose increases to > 215 mg/dl (> 12 mmol/l). previous studies have shown that high levels of insulin-like growth factor binding protein 1 (a very good marker of lack of hepatic insulin effect) predict mortality [46, 47] . patients with high insulin-like growth factor binding protein 1 also tend to have the lowest insulin levels, indicating that beta cell function is impaired and, therefore, not enough insulin is being produced. these results indicate that hyperglycemia may not always be adaptive and that it should be treated to avoid the onset of specific complications. nevertheless, conventional wisdom in the icu has been that hyperglycemia is beneficial and that hypoglycemia should be avoided. the hypothesis that hyperglycemia (> 110 mg/dl, > 6.1 mmol/l) predisposes to specific icu complications, prolonged intensive care dependency and death was tested in a prospective, randomized, controlled trial [48] . for a summary of the protocol used in this study, see appendix 5. thirty-five of the 765 patients (4.6%) in the intensive insulin group died in the icu, compared with 63 patients (8.0%) in the conventional therapy group. for further mortality data on both the length of hospital stay and the cause of death, see tables 5 and 6 . for morbidity data, see figure 5 . tight control of blood sugar, as outlined in appendix 5, requires a strict protocol for insulin administration and repeated determination of blood sugar. this is yet to be proven, and is the subject of an ongoing study. because medical patients tend to stay in the icu longer than surgical patients, the results from this study indicate that this intervention would be even more favorable to medical icu patients. however, one needs to be careful with application of the algorithm in certain disease states, especially severe hepatic dysfunction and renal failure. no, all carbohydrates are included. see appendix 5 for guidelines on feeding. the level was chosen because it is in the physiologic range for healthy people. as well as its effect on glycemia, insulin has been shown to inhibit tnf-α and macrophage inhibitory factor (when infused concomitantly with glucose). this has led to some doubts as to whether the effect in this study was due to normalization of blood glucose levels. however, multivariate analysis of all the risk factors for mortality, including severity of illness on admission, indicated that blood glucose determines the outcome; there was a 75% increase in risk of death per 50 mg/dl increase in blood glucose. it is not yet possible to determine this. although it was blood glucose levels that were measured, the effects of insulin may in fact be on free fatty acids, as they change in parallel with s11 blood glucose. one of the key mechanisms may be prevention of hypertriglyceridemia and high concentrations of free fatty acids. it is strongly advisable to tightly control blood sugar close to physiologic levels, especially in surgical patients. implemen-tation of this recommendation requires a well-defined icu protocol. the interventions discussed in the present article have been applied in different patient populations and at different times in the course of the disease (see table 7 ). it is essential for physicians to understand that these therapies are not mutually exclusive. optimal patient management may require a combination of approaches: mechanical ventilation to preserve lung function, hemodynamic support to maintain adequate scvo 2 , intensive insulin therapy to normalize blood sugar, steroids to provide adequate immunosuppression, and drotrecogin alfa (activated) to prevent the systemic coagulopathy characteristic of severe sepsis and, hence, to preserve organ function. a sound understanding of the indications and contraindications of these interventions will guide appropriate intervention. similarly, the timing of therapy needs to be closely monitored. education in the signs and symptoms of sepsis and severe sepsis should prompt early initiation of therapy. many of the interventions discussed in this article were tested at specific available online http://ccforum.com/content/6/s3/s1 multiple organ failure, no sepsis focus 18 14 multiple organ failure, with sepsis focus 33 8 most important effects on morbidity [46] . cvvh, continuous venovenous hemofiltration; icu, intensive care unit; nnt, number needed to treat; rrr, relative risk reduction. despite the wealth of data to support the approaches discussed, it is clear that uptake of these interventions into clinical practice has been slow. although there may be practical reasons for this, it would appear in many cases to involve either unfamiliarity with the data or a reluctance, or at least inertia, to change established practices (witness the necessity of proving that hypoglycemia is beneficial in icu patients despite no good evidence to the contrary). the icu has changed in the past 30 years; there are more tools to use and more interventions to implement. despite application of new methods, however, outcomes have changed very little and certainly not in proportion to the changes that were expected based on the results from clinical trials. efficient integration of new interventions into the wider icu population is clearly essential. the panel believes that optimal use of existing therapies and the integration of proven new therapies will reduce mortality rates. further positive results from new trials with improved trial designs should encourage intensivists to incorporate new interventions into their practice. protocols are essential to ensure efficient integration of new therapies and to improve outcomes on the wards. morris predicted in a recent paper that an increase in compliance with evidence-based recommendations through the use of protocols would decrease error and would enhance patient safety [49] . however, a complete treatment protocol is only effective when each ward (inside and outside of the icu) has the trained staff to implement it, and when a skilled intensive care physician is available to lead the team. training and education of staff is essential. all five of the interventions discussed in this article have generated convincing evidence for their use, and they hold out hope for reducing mortality in patients with sepsis, severe sepsis and septic shock. yet, despite compelling data, the application of these interventions has yet to become routine practice in most icus. it is our hope that this article will enable physicians to understand how best to apply these therapies in clinical practice; from appropriate patient selection and timing of therapy, to combining different approaches for optimal patient management. a willingness to embrace new interventions, coupled with the development and implementation of rigorous protocols to ensure appropriate use, will improve outcomes and lead to a substantial reduction in mortality in these patients. • a respiratory rate ≥ 20 breaths/min or a partial pressure of arterial carbon dioxide ≤ 32 mmhg, or the use of mechanical ventilation for an acute respiratory process. • a white cell count ≥ 12,000/mm 3 or ≤ 4000/mm 3 , or a differential count showing >10% immature neutrophils. patients should meet at least one of the following five criteria: • pregnancy or breastfeeding. • aged younger than 18 years or weight >135 kg. • platelet count < 30,000/mm 3 . • conditions that increase the risk of bleeding: • surgery requiring general or spinal anesthesia within 12 hours before the infusion, the potential need for such surgery during the infusion, or evidence of active bleeding postoperatively; • a history of severe head trauma requiring hospitalization, intracranial surgery, or stroke within 3 months before the study, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or mass lesions of the central nervous system; • a history of congenital bleeding diatheses; gastrointestinal bleeding within 6 weeks before the study unless corrective surgery had been performed; or • trauma considered to increase the risk of bleeding. • a known hypercoagualable condition including: • resistance to activated protein c; • hereditary deficiency of protein c, protein s, or antithrombin iii; • presence of anticardiolipin antibody, antiphospholipid antibody, lupus anticoagulant, or homocysteinemia; or • recently documented (within 3 months) or highly suspected deep-vein thrombosis or pulmonary embolism. • patient's family or physician, or both, not in favor of aggressive treatment of the patient, or the presence of an advanced directive to withhold life-sustaining treatment. • patient not expected to survive 28 days because of an uncorrectable medical condition, such as poorly controlled neoplasm or other end-stage disease. • moribund state in which death is perceived to be imminent. • human immunodeficiency virus infection in association with a last known cd4 cell count ≤ 50/mm 3 . • history of bone marrow, lung, liver, pancreas, or smallbowel transplantation. • chronic renal failure requiring hemodialysis or peritoneal dialysis (acute renal failure was not an exclusion criterion). • known or suspected portosystemic hypertension, chronic jaundice, cirrhosis, or chronic ascites. • acute pancreatitis with no established source of infection. • participation in an investigational study within 30 days before treatment. • use of any of the following medications or treatment regimens: • unfractionated heparin to treat an active thrombotic event within 8 hours before the infusion (prophylactic treatment with a dose of unfractionated heparin of up to 15,000 u/day was permitted); • low molecular weight heparin at a higher dose than recommended for prophylactic use (as specified in the package insert) within 12 hours before the infusion; • warfarin (if used within 7 days before study entry and if the prothrombin time exceeded the upper limit of the normal range for the institution); • acetylsalicylic acid at a dose of more than 650 mg/day within 3 days before the study; • thrombolytic therapy within 3 days before the study (thrombolytic agents permitted for the treatment of thromboses within a catheter); • glycoprotein iib/iiia antagonists within 7 days before study entry; • antithrombin iii at a dose of more than 10,000 u within 12 hours before the study; • protein c within 24 hours before the study. drotrecogin alfa (activated) should be given at a dose of 24 µg/kg/hour for 96 hours. infusion should be interrupted 1 hour prior to any percutaneous procedure or major surgery, and should be resumed 1 and 12 hours later, respectively, in the absence of bleeding complications. there was an 8-hour time window from shock onset to check for eligibility and to perform a short acth test (blood samples before and 30 and 60 min after a 250 µg intravenous bolus of tetracosactrin). patients were then randomly assigned to receive 50 mg hydrocortisone as an intravenous bolus every 6 hours and one 50 µg tablet of fludrocortisone through a nasogastric tube once a day, or their respective placebos. treatments were given for 7 days, and patients were followed up for 1 year. on admission, patients should receive continuous intravenous glucose (200-300 g over 24 hours). after 24 hours, total parenteral, combined parenteral and enteral, or total enteral feeding should be instituted: 20-30 nonprotein kcal/kg/day with a balanced composition (0.13-0.26 g nitrogen/kg/day and 20-40% nonprotein calories in the form of lipids). total enteral feeding should be attempted as early as possible. national vital statistics reports epidemiology of severe sepsis in the united states: analysis of incidence, outcome, and associated costs of care the task force on the management of acute myocardial infarction of the european society of cardiology epidemiology of sepsis: an update severe sepsis and septic shock. definitions, epidemiology, and clinical manifestations gram-negative sepsis: a dilemma of modern medicine sepsis definitions. lancet infect dis use of the sofa score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study improved survival of patients with acute respiratory distress syndrome (ards): 1983-1993 [concepts in emergency and critical care treatment of gram-negative bacteremia and septic shock with ha-1a human monoclonal antibody against endotoxin. a randomized, double-blind, placebo-controlled trial treatment of gram-negative bacteremia and shock with human antiserum to a mutant escherichia coli the tnfα α mab sepsis study group: monoclonal antibody to human tumor necrosis factor alpha (tnfα α mab): efficacy and safety in patients with the sepsis syndrome lenercept study group: lenercept (p55-tumor necrosis factor receptor fusion protein, ro 45-2081, tenefuse) patients with severe sepsis or early septic shock. a randomized double-blind placebo-controlled multicenter phase iii trial with 1342 patients recombinant human protein c worldwide evaluation in severe sepsis (prowess) study group: efficacy and safety of recombinant human activated protein c for severe sepsis current concepts: treating patients with severe sepsis need for intensivists in intensive care units randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: isis-2 (second international study of infarct survival) collaborative group injurious ventilatory strategies increase cytokines and c-fos m-rna expression in an isolated rat lung model effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network airway and lung in sepsis elevation of systemic oxygen delivery in the treatment of critically ill patients a trial of goal-oriented hemodynamic therapy in critically ill patients. svo 2 collaborative group early goal-directed therapy collaborative group: early goal-directed therapy in the treatment of severe sepsis and septic shock task force of the american college of critical care medicine, society of critical care medicine: practice parameters for hemodynamic support of sepsis in adult patients in sepsis critical care in the emergency department: a physiologic assessment and outcome evaluation critical care provided in an urban emergency department a hemodynamic comparison of early and late phase severe sepsis and septic shock low levels of protein c are associated with poor outcomes in severe sepsis protein c, protein s, c4b-binding protein in severe infection and septic shock prognostic value of protein c concentrations in neutropenic patients at high risk of severe septic complications van der voort e: protein c and s deficiency in severe infectious purpura of children: a collaborative study of 40 cases. intensive care med epidemic meningioccemia and purpura fulminans with induced protein c deficiency protein c prevents the coagulopathic and lethal effects of escherichia coli infusion in the baboon the endothelial cell protein c receptor aids in host defense against escherichia coli sepsis corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature steroid controversy in sepsis and septic shock: a meta-analysis a 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blinded, singlecenter study prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids patterns of corticosteroidbinding globulin and the free cortisol index during septic shock and multitrauma adrenal insufficiency during the late stage of polymicrobial sepsis reversal of late septic shock with supraphysiologic doses of hydrocortisone effect of a treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness a paradoxical gender dissociation within the growth hormone/insulin-like growth factor i axis during protracted critical illness bouillon r: intensive insulin therapy in the critically ill patients decision support and safety of clinical environments. qual saf health care the roundtable discussion was supported by an unrestricted educational grant from eli lilly and company. jlv, ea, gb and er are consultants to eli lilly and company. all authors received an honorarium/grant for participating in this meeting. inclusion criteria • partial pressure of arterial oxygen/fio 2 ≤ 300 mmhg. • bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph.• no clinical evidence of left atrial hypertension, pulmonary artery wedge pressure ≤18 mmhg if measured. • positive pressure ventilation via endotracheal tube. inclusion criteria patients must have a known infection or a suspected infection, as evidenced by one or more of the following:• white cells in a normally sterile body fluid.• perforated viscus.• radiographic evidence of pneumonia in association with the production of purulent sputum. • a syndrome associated with a high risk of infection (e.g. ascending cholangitis). patients should meet at least three of the following four criteria:• a core temperature ≥ 38°c (100.4°f) or ≤ 36°c (96.8°f).• a heart rate ≥ 90 beats/min, except in patients with a medical condition known to increase the heart rate or those receiving treatment that would prevent tachycardia.available online http://ccforum.com/content/6/s3/s1 the study included all mechanically ventilated patients entering the icu: predominantly surgical patients, with some neu-rological patients (the icu in which the trial took place also sees such patients). medical icu patients (e.g. those with chronic obstructive pulmonary disease or oncologic or hematological disorders) were not included as they are not treated in the unit where the study was conducted. however, septic patients that were initially surgical but then came back from the ward with sepsis were included.only those patients who were moribund or had do-notresuscitate status at icu admission were excluded from the trial. if blood glucose ≥110 mg/dl (≥ 6.1 mmol/l), infuse with insulin to maintain normoglycemia (80-110 mg/dl, 4.4-6.1 mmol/l). do not exceed 50 iu/hour. adjust insulin dose based on measurements of whole-blood glucose in undiluted arterial blood, performed at 1-4 hour intervals, based on the following algorithm: adjust the dose in proportion to the observed change in blood glucose level (if blood glucose decreases by 50% then the insulin dose should be decreased by 50% and checked within the next hour). appendix 5 table 1 provides information on the appropriate action depending on the blood glucose level. the numerical instructions provided in appendix 5 table 1 are a guide; insulin dosage should always be done with common sense, proportionate to the previous changes in blood glucose observed upon previous changes in dosage.available online http://ccforum.com/content/6/s3/s1appendix 5 table 1 appropriate action depending on blood glucose level key: cord-262489-cecg3geg authors: zhao, zhanqi; kung, wan-hsuan; chang, hou-tai; hsu, yeong-long; frerichs, inéz title: covid-19 pneumonia: phenotype assessment requires bedside tools date: 2020-05-29 journal: crit care doi: 10.1186/s13054-020-02973-9 sha: doc_id: 262489 cord_uid: cecg3geg nan we read with interest the editorial by gattinoni et al. proposing two phenotypes for covid-19 pneumonia and the corresponding respiratory treatments [1] . type 1 is characterized with high compliance, low ventilationto-perfusion ratio and low lung recruitablity. type 2 is with low compliance and high lung recruitability. we appreciate the effort to classify covid-19 into phenotypes and to propose the corresponding respiratory treatments. we would like to point out that another phenotype is often presented in covid-19-associated moderate to severe ards, based on our observation and discussions with colleagues treating these patients. different from the phenotypes described in [1] , the covid-19 patients we encountered had rather low compliance and their lungs were non-recruitable, despite of large amount of non-aerated tissue. when assessing the lung recruitability with either the bedside estimates suggested in [2] , or with electrical impedance tomography (eit) [3, 4] , we found that instead of recruiting non-aerated lung tissue, increasing peep to around 15 cmh 2 o rather induced overdistension in previously ventilated regions. the finding was coincided with the results of a recent study where the majority of the reported patients were poorly recruitable with high peep even though the compliance was fairly low [5] . figure 1 shows eit measurement of a covid-19 patient during peep increase from 8 to 16 cmh 2 o, and the chest x-ray on the same day. the patient was ventilated under volume-controlled mode. respiratory system compliance slightly decreased from 23 to 22 ml/cmh 2 o. overdistension was observed in non-dependent regions compared to the lower peep (orange regions in fig. 1c) . no recruitment was found in dependent regions. since the tidal volume was fixed (6 ml/kg predicted body weight), ventilation was redistributed from overdistended regions to other open regions (blue regions in fig. 1c ). in such case, although the compliance was low, high peep would not recruit lung tissues but rather pose a risk of barotrauma. the disease status of covid-19 patients developed rapidly. as pointed out in [1] , ct could be the best way to identify the phenotypes; however, it might not be practical due to the overwhelming number of patients. besides, the sars-cov-2 virus is highly infectious, which makes the transportation of patients for ct examination very difficult. bedside tools such as eit and ultrasound may play an important role in identifying different phenotypes for covid-19 patients. in addition, such functional tools permit monitoring of the patients' response to various therapeutic interventions, which in turn helps guiding treatments. we thank zhao [6] and coworkers for their interest in our editorial [1] . we proposed two phenotypes (types 1 and 2, that we later called l and h) as a two "extremes" of a spectrum of respiratory failure in covid-19 pneumonia. what for us was more striking was the remarkable dissociation between compliance and hypoxemia in l patients [7] , when some of them, because of either the natural progression of the disease or the lack of prevention of possible patient self-inflicted lung injury, shift to the type h, which qualifies as typical ards. what zaho et al. added to this framework is the possibility of a further progression of the disease to fibrotic state, which we also observed in type 2 covid-19 patients in late stages (more than 1 week), if unable to heal from the disease [8] . shifting from prevalent edema to prevalent fibrosis is characterized by a progressive reduction of response to peep. unfortunately, the prevalent fibrosis typical of the later stage, instead of prevalent edema, cannot be easily detected by imaging, but it is associated with a progressive deterioration of lung mechanics and paco 2 rise, associated to severe structural damage of the lung [9] . what is important to realize, however, in this disease is that the mechanism of hypoxemia and the respiratory treatment in the type 1 early phase are different from typical ards. the type 2, if unsolved, with time shifts, as observed by our colleagues in their correspondence, to a fibrotic status, typical of late ards. covid-19 pneumonia: ards or not? lung recruitment in patients with the acute respiratory distress syndrome thoracic electrical impedance tomography in chinese hospitals: a review on clinical research and daily applications chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the translational eit development study group lung recruitability in sars-cov-2 associated acute respiratory distress syndrome: a single-center, observational study covid-19 pneumonia: phenotype assessment requires bedside tools. crit care covid-19 does not lead to a "typical" acute respiratory distress syndrome time to consider histologic pattern of lung injury to treat critically ill patients with covid-19 infection lung structure and function in different stages of severe adult respiratory distress syndrome none. the authors equally contributed to the idea presented in the manuscript, which is derived from the observation of numerous covid-19 patients treated in the intensive care. the authors read and approved the final manuscript. availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declared that they have no conflict of interest. key: cord-281711-whr4pfx9 authors: joebges, susanne; biller-andorno, nikola title: ethics guidelines on covid-19 triage—an emerging international consensus date: 2020-05-06 journal: crit care doi: 10.1186/s13054-020-02927-1 sha: doc_id: 281711 cord_uid: whr4pfx9 nan covid-19-classified as a pandemic by the who on march 11, 2020-is expected to put tremendous strain on many healthcare systems. early epidemiological analyses show that compared to the seasonal flu, covid-19 patients may require ventilation much more frequently [1] . this can lead to a shortage of ventilators and intensive care resources, resulting in limited medical care and death [2] . whereas some countries have been exposed very early [3] , others had the opportunity to prepare for the ethical challenges that emerge when intensive care resources become scarce. in everyday medical practice, ventilation may be withheld or withdrawn if it is not or no longer indicated or against a patient's will [4] . in crisis situations, such as pandemics, this practice is superimposed by an additional triaging process. medical factors of triage recommendations typically contain exclusion criteria, a mortality assessment (e.g., sequential organ failure assessment (sofa) score), and a reevaluation requirement [2] . beyond the medical aspects, however, triaging unavoidably involves moral choices. the main ethical considerations for making such choices concern equity and maximizing benefits [5, 6] . other criteria such as considering life stages, rewarding prosocial behavior, or giving priority to the worst off have been subject to long-standing controversy [5, 7, 8] . over the past few weeks, a number of triaging guidelines have been issued in various countries, including italy, switzerland, austria, germany, the uk, and belgium. the table provides a synopsis of the key aspects that are being covered (table 1) . for the purposes of this synopsis, we have chosen to limit ourselves to guidelines of european countries that are available in english or german (cf. https://prioritiesinhealth.org/guidelines). all guidelines (table 1) concur that in a situation of scarcity, covid and non-covid patients should be treated equitably according to the same criteria [9] [10] [11] [12] [13] [14] . however, no guideline argues in favor of a lottery or a "first come, first served" approach. rather, prognosisassessed in accordance with current intensive care standards-is seen as an indispensable precondition for maximizing benefit. there is some difference between the guidelines as to the role of short-term vs. long-term survival. whereas some guidelines (ch, a) refer to shortterm survival only as a key triaging criterion, others either do not specify survival (uk, be) or explicitly allow for the possibility that long-term prognosis (g) or a reduced lifespan, due to old age or to comorbidities, could affect a patient's access to a ventilator (i). in switzerland, an age limit is rejected as a criterion in itself, yet an age of over 85 years is mentioned as an exclusion criterion to admission to the icu if no free beds are available. all guidelines cite the will of the patient (as expressed in person, through an advance directive or a legal representative) as guiding treatment choices. futility is also recognized by all guidelines as a justification to end treatment even against patient will. no preferential treatment for specific subgroups is advocated, except for health staff (ch) with a view to maintaining the workforce. rather, fair decision-making processes are emphasized as well as good palliative care (i, ch, a, g, be). most guidelines (ch, a, g, be) call in their statements for interprofessional teams to make and document triage decisions fairly and transparently; others (i) require a second opinion in case of uncertainty. all guidelines demand regular re-evaluation of the decisions taken. in recognition of the moral stress that taking these decisions may bring on, all guidelines call for psychosocial support for health professionals. all guidelines have gone through intense deliberations of national associations and bodies to arrive at very similar recommendations. respect for the patient's will, fair distribution, and maximization of benefits based on chance of survival are at the heart of the recently issued triaging guidelines. there is some disagreement as to whether only short-term survival should be considered or if more long-term considerations-life expectancy, possibly in combination with quality of life-should have a place as well. age limits or the exclusion of other patient groups with reduced long-term survival may be very sensitive from a political and psychological point of view. it might be preferable to strengthen advance care planning, assuming that a significant number of patients with a high likelihood of poor outcomes would not opt for intensive care if other choices, such as good palliative care, were readily available to them. guidelines have the potential to reduce the burden on those who need to determine which patient gets access to a scarce resource. to the extent that it is unavoidable that physicians "have to decide who must die and whom (they) shall keep alive" [3] , this should not happen without clear criteria that result from a consensus process of professional associations, a team approach to decisionmaking, and the offer of psychological support [9] . it will be of interest to see if artificial intelligence can play an assistive role in such situations [15] . the allocation of scarce resources has been debated within medical ethics for a long time, and procedural criteria have been defined. in order to claim moral legitimacy, the prioritization process must be transparent, inclusive (allowing for participation of all those who may be affected by decisions resulting from the process), evidence-based, and revisable in the light of new information or arguments [8] . it is encouraging to see that the consultative processes that various national bodies have gone through have yielded similar results. whereas some differences may be due to contextual factors, the high degree of overlap inspires confidence in the robustness of the core. communicating these guidelines well is going to be an important task, particularly when dealing with individual patients and their families. the time constraints in developing the guidelines may have precluded a fully participatory approach, but now that a solid basis exists, it will be important to listen to the voices of all those concerned-health professionals, citizens, and other experts-to see if the status quo can be further amended and improved. clinical characteristics of coronavirus disease 2019 in china the toughest triage -allocating ventilators in a pandemic facing covid-19 in italy -ethics, logistics, and therapeutics on the epidemic's front line reasons, considerations, difficulties and documentation of end-of-life decisions in european intensive care units: the ethicus study fair allocation of scarce medical resources in the time of covid-19 a framework for rationing ventilators and critical care beds during the covid-19 pandemic too many patients … a framework to guide statewide allocation of scarce mechanical ventilation during disasters how to achieve fair distribution of arts in 3 by 5: fair process and legitimacy in patient selection www.who.int2004 clinical ethics recommendation for the allocation of intensive care treatments, in exceptional covid-19 pandemic: triage for intensive-care treatment under resource scarcity oegari. allokation intensivmedizinischer ressourcen aus anlass der covid 19 pandemie entscheidungen über die zuteilung von ressourcen in der notfall -und der intensivmedizin im kontext der covid -19 nice. covid-19 rapid guideline ethical principles concerning proportionality of critical care during the 2020 covid-19 pandemic in belgium: advice by the belgian society of intensive care medicine -_update 26-03-2020 algorithm-aided prediction of patient preferences -an ethics sneak peek publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.authors' contributions sj prepared the guideline synopsis, which was checked and amended by nba. sj wrote a first draft of the manuscript, which was revised by nba. both authors read and approved the final manuscript. susanne joebges is an ethicist and intensive care physician who was involved in drafting the german guidelines. one of the authors (sj) received salary support from the käthe-zingg-schwichtenberg fonds, swiss academy of medical sciences. the funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests.received: 15 april 2020 accepted: 27 april 2020 key: cord-048343-nzk8m912 authors: milbrandt, eric b; angus, derek c title: bench-to-bedside review: critical illness-associated cognitive dysfunction – mechanisms, markers, and emerging therapeutics date: 2006-11-15 journal: crit care doi: 10.1186/cc5078 sha: doc_id: 48343 cord_uid: nzk8m912 cognitive dysfunction is common in critically ill patients, not only during the acute illness but also long after its resolution. a large number of pathophysiologic mechanisms are thought to underlie critical illness-associated cognitive dysfunction, including neuro-transmitter abnormalities and occult diffuse brain injury. markers that could be used to evaluate the influence of specific mechanisms in individual patients include serum anticholinergic activity, certain brain proteins, and tissue sodium concentration determination via high-resolution three-dimensional magnetic resonance imaging. although recent therapeutic advances in this area are exciting, they are still too immature to influence patient care. additional research is needed if we are to understand better the relative contributions of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention. since its advent more than 40 years ago, the specialty of critical care has made remarkable advances in the care of severely ill patients. mortality rates for many commonly encountered critical illnesses such as severe sepsis [1] and acute respiratory distress syndrome (ards) [2] have declined sharply over the past 2 decades. as greater numbers of patients survive intensive care, it is becoming increasingly evident that quality of life after critical illness is not always optimal. for instance, nearly half of ards survivors manifest neurocognitive sequelae 2 years after their illness, falling to below the 6th percentile of the normal distribution of cognitive function [3] . considering that 89% of americans would not wish to be kept alive if they had severe, irreversible neurologic damage [4] , these findings are quite concerning. cognitive dysfunction (cd) is quite common in critically ill patients, not only during the acute illness but also long after the acute illness resolves [5] . delirium, a form of acute cd that manifests as a fluctuating change in mental status, with inattention and altered level of consciousness, occurs in as many as 80% of mechanically ventilated intensive care unit (icu) patients [6] . most clinicians consider icu delirium to be expected, iatrogenic, and without consequence. however, recent data associate delirium with increased duration of mechanical ventilation and icu stay [7] , worse 6-month mortality [8] , and higher costs [9] . chronically, critical illnessassociated cd manifests as difficulties with memory, attention, executive function, mental processing speed, spatial abilities, and general intelligence. interestingly, patients who develop acute cd often go on to develop chronic cd after hospital discharge [10] [11] [12] [13] , suggesting that the two entities may share a common etiology. although there are clearly defined risk factors for critical illness-associated cd, there is little understanding of the underlying pathophysiology. the precise mechanisms are unknown and there are likely to be multiple mechanisms at work in any given patient ( figure 1 ) [5, 14, 15] . we have chosen to focus on two mechanisms that appear to have the greatest merit: neurotransmitter abnormalities and occult diffuse brain injury. in this bench-to-bedside review, we discuss the evidence supporting these mechanisms, potential markers that could be used to evaluate each mechanism in individual patients, and emerging therapies that may prevent or mitigate critical illness-associated cd. relative dopamine excess in the central nervous system (cns). antipsychotics such as haloperidol, which antagonize central dopamine receptors, can counteract the cognitive effects of anticholinergic medications, further supporting the anticholinergic hypothesis. drugs with potent central anticholinergic effects, such as tricyclic antidepressants and antihistamines, are particularly likely to cause delirium. many medications that are commonly used in the icu yet not generally considered to be anticholinergic, such as h 2 blockers, opiates, furosemide, digoxin, glucocorticoids, and benzodiazepines, were recently shown to have central anticholinergic properties [16, 17] . volatile anesthetics, such as sevoflurane, and intravenous anesthetics, such as propofol, also have anticholinergic effects and may be responsible not only for postoperative delirium but also for the more complex phenomena of postoperative cognitive dysfunction [18] . acute illness itself may be associated with production of endogenous anticholinergic substances [19] . in one study, 8 out of 10 elderly medical inpatients had had detectable anticholinergic activity in their serum, even though no medication used by these individuals had anticholinergic activity. characterization of such substances might improve our understanding of delirium and lead to useful intervention strategies. considering that activation of specific cholinergic pathways can inhibit proinflammatory cytokine synthesis and protect against endotoxemia and ischemia-reperfusion injury [20] , it is tempting to speculate that inhibition of these pathways, whether exogenous or endogenous, might contribute not only to cd but also to other outcomes of critical illness. in assessing the overall risk for developing cd posed by medications with central anticholinergic activity in a given patient, individual differences in drug pharmacokinetics make the dose received a poor estimate of a patient's overall anticholinergic burden [21, 22] . however, we can objectively measure anticholinergic burden in individual patients using an assay referred to as serum anticholinergic activity (saa) [16] . first described by tune and coyle [23] , saa measures the ability of a individual's serum to block central muscarinic receptors using a rat forebrain preparation. elevated saa levels are associated with cognitive impairment in studies of medical ward inpatients and community dwelling seniors [16, [24] [25] [26] [27] . only a single, small study has used this assay to investigate cd in icu patients. golinger and colleagues [28] examined saa levels in surgical icu patients and found the mean saa level drawn 4 hours after mental status change was significantly greater in delirious patients (n = 9) than in those without delirium (n = 16; 4.67 ng/ml versus 0.81 ng/ml; p = 0.007). whether these results apply to all critically ill patients is uncertain because no study has examined saa across a broad range of icu admitting diagnoses or in medical icu settings. furthermore, because saa measurement requires fresh rat brain preparations, its use is likely to remain limited to research settings for the foreseeable future. pathophysiologic mechanisms and predisposing factors thought to underlie critical illness-associated cognitive dysfunction [5, 14, 15] . apo, apolipoprotein; hiv, human immunodeficiiency virus; 5-ht, serotonin (5-hydroxytryptamine); gaba, γ-aminobutyric acid; ne, norepinephrine (noradrenaline). other neurotransmitter systems such as dopamine, serotonin, γ-aminobutyric acid (gaba), norepinephrine (noradrenaline), and glutamate are also thought to contribute to critical illnessassociated cd. dopaminergic hyperfunction is thought to underlie the cognitive symptoms of schizophrenia, and dopamine administration itself may be a risk factor for delirium [29] . serotonin syndrome, a consequence of excess serotonergic agonism, can be seen not only with selective serotonin reuptake inhibitors but also with a variety of drugs and drug combinations [30] . even a single therapeutic dose of an selective serotonin reuptake inhibitor can cause the syndrome, which manifests as mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. gaba abnormalities are thought to contribute to hepatic encephalopathy, perhaps mediated by branched chain and aromatic amino acids acting as false neurotransmitters [31] . excess gaba activity, such as that which occurs after withdrawal from chronic ethanol or benzodiazepine use, is a well known and quite dangerous cause of delirium [32] . acutely, sedatives that stimulate gaba receptors, such as benzodiazepines and (probably) propofol, impair cognitive function and are deliriogenic [8, [33] [34] [35] . this raises the possibility that strategies to minimize sedative drug accumulation, such as daily interruption of sedative infusions [36] , which have been shown to reduce duration of mechanical ventilation, and icu and hospital length of stay, might also reduce the incidence or duration of delirium. whether these sedative drugs lead to neurocognitive deficits long after their use is unknown, but this has been suggested in certain high-risk groups, such as the very old (>75 years) and those with pre-existing cognitive impairment [37, 38] . noradrenergic hyperfunction, as part of the 'fight or flight' response, can lead to panic attacks and delusions. glutamate has been implicated in the 'chinese food syndrome', in which food with high amounts of monosodium glutamate interferes with normal neurotransmission causing confusion [39] . for a more complete review of the other neurotransmitter abnormalities that may underlie delirium, the reader is referred elsewhere [40, 41] . if critical illness-associated cd were solely due to acute medication effects, it would probably resolve after the exposure has ended. however, a significant percentage of individuals developing delirium in the hospital continue to demonstrate symptoms of cd after discharge [10] [11] [12] [13] . these patients manifest decreased cerebral activity and increased cognitive deterioration, and are more likely to develop dementia than patients without delirium. also, patients who develop delirium have a greater rate of decline on cognitive tests than do nondelirious patients [10] [11] [12] [13] . taken together, these observations raise the possibility that some degree of occult diffuse brain injury, as a consequence of the local hypoxia, hypoperfusion, cytokine-mediated inflammation and microvascular thrombosis that characterize the multisystem organ dysfunction of critical illness, might have occurred in these patients [42] . given that every other organ system can be damaged by these forces, it seems implausible that the brain would be uniquely spared. many of the data supporting occult diffuse brain injury as a cause of critical illness-associated cd come from studies of sepsis and septic encephalopathy, a form of delirium. in animal models of sepsis, oxidative damage occurs early in the hippocampus, cerebellum, and cortex [43] , and significant alterations in cerebral vascular hemodynamics and tissue acid-base balance indicate that cerebral ischemia and acidosis do occur [44] [45] [46] [47] [48] . sharshar and colleagues completed several studies comparing brain pathology in small numbers of patients who died from septic shock with that in patients who died from other causes. septic patients demonstrated diffuse severe ischemic and hemorrhagic cns lesions [49] , which correlated with persistent hypotension and severe coagulation disorders. multiple microscopic foci of necrosis involving the white matter of the pons [50] were seen, as well as ischemia and apoptosis within the cerebral autonomic centers [51] . the white matter lesions were associated with elevated levels of proinflammatory cytokines, suggesting a possible role of inflammation and microvascular thrombosis in the genesis of cns injury [52] . although those studies demonstrated that ischemic brain injury occurs in sepsis, they did not determine whether delirium occurred. two studies attempted to examine the relationship of ischemic brain injury to delirium. in one study of 84 patients with severe sepsis and multiple organ dysfunction [53] , severe hypotension was the only factor in multivariable analyses that was associated with delirium, suggesting that sepsis-related encephalopathy may be caused by ischemic damage rather than metabolic abnormalities. another study examined cerebral blood flow and cerebral oxygen metabolic rates in patients with septic encephalopathy and multiple organ dysfunction [54] , and it found that both were significantly lower than those in normal awake individuals. although these studies support the idea of occult brain injury as a cause of delirium, the authors did not use a standardized diagnostic and statistical manual of mental disorders (dsm)-iv based tool to diagnose delirium, such as the confusion assessment method for the icu [6] . lending support to the hypothesis that acute inflammation leads to brain injury and subsequent development of delirium, a recent study found that delirium in postoperative hipfractured patients was significantly associated with serum levels of c-reactive protein, an acute-phase protein that is a marker of acute inflammation [55] . importantly, patients in the study were diagnosed with delirium using the confusion assessment method (the ward-based predecessor to the confusion assessment method for the icu), providing the first dsm-iv based evidence that acute inflammation may be in the causative pathway of delirium. the brain is a target for free radical damage because of its large lipid content, high rate of metabolism, and low antioxidant capacity. free radical induced oxidative stress may play a role in the delirium seen after cardiopulmonary bypass. karlidag and colleagues [56] noted that patients with low preoperative levels of catalase, a erythrocyte-based antioxidant enzyme, were more susceptible to delirium postoperatively. they suggested that preoperative catalase levels might some day be used to identify at-risk patients who could then be put on antioxidant treatment preoperatively. whether this would reduce the incidence of delirium remains speculative. regional cerebral blood flow appears to be reduced in delirium. using xenon-enhanced computed tomography (ct), yakota and colleagues [57] demonstrated significant focal and global brain hypoperfusion in 10 icu patients with hypoactive delirium. after recovery from delirium cerebral blood flow returned to normal, implying that cerebral hypoperfusion may contribute to the development of delirium. studies of ards survivors suggest that a combination of acute hypoxia, hypoperfusion, and hyperglycemia plays an important role in the long-term cognitive sequelae of critical illness [3, 58, 59] . however, it has been difficult to demonstrate a clear relationship, given the lengthy interval between stimulus and effect and the great number of additional contributing variables that can obscure downstream effects. among ards survivors, hopkins and colleagues showed that the degree of cd at 1 year is significantly correlated with the durations of hypoxia [58] and mean arterial blood pressure less than 50 mmhg during the icu stay [3] . in animals, hyperglycemia markedly enhances hypoxic-ischemic brain damage due to increased brain edema and disrupted cerebral metabolism [60] . in ards survivors, the duration of blood glucose greater than 180 mg/dl has been shown to correlate with worse visual spatial abilities, visual memory, processing speed, and executive function at 1 year [59] . given the recent interest in maintaining tight glucose control during critical illness as a means of reducing mortality, it will be interesting to see whether patients managed using this technique have better cognitive outcomes. clearly, such an approach will need to balance the benefits of tight glucose control with the known risks that hypoglycemia poses to the cns. one of the perceived difficulties with looking for evidence of occult brain injury in humans is the apparent need for cns tissue specimens to prove that brain injury actually occurred. however, studies of stroke, trauma, and cardiopulmonary bypass-associated brain injury show that serum markers of brain injury correlate well with the extent of cns damage. s-100β, neuron-specific enolase (nse), and myelin basic protein (mbp) are three such markers that could be used to look for evidence of occult brain injury in critical illnessassociated cd. s-100 is a dimeric calcium-binding protein consisting of two subunits (α and β) [61] . the β unit (s-100β) is highly brain specific, located mainly in astrocytes. circulating levels of s-100β are elevated in patients with cerebral ischemia [62] , cardiopulmonary bypass-associated decline in explicit memory function [63, 64] , and traumatic brain injury (tbi) [65] [66] [67] . even in mild head injury, serum levels of s-100β are correlated with clinical measures of injury severity, neuroradiologic findings, and outcomes, including postconcussion symptoms [68] . elevated serum s-100β levels were recently demonstrated in critically ill patients with respiratory failure [69] and in porcine models of endotoxic shock [70] and acute lung injury [71] . in this latter group, elevated s-100β levels were associated with hippocampal histopathologic changes, including basophilic shrunken neurons in the pyramidal cell layer [71] . interestingly, s-100β may have both beneficial and detrimental effects, in that lower levels may have protective neurotrophic effects, yet higher levels can lead to exacerbation of neuroinflammation and neuronal dysfunction [72] . whereas s-100β is a marker of astrocyte damage, nse and mpb are markers of neuron and white matter (myelin) damage, respectively. nse is protein-based enzyme that is found primarily in neurons. serum levels of nse are elevated after tbi, exhibiting a close relationship with outcome in severe head injury [73, 74] and with volume of contusion in minor head injuries [75] . interestingly, elevated nse levels were recently shown to predict death in one small study (n = 29) of patients with severe sepsis [76] , even though these patients had no acute cns disorders, such as stroke or neurotrauma. mbp is the major protein component of myelin. serum levels of mbp are elevated in diseases in which there is myelin breakdown. studies of patients with tbi have shown that mbp levels correlate with clinical measures of severity and may allow early prediction of outcomes [74, 77, 78] . new developments in neuroimaging, such as functional magnetic resonance imaging (mri) and positron emission tomography, have revolutionized our understanding of abnormal brain function in many disease states, including schizophrenia, parkinson's disease, and post-traumatic stress disorder. to study further whether critical illness-associated cd is associated with occult brain injury in humans, it would be useful to have an imaging test that can detect subtle evidence of brain injury. unfortunately, traditional ct scans and mri do not appear to be sensitive enough to pick up the microscopic cellular changes that may underlie cd [42] . two small studies assessed brain ct findings in critically ill patients with sepsis [79, 80] . neither study demonstrated any ct abnormalities, although brain pathology in nonsurvivors was consistent with the previously cited findings of sharshar and colleagues [49] [50] [51] [52] . a recent study of ards survivors (n = 15) [81] found that many of these individuals exhibited signs of significant brain atrophy and ventricular enlargement on head cts obtained during their acute illness, but there were no significant correlations between these abnormalities and subsequent neurocognitive scores. a new mri technique may prove useful for identifying occult brain injury in critically ill patients. specifically, highresolution, three-dimensional mri can be used to assess noninvasively differences in brain tissue sodium concentration, which is a highly sensitive marker of tissue viability that highlights areas that traditional mri can miss [82] [83] [84] [85] [86] . the method is based on sodium ion homeostasis, which is tightly regulated in the body and is a major energy consuming process. any event that perturbs the energy level of the cell enough to disrupt the sodium ion gradient, such as ischemia, has an important impact on cell viability. although tissue sodium concentration mri has been successfully used to evaluate the cns, including nonhuman primate studies and clinical studies of stroke and reversible focal brain ischemia [87] [88] [89] , it has not been used to assess patients with either acute or chronic critical illnessassociated cd. there are several recent developments that, although preliminary, are of interest because of their potential to prevent or mitigate critical illness-associated cd. haloperidol has been used for many years to manage agitation in mechanically ventilated icu patients, and it is the recommended drug for treatment of icu delirium [90] . kalisvaart and colleagues [91] compared the effect of haloperidol prophylaxis (1.5 mg/day preoperatively and up to 3 days postoperatively) with that of placebo in 430 elderly hip surgery patients at risk for delirium. although there was no difference in the incidence of postoperative delirium between treatment and control groups, those in the haloperidol group had significantly reduced severity and duration of delirium (5.4 days versus 11.8 days; p < 0.001). haloperiodol also appeared to reduce the length of hospital stay among those who developed delirium (17.1 days versus 22.6 days; p < 0.001). a recent retrospective cohort study examined haloperidol use in 989 patients who were mechanically ventilated for longer than 48 hours [92] . despite similar baseline characteristics, patients treated with haloperidol had significantly lower hospital mortality than did those who never received the drug (20.5% versus 36.1%; p = 0.004), an association that persisted after adjusting for potential confounders. because of the observational nature of the study and the potential risks associated with haloperidol use, these findings require confirmation in a randomized, controlled trial before they may be applied to routine patient care. leung and colleagues [93] tested the hypothesis that using gabapentin as an add-on agent for treating postoperative pain reduces the occurrence of postoperative delirium. patients aged 45 years or older undergoing spine surgery were randomly assigned to gabapentin 900 mg or placebo by mouth 1 to 2 hours before surgery and continued for the first 3 days postoperatively. postoperative delirium occurred in 0% (0/9) of gabapentin-treated patients and 42% (5/12) of placebo patients (p = 0.045). reduction in delirium appeared to be due to the opioid-sparing effect of gabapentin. given the small size of the study, these results require confirmation. donepezil, a cholinesterase inhibitor that increases synaptic availability of acetylcholine, improves cognitive function in alzheimer's disease. sampson and colleagues [94] randomly assigned 33 elderly patients undergoing elective total hip replacement to donepezil 5 mg or placebo immediately following surgery and every 24 hours for 3 days. donepezil was well tolerated with no serious adverse events. although the drug did not significantly reduce the incidence of delirium (9.5% versus 35.7%; p = 0.08) or length of hospital stay (mean ± standard error: 9.9 ± 0.73 days versus 12.1 ± 1.09 days; p = 0.09), both outcomes showed a consistent trend suggesting possible benefit. the authors project that a sample size of 95 patients would be required for a definitive trial. dexmedetomidine's sedative effects are due to selective stimulation of α 2 -adrenoreceptors in the locus ceruleus of the cns. because it does not have anticholinergic or gaba-stimulating effects, it has the potential to be a delirium-sparing sedative. in preliminary results presented in abstract form [95] , cardiac surgery patients (n = 55) randomly assigned to dexmedetomidine for postoperative sedation had a nonsignificantly lower incidence of postoperative delirium as compared with those sedated with propofol or a combination of fentanyl and midazolam (5% versus 54% versus 46%). the authors of that report plan to enroll a total of 90 patient in the study; perhaps these impressive differences will be statistically significant with a greater number of patients. recombinant human erythropoietin (rhuepo) has received considerable attention as a potential transfusion sparing strategy in the icu. interestingly, epo and its receptor are both expressed by the nervous system, and systemically administered rhuepo can reach sites within the brain. in preclinical studies, rhuepo reduced neuronal injury produced by focal ischemia, tbi, spinal cord injury, and subarachnoid hemorrhage [96] [97] [98] . enthusiasm regarding its use as a general neuroprotectant in the icu has been tempered by potential risks such as thromboembolism and the considerable cost of the drug. concerns over safety may be at least partially addressed by the recent finding of erythropoietin derivatives with tissue protective but not hematopoietic properties [99] . xenon is a chemically inert gas that has been used as an anesthetic agent and for contrast enhancement in ct scans. in rats xenon appears to protect the brain from the neurologic damage associated with the use of cardiopulmonary bypass, an effect that is potentially related to n-methyl-d-aspartate receptor antagonism [100] . however, its tendency to expand gaseous bubbles, such as bypass-associated cerebral air emboli, could abolish any beneficial effect or even worsen cerebral outcome [101] . in the setting of ischemic stroke or tbi, there are a variety of compounds with the potential to improve neurologic outcomes. for example, nxy-059, a free radical trapping agent, reduced disability at 90 days when given within 6 hours of stroke onset [102] . in a pilot randomized trial in 56 patients, simvastatin given up to 12 hours after stroke onset significantly improved neurologic functioning (national institutes of health stroke scale score) at 90 days [103] . ethyl pyruvate, a pyruvate derivative that prevents mortality in murine sepsis models, reduced motor impairments, neurologic deficits, and infarct volume in a rat stroke model when given as late as 12 hours after middle cerebral artery occlusion [104] . in rodent models of tbi, cyclosporin a reduced acute motor deficits and improved cognitive performance, even when given after the traumatic insult [105] . a phase ii dose escalation trial is currently underway in humans. mounting evidence suggests that mild-to-moderate hypothermia can mitigate neurologic injury. shankaran and colleagues [106] found that whole-body hypothermia (33.5°c for 72 hours) reduced the risk for death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy. in adults successfully resuscitated after cardiac arrest, moderate hypothermia (32-34°c for 12 to 24 hours) increased rates of favorable neurologic outcomes and reduced mortality [107, 108] . a practical limitation of therapeutic hypothermia is that reaching target temperatures takes at least 2 hours using the fastest currently available cooling techniques. however, polderman and colleagues [109] demonstrated that hypothermia could be induced safely and quickly (about 60 min) by means of ice-cold intravenous fluid combined with icewater cooling blankets. cognitive rehabilitation involves the teaching of skills and strategies to target specific problems in perception, memory, thinking and problem solving, with the goal of improving function and compensating for deficits. the benefits of cognitive rehabilitation are well known to those that care for patients with stroke, anoxia, or tbi. predicting who will benefit and how much has proven challenging, but even severely disabled patients sometimes make dramatic neurocognitive recoveries [110] . although there are no studies evaluating the effectiveness of cognitive rehabilitation in patients recovering from non-neurologic critical illness, it stands to reason that such patients could benefit when they are found to be cognitively impaired. because cognitive impairments in critically ill patients appear to be underrecognized by icu and physical rehabilitation providers [111] , few patients are referred for cognitive rehabilitation therapy [3] . education regarding the cognitive sequelae of critical illness is needed to enhance referrals for rehabilitation, not only for weakness and physical debilitation but also for cognitive impairments. cognitive function is an important and relatively understudied outcome of critical illness. evidence suggests that neurotransmitter abnormalities and occult diffuse brain injury are important pathophysiologic mechanisms that underlie critical illness-associated cd. markers that could be used to evaluate the influence of these mechanisms in individual patients include the following: saa, certain brain proteins (s-100β, nse, and mpb), and mri tissue sodium concentration. although recent advances in this area are exciting, they are still too immature to influence patient care. additional research is needed if we are to understand better the relative contributions of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention. this article is part of a thematic series on translational research, edited by john kellum. other articles in the series can be found online at http://ccforum.com/articles/ theme-series.asp?series=cc_trans the epidemiology of sepsis in the united states from 1979 through 2000 improved survival of patients with acute respiratory distress syndrome (ards): 1983-1993 two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome understanding the treatment preferences of seriously ill patients potential mechanisms and markers of critical illness-associated cognitive dysfunction delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (cam-icu) the impact of delirium in the intensive care unit on hospital length of stay delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit costs associated with delirium in mechanically ventilated patients marcantonio er: delirium among newly admitted postacute facility patients: prevalence, symptoms, and severity the occurrence and persistence of symptoms among elderly hospitalized patients delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery delirium in the intensive care unit: occurrence and clinical course in older patients apolipoprotein e4 polymorphism as a genetic predisposition to delirium in humans delirium in older persons serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance a critical appraisal of the utility of the serum anticholinergic activity assay in research and clinical practice drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium endogenous anticholinergic substances may exist during acute illness in elderly medical patients neural inhibition of inflammation: the cholinergic anti-inflammatory pathway the relationship of an anticholinergic rating scale with serum anticholinergic activity in elderly nursing home residents comparing models for estimating anticholinergic burden from medications using serum anticholinergic activity as the gold standard serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects association of postoperative delirium with raised serum levels of anticholinergic drugs the association of serum anticholinergic activity with delirium in elderly medical patients clarifying confusion: the confusion assessment method. a new method for detection of delirium importance of serum anticholinergic activity in the assessment of elderly patients with delirium association of elevated plasma anticholinergic activity with delirium in surgical patients is dopamine administration possibly a risk factor for delirium? the serotonin syndrome the effect of normalization of plasma amino acids on hepatic encephalopathy in man overexcitement and disinhibition. dynamic neurotransmitter interactions in alcohol withdrawal association between psychoactive medications and delirium in hospitalized patients: a critical review sedative and analgesic medications: risk factors for delirium and sleep disturbances in the critically ill lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly postoperative cognitive deficit in the elderly surgical patient agitation in the icu: part one -anatomical and physiologic basis for the agitated state neural mechanisms of delirium: current hypotheses and evolving concepts the brain in sepsis dal pizzol f: oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation cerebral circulation during endotoxic shock with special emphasis on the regional cerebral blood flow in vivo cerebral hemodynamics, oxygen uptake and cerebral arteriovenous differences of catecholamines following e. coli endotoxin in dogs cerebral blood flow and oxygen uptake in endotoxic shock. an experimental study in dogs cerebral hemodynamics, vascular reactivity, and metabolism during canine endotoxin shock group b streptococcal sepsis impairs cerebral vascular reactivity to acute hypercarbia in piglets neuropathology of septic shock multifocal necrotizing leukoencephalopathy in septic shock apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock the neuropathology of septic shock the role of hypotension in septic encephalopathy following surgical procedures cerebral circulation and metabolism in patients with septic encephalopathy different c-reactive protein kinetics in post-operative hip-fractured geriatric patients with and without complications the role of oxidative stress in postoperative delirium regional cerebral blood flow in delirium patients neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome hyperglycemia and neurocognitive outcome in ards survivors hyperglycemia augments ischemic brain injury: in vivo mr imaging/spectroscopic study with nicardipine in cats with occluded middle cerebral arteries signs of brain cell injury during open heart operations: past and present release of glial tissue-specific proteins after acute stroke: a comparative analysis of serum concentrations of protein s-100b and glial fibrillary acidic protein is there an association between release of protein s100b during cardiopulmonary bypass and memory disturbances? scand cardiovasc j significance of serum s100 release after coronary artery bypass grafting s-100 protein and neuron-specific enolase in csf after experimental traumatic or focal ischemic brain damage correlation of computed tomography findings and serum brain damage markers following severe head injury serum s-100b protein in severe head injury biochemical serum markers for brain damage: a short review with emphasis on clinical utility in mild head injury increased levels of serum s100b protein in critically ill patients without brain injury bloodbrain barrier damage is an early event in porcine endotoxemic shock s-100 protein and neurohistopathologic changes in a porcine model of acute lung injury the janus face of glial-derived s100b: beneficial and detrimental functions in the brain severe head trauma and the changes of concentration of neuron-specific enolase in plasma and in cerebrospinal fluid diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head injury increased serum creatine kinase bb and neuron specific enolase following head injury indicates brain damage bardenheuer hj: neuron-specific enolase as a marker of fatal outcome in patients with severe sepsis or septic shock serum-myelin-basicprotein assay in diagnosis and prognosis of patients with head injury serum myelin basic protein, clinical responsiveness, and outcome of severe head injury the encephalopathy of sepsis neurologic complications of systemic critical illness brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome fast three dimensional sodium imaging mr imaging of sodium in the human brain with a fast three-dimensional gradient-recalled-echo sequence at 4 t noninvasive quantification of total sodium concentrations in acute reperfused myocardial infarction using 23na mri three-dimensional triplequantum-filtered (23)na imaging of in vivo human brain direct, longitudinal comparison of (1)h and (23)na mri after transient focal cerebral ischemia sodium mri of reversible focal brain inchemia in the monkey comprehensive mr imaging protocol for stroke management: tissue sodium concentration as a measure of tissue viability in nonhuman primate studies and in clinical studies direct, longitudinal comparison of (1)h and (23)na mri after transient focal cerebral ischemia clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study haloperidol use in mechanically ventilated patients is associated with lower hospital mortality pilot clinical trial of gabapentin to decrease postoperative delirium in older patients a randomized, double-blind, placebo-controlled trial of donepezil hydrochloride (aricept) for reducing the incidence of postoperative delirium after elective total hip replacement dexmedetomidine: can it reduce the incidence of icu delirium in postcardiotomy patients? a potential role for erythropoietin in focal permanent cerebral ischemia in mice erythropoietin crosses the bloodbrain barrier to protect against experimental brain injury beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage derivatives of erythropoietin that are tissue protective but not erythropoietic xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat xenon impairs neurocognitive and histologic outcome after cardiopulmonary bypass combined with cerebral air embolism in rats nxy-059 for acute ischemic stroke safety and efficacy of statin in the acute phase of ischemic stroke: the mistics trial inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window cyclosporin a improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats whole-body hypothermia for neonates with hypoxicischemic encephalopathy hypothermia after cardiac arrest study group: mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid anoxic-hypotensive brain injury: neuropsychological performance at 1 month as an indicator of recovery chronic neurocognitive effects of critical illness this work was performed at the university of pittsburgh school of medicine, pittsburgh, philadelphia, usa. the authors declare that they have no competing interests. key: cord-280278-gq1hnnwh authors: chi, meng; lou, changming; zhao, xiuli; sui, xin; han, fei title: a simple custom appliance against droplet and aerosol transmission of covid-19 during advanced airway management date: 2020-06-08 journal: crit care doi: 10.1186/s13054-020-02985-5 sha: doc_id: 280278 cord_uid: gq1hnnwh nan health care workers are exposed to high-risk environments when patients infected with covid-19 require advanced airway management. the virus tends to be transmitted in the air by droplets and aerosols during these procedures [1, 2] . it was demonstrated that a mask over a patient's nose and mouth to prevent airborne transmission was effective in protecting health care workers [3] . however, patients cannot wear masks during positive pressure ventilation and endotracheal intubation, exposing health care workers to high-risk environments, even if effective protective measures were taken. one study showed that when a human-patient simulator simulated a cough in the supine position, the aerosol spread in the sagittal plane by approximately 86 cm [4] . the propagation distance reached 26.7 cm during mask positive pressure ventilation. the spread range of a cough reached 46 cm after endotracheal intubation. during endotracheal intubation, the operator is directly exposed to the front of the patient's respiratory tract. a large amount of aerosols is spread to the operator's face, hands, and surrounding equipment, seriously increasing the operator's risk of infection. therefore, the establishment of a barrier between the patient and the operator can decrease the diffusion area of the patient's exhaled gas, thus greatly reducing the concentration of droplets and aerosols in the surrounding environment and the risk of infection of the operator. we use the pvc membrane as a barrier that is easy to fabricate during advanced airway management ( fig. 1a-d) . it is used to block the spread of droplets and aerosols, and operators can view patients easily because the membrane is waterproof and transparent. the pvc membrane should be sufficiently large (> 100 cm × 100 cm is recommended) to cover the head of the patient and have a hole (sealed when necessary) in the center for the connection between the face mask and the circuit during oxygen inhalation and positive pressure ventilation. before advanced airway management, the pvc membrane with an assembled face mask under the membrane is placed over the patient's mouth and nose for the induction of intubation (fig. 1a) . the artificial nose and the circuit of the ventilator are on the operator's side. there is the other hole (sealed when necessary) of the pvc membrane for laryngoscopy insertion and intubation (fig. 1b) . sedatives and muscle relaxants are given to the patient to reduce the cough and choking responses during intubation. the appliance covers the head and face of the patient throughout the intubation, the mechanical ventilation (fig. 1c) , and the extubation periods. the mask is reapplied to the patient for oxygen inhalation after extubation (fig. 1d) . the custom appliance theoretically reduces the spread of droplets and aerosols originating from patients, reducing the risk of infectious disease transmission. first, the barrier acts as a mask and an isolation ward, reducing the spread of droplets and aerosols in the air, and it simply isolates the patient, reducing the potential for air transmission. second, the barrier covers the patient, which greatly reduces the risk of contact between the operator and the patient and blocks the transmission route of the virus by contact. finally, this device is inexpensive and easy to apply. it does not require any additional training. in view of the high infection and transmission rate of covid-19, it is equally important to control the source of infection and enhance the protective measures of health care workers. our appliance reduces the spread of droplets and aerosols from patients, blocking the airborne transmission route of the virus to a large extent and providing a new layer of protection for health care workers during advanced airway management. fig. 1 the process of advanced airway management from intubation to extubation. the photographs are demo on a non-covid-19 patient. a positive pressure ventilation before intubation. b intubation. c mechanical ventilation. d oxygen inhalation after extubation aerobiology and its role in the transmission of infectious diseases world health organization: infection prevention and control of epidemicand pandemic-prone acute respiratory infections in health care quantifying exposure risk: surgical masks and respirators exhaled air dispersion during bag-mask ventilation and sputum suctioning-implications for infection control publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions cm, cl, xz, and fh designed this appliance; xs and fh wrote this manuscript. the authors read and approved the final manuscript. none.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord-300510-fhpkdqr0 authors: mojoli, francesco; mongodi, silvia; orlando, anita; arisi, eric; pozzi, marco; civardi, luca; tavazzi, guido; baldanti, fausto; bruno, raffaele; iotti, giorgio antonio title: our recommendations for acute management of covid-19 date: 2020-05-08 journal: crit care doi: 10.1186/s13054-020-02930-6 sha: doc_id: 300510 cord_uid: fhpkdqr0 nan disease, with cough, fever and flu-like syndrome, evolving to dyspnoea after 2-10 days and presenting with bilateral chest infiltrates. blood gas analysis initially shows moderate hypoxaemia, metabolic acidosis with/without respiratory compensation, normal lactates and increased anion gap; ketoacids are found in urinary sticks. blood samples show high c-reactive protein, normal procalcitonin, increased lactate dehydrogenase, creatine phosphokinase, amylases, lipases and hyperglycaemia. a nasal swab for 2019 novel coronavirus is routinely performed in any upper/lower airways disease [2] [4] . for this same purpose, add a highefficiency particulate air filter before the positive end-expiratory pressure valve or, better, connect the valve to wall gas aspiration [6] [7] [8] . 7. perform early intubation if poor response to continuous positive airway pressure in terms of oxygenation: do not trust patients' relatively good respiratory mechanics and feeling of improved dyspnoea, since these patients may have relatively normal lung compliance and the only clinical sign of fatigue may be high respiratory rate. connect ventilator expiratory valve to wall gas aspiration to limit droplets' spread. 8. once intubated, perform a closed system bronchoalveolar lavage to confirm diagnosis: minimize the use of fiberbronchoscopes to limit airways' opening; we connect a bronchoalveolar lavage test tube to the closed aspiration system-mandatory in these patients-for deep bronchial sampling. thereafter, repeat the sampling every 7 days for viral charge assessment and bacterial over-infection detection [4] . 9. after intubation, evaluate basic lung mechanics: it usually shows a respiratory system compliance of 0.5-1 ml/cmh 2 o per kilogramme of predicted body weight with high recruitability at pressure-volume curve and normal resistances. these patients usually show good response to high positive end-expiratory pressure levels; calibrated oesophageal pressure may help its setting [9] . consider neuromuscular blocking agents if deep sedation does not control the patient's trigger and ventilation is not protective; perform daily a trial of neuromuscular blocking agents stop. it is accurate in interstitial diseases and may show pathological signs before chest x-ray. a basic assessment helps deciding the ventilatory strategy: if diffuse loss of aeration, keep high positive endexpiratory pressure levels; if posterior consolidations, consider pronation. lung ultrasound may also help in limiting traditional imaging, avoiding patients' transportation to radiology department. it also allows a daily monitoring of clinical evolution, response to treatment and possible complications (pneumothorax, over-infections) [10] [11] [12] . 11. avoid positive fluid balance: perform fluid challenges and stop fluid resuscitation if no haemodynamic response; use vasoactive drugs instead to optimize tissue perfusion [4] . we accept moderate elevation of creatinine without urinary output impairment to improve the lung status. 12. fever is a frequent issue, reaching values as high as 40°c; we decided to treat it only if > 39°c, if oxygenation is acceptable. spontaneous defervescence can be the first sign of clinical improvement. 13. as soon as possible according to gas exchanges (pao 2 /fio 2 > 150 with fio2 < 50%) and lung ultrasound score (≤ 12), start assisted ventilation with a sigh while maintaining moderate to high positive end-expiratory pressure to prevent derecruitment. regularly check patient's respiratory drive (p0.1), tidal volume and plateau pressure to keep ventilation safe. dexmedetomidine may help in the weaning phase. 14. in patients having received prolonged sedation, we frequently observed prolonged awakening with altered respiratory drive and difficult patientventilator interaction; if no prompt awakening is observed, perform early tracheostomy to accelerate the weaning and discharge from icu. the number of patients requiring intensive care rapidly increases; therefore, rapid discharge is mandatory. 15. hyperinflammatory status increases the risk of thrombosis and pulmonary embolism; check for thrombotic complications systematically, mainly in correspondence of central lines [13, 14] . 16. communication with families is difficult since patients' relatives are frequently in quarantine and access to the hospital is limited; moreover, while wearing personal protective equipment, physicians' possibility to answer to relatives' phone call is limited. consider identifying each day one person in charge of phone calls to daily update relatives on clinical conditions [15] . we hope sharing our experience while facing the italian outbreak of 2019 novel coronavirus may help other units eventually facing the same threat in the future. abbreviations sars-cov-2: severe acute respiratory syndrome coronavirus 2; icu: intensive care unit critical care utilization for the covid-19 outbreak in lombardy, italy: early experience and forecast during an emergency response characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention severe sars-cov-2 infections: practical considerations and management strategy for intensivists surviving sepsis campaign guidelines on the management of critically ill adults with coronavirus disease 2019 (covid-19) rapid response to covid-19 outbreak in northern italy: how to convert a classic infectious disease ward into a covid-19 response centre effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial critical care management of adults with community-acquired severe respiratory viral infection clinical management of severe acute respiratory infection when novel coronavirus (2019-ncov) infection is suspected: interim guidance 28 esophageal and transpulmonary pressure in the clinical setting: meaning, usefulness and perspectives lung ultrasound for critically ill patients assessment of lung aeration and recruitment by ct scan and ultrasound in acute respiratory distress syndrome patients lung ultrasound for early diagnosis of ventilator-associated pneumonia risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china thrombotic events in sars-cov 2 patients: an urgent call for ultrasound screening setup of a dedicated coronavirus intensive care unit: logistical aspects publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all the healthcare professionals involved in the management of such epidemics, in particular nurses and physicians of intensive care unit at s. matteo hospital. authors' contributions all the authors actively contributed to the conception, redaction and final revision before submission of the manuscript. the authors read and approved the final manuscript. availability of data and materials not applicable ethics approval and consent to participate not applicable key: cord-267348-bkirv9pt authors: sakano, takashi; bittner, edward a.; chang, marvin g.; berra, lorenzo title: above and beyond: biofilm and the ongoing search for strategies to reduce ventilator-associated pneumonia (vap) date: 2020-08-18 journal: crit care doi: 10.1186/s13054-020-03234-5 sha: doc_id: 267348 cord_uid: bkirv9pt nan we read with great interest the article by thorarinsdottir et al. [1] that compared biofilm formation on three endotracheal tube (ett) types with the finding that biofilm formation was reduced in silicone and noble-metal coated etts compared to uncoated etts. their findings have significant implications during the current pandemic given the prolonged intubation times of covid-19 patients and many develop superimposed pneumonias during their hospital course. it is intriguing that simply changing the ett's coating may have significant implications in this patient population with already limited pulmonary reserve that is unable to tolerate additional insults to their lung from a ventilator-associated pneumonia (vap). however, given the prolonged intubation times of covid-19 patients, it is likely that the ett biofilm burden will be substantial no matter which surface coating is utilized. here, we discuss other strategies to reduce the incidence of vap. it is widely accepted that two mechanisms lead to vap: aspiration of oral-gastric contents and microbial biofilm development on the ett. prevention is further complicated by a reduction in host mechanisms such as coughing and mucociliary clearance. biofilms specifically cause two primary issues: (1) non-microbiological problem of intraluminal narrowing and (2) microbiological problem of biofilm development on the inner/outer surfaces of the ett. the latter issue relates to our current discussion here. table 1 summarizes the mechanism, preventive measures, and methods that have been investigated to prevent aspiration and minimize biofilm burden related to tracheal seeding, microaspiration, biofilm formation, ciliary dysfunction, and the cough reflex. despite substantial research that has continued, available tools to prevent vap have changed very little. many of the recommendations from the most recent 2014 society for healthcare epidemiology of america (shea) and infectious diseases society of america (idsa) [2] consensus recommendations aimed at preventing vap are controversial and have been questioned, including the efficacy and safety of oral chlorhexidine and head of bed elevation [3, 4] . while it is important to develop technologies that minimize ett microbial burden, other more practical, easily accessible, and affordable preventative measures should continue to be practiced and investigated. as previously advised by klompas et al. [5] , continuing with simple and proven methods that decrease aspiration load and biofilm formation should be maximized. while avoiding intubation may be the surest way to prevent vap, this is not always possible. incorporating the latest evidence into our current practice bundles may be key to improving clinical outcomes of covid-19 patients. biofilm formation on three different endotracheal tubes: a prospective clinical trial strategies to prevent ventilatorassociated pneumonia in acute care hospitals: 2014 update semi-recumbent position versus supine position for the prevention of ventilator-associated pneumonia in adults requiring mechanical ventilation associations between ventilator bundle components and outcomes beware the siren's song of novel endotracheal tube designs publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions ts, eab, mgc, and lb wrote and reviewed the article. the authors read and approved the final manuscript. none.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. received: 1 august 2020 accepted: 9 august 2020 key: cord-291955-mlju5f9u authors: haas, lenneke e. m.; de lange, dylan w.; van dijk, diederik; van delden, johannes j. m. title: should we deny icu admission to the elderly? ethical considerations in times of covid-19 date: 2020-06-09 journal: crit care doi: 10.1186/s13054-020-03050-x sha: doc_id: 291955 cord_uid: mlju5f9u nan the sars-cov-2 (covid-19) pandemic leads to severe shortages of intensive care unit (icu) facilities in many countries. although most people appear to be asymptomatic, some reports suggest that 5 to 25% of infected people require hospitalization and 2-4% require mechanical ventilation [1] . this strains many icus beyond their maximum capacity. national critical care societies have adopted protocols to increase their beds up to 200% or more. however, although a lot of effort can be done to increase the icu capacity, demand may still outpace the supply. as a consequence, a scenario can arise in which not every patient who needs icu treatment can be admitted, and difficult decisions about allocation of icu beds need to be made [2] [3] [4] . in this article, we discuss the use of age as a criterion for icu treatment in times of scarce icu capacity by contrasting it with deciding under normal conditions. medical treatment has to be justified by serving the wellbeing of the patient, and it should be aligned with the wishes of the patient. the burden of an icu treatment has to be carefully balanced against the estimated chance of recovery. this chance of recovery is affected by age and many other factors like the admission diagnosis, severity of organ failure, comorbidities, frailty, and preadmission performance status [5] . sometimes, icu admission might be more appropriate for a fit 90-year-old patient than for a vulnerable 65-year-old patient. elderly patients (defined as 70 years and older) have a higher risk of death and of functional decline than younger patients. however, the majority of them survives, and in addition, several studies have demonstrated that elderly icu survivors might accept their disabilities and accommodate to a degree of physical disability quite well, consider their quality of life to be good or satisfactory, and report good emotional and social well-being after hospital discharge [6] . the carefully balancing of pros and cons of icu treatment should be done before icu admission (as advance care planning) but also during a (prolonged) icu admission. what is common to all decisions on starting, continuing, or foregoing life support is that they should be justified by the autonomous wish of the patient and the benefit of treatment for that unique patient. age may play a role in these decisions in several ways. it is proxy for the medical condition of the patient, and advanced age is clearly a factor that should be weighed together with other risk factors for a poor outcome of icu treatment. elderly patients themselves may also have the feeling that they have lived life to its full and that therefore life-sustaining treatments should not be applied in their own case. there is, however, no valid reason to limit icu admissions to those under a specific age. elderly patients admitted to the icu with covid-19 are at increased risk of death [7, 8] . although we need more robust data about short-and long-term outcomes of elderly patients admitted to the icu because of covid-19, the mortality rates reported up to now are 40 to 80% [7, 9] . these numbers will even become higher, since at the time of reporting a substantial portion of the patients was still in the icu and the follow-up was short. in circumstances of a pandemic, not only the autonomy of the patient and proportionality of treatment, but also shortage of resources may play a role in decisions about icu treatment. emanuel and colleagues proposed to use a utilitarian framework [10] . this strategy aims to maximize the benefits for the largest number of people and prioritize care based on the (estimated) greatest advantage of icu treatment, the so called incremental probability of survival. according to this approach, for instance, parents of young children should be prioritized, then parents of teenagers, middle-aged people, then elderly. chances of survival rates after icu admission decrease with increasing age, making age an important factor in this utilitarian approach. the use of age as a selection criterion in case of scarcity can also be justified by pointing at the "fair innings" that a patient has had, meaning that older patients have already had their opportunity to reach a certain "mature" age, which has given them a fair equality of opportunity. the idea is that everyone should have an equal opportunity to lead a life of a certain duration. while there is no hard and fast rule for what is an unfulfilled life age for a person, most policies distributing lifesaving resources look to those under 18 as gaining priority while those in their 80s and beyond, who have had a chance to experience life and flourish as human being, receive lower priority. we submit that this strategy does not amount to age discrimination as all people are treated alike: when they become older, their claim on lifesustaining treatment decreases. in this article, we discussed two ways of using age in the triage of icu admission. under normal circumstances, age should be weighed as a risk factor for poor outcome. together with other risk factors, it may lead to the shared decision to forego icu treatment. it cannot be justified to withhold icu admission for all patients above a certain age. in times of scarcity, however, we believe it is justified to prioritize the younger patients, in order to maximize the benefits for the largest number of people, and because of the fair innings that an elderly patient has already had. abbreviation icu: intensive care unit clinical characteristics of coronavirus disease 2019 in china intensive care management of coronavirus disease 2019 (covid-19): challenges and recommendations facing covid-19 in italy -ethics, logistics, and therapeutics on the epidemic's front line triage: care of the critically ill and injured during pandemics and disasters: chest consensus statement the contribution of frailty, cognition, activity of daily life and comorbidities on outcome in acutely admitted patients over 80 years in european icus: the vip2 study long-term survival, quality of life, and quality-adjusted life-years among critically ill elderly patients baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a singlecentered, retrospective, observational study icnarc case mix programme database publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions lh, ddl, dvd, and jvd contributed to the ideas of this paper. all authors contributed to the writing of the paper and read and approved the submitted final version. not applicable.availability of data and materials not applicable.ethics approval and consent to participate not applicable. the authors have approved the manuscript for submission and consent for publication. the content has not been published elsewhere. the article does not contain individual person's data. the authors declare that they have no competing interests. key: cord-263346-pu1jci26 authors: peng, qian-yi; wang, xiao-ting; zhang, li-na title: using echocardiography to guide the treatment of novel coronavirus pneumonia date: 2020-04-10 journal: crit care doi: 10.1186/s13054-020-02856-z sha: doc_id: 263346 cord_uid: pu1jci26 nan the echocardiographic features of covid-19 are mainly related to the severity of disease and cardiovascular complications. abnormal findings include (1) hyperdynamic cardiac function, presented as the increase of cardiac output (co) and ejection faction (ef) of the left ventricular (lv), with/without the decrease of peripheral vascular resistance, which is often seen in the early stage following the systemic inflammatory response; (2) acute stress-induced (takotsubo) cardiomyopathy, characterized as lv segmental contraction abnormalities and apical ballooning [1] ; (3) right ventricular (rv) enlargement and acute pulmonary hypertension, which are mainly caused by "internal factors" (including alveolar and pulmonary capillary damage caused by inflammation, hypoxia, and hypercapnia, leading to the increase of rv afterload) and "external factors" (including fluid overload, which causes the increase of rv preload, and unsuitable mechanical ventilation parameter setting, which affects the cardiac function by cardiopulmonary interaction); further, lv function will be affected because the right and left hearts are in the same pericardium; and (4) diffuse myocardial inhibition in the late stage, which is often caused by severe hypoxia, and long term of anoxia and inflammation. the echocardiographic features of ncov pneumonia and their probable causes are shown in table 1 . echocardiography can help to quickly identify the circulatory status of ncov pneumonia patients and guide hemodynamic management. five basic views of echocardiography (apical four chamber view, parasternal long axis view, parasternal short axis view, subarachnoid four chamber view, subarachnoid inferior vena cava (ivc) long and short axis view) should be measured, which help to quickly understand the patient's volume status, cardiac function, and organ perfusion and help to develop hemodynamic management plans. it is suggested to measure the diameter of ivc, ef, velocity-time integral of the left ventricular outflow during continuous and dynamic evaluation of patients' volume state and fluid responsiveness, left ventricular systolic function, and left ventricular output effect. if necessary, hemodynamic management can follow the "5p" principle, i.e., lower central venous pressure, optimized pulse/heart rate, appropriate pump function and blood pressure, and organ perfusion as the final goal. fast identify the circulatory status and the types of shock according to the pathophysiological mechanism of shock, it can be divided into 4 types: distributed shock, cardiogenic shock, hypovolemic shock, and obstructive shock. critical ultrasonography is of great significance in fast identifying the types of shock and guide hemodynamic management. since the focused cardiac ultrasound (focus) was proposed in 2010 [2] , many different types of focus exams for rapid evaluation of emergency or icu patients have been introduced, including the focus-assessed transthoracic echocardiography (fate) advanced fate protocol [3] , fluid administration limited by lung sonography (falls) protocol [4] , and critical care chest ultrasonic examination (ccue) protocol [5] . in covid-19 patients, the most common types of shock are septic shock and cardiogenic shock; however, we still need to exclude obstructive shock (massive pericardial effusion, right heart collapse, heart swing, rv enlargement and "d sign," tricuspid valve regurgitation, pulmonary artery or deep vein thrombosis, etc.) and hypovolemic shock (decrease of co, "papillary muscle kissing sign," ivc collapse and high respiratory variability, etc.) first. further, we assess whether there are signs supporting cardiogenic shock (enlargement of the heart, segmental or diffuse contraction abnormalities, ivc dilation, b lines in the lungs and pleural effusion, etc.). if the above three kinds of shock are excluded, then we may consider distributed shock according to clinical history and laboratory tests. novel coronavirus pneumonia may cause the increase in pulmonary vascular resistance due to hypoxia, pulmonary vasospasm, hypercapnia, and inflammation, which further affect the right heart function. mechanical ventilation itself, especially when lung protective ventilation is not implemented properly, will further increase pulmonary artery pressure and aggravate right heart dysfunction. right heart dysfunction can be detected by echocardiography, therefore providing important information for circulatory and respiratory management strategies in patients with ncov pneumonia. novel coronavirus pneumonia is different from severe acute respiratory syndrome (sars) in that severe lung injury occurs at the beginning. some critically ill patients suffer from multiple organ failure, which worsen dramatically in the late stage of disease. it could be a kind of like the "inflammatory storm" with uncontrolled inflammatory reaction in the body. during hypoxia, respiratory distress, intense stress status, and inflammation, the left heart may go through the following abnormalities: segmental dyskinesia, overall hyperdynamic, and diffuse cardiodepression. diffuse cardiodepression often occurs during lethal hypoxia, in the process of intubation, or after cardiopulmonary resuscitation. the long term of anoxia and inflammation should also be considered. the circulatory failure is often caused by diffuse cardiodepression after arrest and the decrease of vascular tension caused by lactic acidosis. sepsis or myocardial infarction can also lead to these changes. left heart function can be evaluated by rapid qualitative and quantitative methods using echocardiography. critical ultrasonography can also provide etiological evaluation and treatment guidance for patients with systolic dysfunction. as an important part of critical ultrasonography, echocardiography is a useful tool for the fast screen of circulatory status, identifying the types of shock, monitoring during the respiratory and hemodynamic management, and guiding the treatment of ncov pneumonia patients, which is especially feasible, convenient, and advantageous in critically ill patients. pathophysiology of takotsubo syndrome cardiac ultrasound in the intensive care unit: point-of-care transthoracic and transesophageal echocardiography focus-assessed transthoracic echocardiography: implications in perioperative and intensive care the rush exam: rapid ultrasound in shock in the evaluation of the critically lll ten basic principles about critical ultrasonography: critical care practitioners need to know publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none.authors' contributions qian-yi peng drafted the manuscript. xiao-ting wang and li-na zhang instructed and revised this manuscript. the author(s) read and approved the final manuscript. available.ethics approval and consent to participate not applicable. all authors have read and approved the content and agreed to submit it for consideration for publication in your journal. there are no conflicts of interest to declare.received: 18 march 2020 accepted: 27 march 2020 key: cord-293690-pxiv0m7n authors: scala, raffaele; renda, teresa; corrado, antonio; vaghi, adriano title: italian pulmonologist units and covid-19 outbreak: “mind the gap”! date: 2020-06-29 journal: crit care doi: 10.1186/s13054-020-03087-y sha: doc_id: 293690 cord_uid: pxiv0m7n nan raffaele scala 1* , teresa renda 2 , antonio corrado 3 the outbreak of covid-19 in italy has shown the inadequacy of the health system to counterbalance a massive request for icu care [1] . one fourth of > 1500 covid-19 patients died after the admission in lombardia icus; in only 11% of them, noninvasive ventilation (niv) and/ or high flow nasal cannula (hfnc) was attempted early to prevent respiratory deterioration and invasive mechanical ventilation (imv). conversely, in chinese reports, niv and hfnc were used respectively in between one third and two thirds of less severely hypoxemic covid-19 patients keeping lower hospital mortality [2] . the success of noninvasive respiratory assistance in avoiding intubation is higher if attempted earlier in hypoxemic patients (pao 2 /fio 2 > 150) [2] . even after failure, niv and/or hfnc may be good players to facilitate weaning from imv and discharge from icu. clinical expertsguided hierarchical covid-19 management strategy including intensivists and pulmonologists might have improved outcomes in some chinese provinces [3] . the delayed admission in lombardia overcrowded icu of severely hypoxemic covid-19 patients meeting the criteria for imv without being offered a hfnc/niv trial must have played a crucial role. where should have been earlier and properly noninvasively supported acute patients with and without covid-19 to keep the highest the icu capacity? respiratory high-dependency care units (rhdcus) are specialised cost-effective environments offering an "intermediate" level of care between icu and ward, where niv/hfnc, weaning from imv and discharge of ventilator-dependent patients are provided [4] . italian rhdcus are mainly located inside the pulmonology ward and work following a step-up/step-down flexibility according to changes in clinical status. the "gap" between the italian rhdcu network and pre-covid-19 respiratory needs might largely explain icu network failure in lombardia [4] . a national survey performed at the beginning and 1 month after the covid-19 outbreak demonstrated an increase rate (94% vs 12%) of italian pulmonologist units (ipus) accounting for 841 extra-beds involved in the fight against covid-19. this was associated with the "up-grading" of 84% ipus towards rhdcus. moreover, 72% of these extra-beds were dedicated to provide niv/hfnc which avoided intubation/death in 40% of cases (http://www.aiponet.it/ news/speciale-covid-19/2463-il-94-delle-pneumologie-ein-prima-linea-nella-lotta-contro-l-infezione-da-covid-1 9.html) ( table 1 ). the expanded ipu network together with national more restrictive measures against virus dissemination after the lombardia outbreak has contributed to the mitigation of covid-19 impact on mortality in other regions. in conclusion, what could we learn from the italian covid-19 outbreak? the italian health system needs a stronger pulmonologists/rhdcus "backbone" for the governance of "ordinary" burden of respiratory diseases to mind the gap against next unforeseen pandemia. we would like to thank claudia diana of aipo ricerche for her precious help in analysing the data and performing table 1 . authors' contributions rs ideated and structured the paper. ac, tr and av contributed to the writing of the paper. rs revised the final version of the paper. all authors have read and approved the final manuscript. ethics approval and consent to participate not applicable baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region intensive care management of coronavirus disease 2019 (covid-19): challenges and recommendations lower mortality of covid-19 by early recognition and intervention: experience from jiangsu province respiratory high-dependency care units for the burden of acute respiratory failure publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations received: 3 june 2020 accepted: 10 june 2020 key: cord-305946-ytabywxd authors: zhu, shiping; dong, lei; cai, wanru title: predictive value of neutrophil to lymphocyte and platelet to lymphocyte ratio in covid-19 date: 2020-08-28 journal: crit care doi: 10.1186/s13054-020-03258-x sha: doc_id: 305946 cord_uid: ytabywxd nan predictive value of neutrophil to lymphocyte and platelet to lymphocyte ratio in covid-19 shiping zhu 1 , lei dong 2 and wanru cai 2* keywords: neutrophil to leucocyte ratio, platelet to lymphocyte ratio, to the editor, in a recent study, dr. ma [1] investigated the neutrophil to lymphocyte ratio (nlr) in predicting moderate-severe acute respiratory distress syndrome (ards) in patients with covid-19 infection. they reported that nlr was significantly higher ards group and was a good predictor for moderate-severe ards, with area under curve (auc) 0.749. this study is well designed. however, several limitations should be mentioned. first, uncontrolled inflammatory response plays a vital role in covid-19 disease, and both nlr and platelet to lymphocyte ratio (plr) have been recognized as inflammatory factors in various lung diseases [2, 3] , such as lung cancer and obstructive lung disease. however, one common limitation is that in most previous studies, nlr or plr was included in the generalized linear models as a continuous variable, with the assumption that there was a linear association between nlr/plr and the dependent outcomes. even in some prediction model [4] , researchers only focused on the impact of higher nlr/plr value while the effect of low nlr/plr was ignored. however, in most cases, extremely low nlr or plr represented low neutrophil and platelet, which, according to clinical experience, was also associated with poor outcomes. thus, the association between nlr/plr and outcomes should be nonlinear, and simply including these parameters into a linear model may lead to a biased conclusion. for instance, we estimated an unadjusted association between nlr/plr and mortality in critically ill patients with lung infection, using data from the mimic database (fig. 1) . although the cohort is different from the current study, the non-linear association, to a certain degree, supports our hypothesis. if this is the case, the predictive value of nlr/plr in auc may also be compromised as both high and low nlr/plr was associated with increased mortality. the following method may improve this limitation: (1) applying non-linear spline regression using the cut-off value of nlr/plr in logistic model, (2) generating predictive values of the logistic model, and (3) neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ards in severe covid-19 patients prognostic value of combined platelet, fibrinogen, neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in patients with lung adenosquamous cancer relationship between neutrophil-lymphocyte ratio and short-term prognosis in the chronic obstructive pulmonary patients with acute exacerbation development and validation of a risk factor-based system to predict short-term survival in adult hospitalized patients with covid-19: a multicenter, retrospective, cohort study none. key: cord-265022-p5cab562 authors: kotfis, katarzyna; williams roberson, shawniqua; wilson, jo ellen; dabrowski, wojciech; pun, brenda t.; ely, e. wesley title: covid-19: icu delirium management during sars-cov-2 pandemic date: 2020-04-28 journal: crit care doi: 10.1186/s13054-020-02882-x sha: doc_id: 265022 cord_uid: p5cab562 the novel coronavirus, sars-cov-2-causing coronavirus disease 19 (covid-19), emerged as a public health threat in december 2019 and was declared a pandemic by the world health organization in march 2020. delirium, a dangerous untoward prognostic development, serves as a barometer of systemic injury in critical illness. the early reports of 25% encephalopathy from china are likely a gross underestimation, which we know occurs whenever delirium is not monitored with a valid tool. indeed, patients with covid-19 are at accelerated risk for delirium due to at least seven factors including (1) direct central nervous system (cns) invasion, (2) induction of cns inflammatory mediators, (3) secondary effect of other organ system failure, (4) effect of sedative strategies, (5) prolonged mechanical ventilation time, (6) immobilization, and (7) other needed but unfortunate environmental factors including social isolation and quarantine without family. given early insights into the pathobiology of the virus, as well as the emerging interventions utilized to treat the critically ill patients, delirium prevention and management will prove exceedingly challenging, especially in the intensive care unit (icu). the main focus during the covid-19 pandemic lies within organizational issues, i.e., lack of ventilators, shortage of personal protection equipment, resource allocation, prioritization of limited mechanical ventilation options, and end-of-life care. however, the standard of care for icu patients, including delirium management, must remain the highest quality possible with an eye towards long-term survival and minimization of issues related to post-intensive care syndrome (pics). this article discusses how icu professionals (e.g., physicians, nurses, physiotherapists, pharmacologists) can use our knowledge and resources to limit the burden of delirium on patients by reducing modifiable risk factors despite the imposed heavy workload and difficult clinical challenges posed by the pandemic. the novel coronavirus, sars-cov-2-causing coronavirus disease 19 , emerged as a public health threat in december 2019 and was declared a pandemic by the world health organization in march 2020 [1] . many hospitalized patients with covid-19 will develop delirium, and given early insights into the pathobiology of this virus indicating invasion into the brain stem, as well as the emerging interventions utilized to treat these critically ill patients, delirium prevention and management may prove exceedingly challenging, especially in the intensive care unit (icu). in addition to the neurobiology of covid-19 and typical deliriogenic factors omnipresent in the icu, this pandemic has created circumstances of extreme isolation and distancing from human contact whenever possible, including loved ones, plus the inability to freely ambulate, which essentially create a "delirium factory" that must be explicitly addressed to maximize human dignity and respect during care. in patients with covid-19, delirium may be a manifestation of direct central nervous system (cns) invasion, induction of cns inflammatory mediators, a secondary effect of other organ system failure, an effect of sedative strategies, prolonged mechanical ventilation time, or environmental factors, including social isolation. drawing from experience with other closely related viruses from the coronaviridae family, direct cns invasion appears to occur rarely and late in the disease course but may be associated with seizures, impairments in consciousness or signs of increased intracranial pressure [2, 3] . such symptoms may require specialized neuro-intensivist management. immunologic responses to coronaviridae appear to be mediated by acute cytolytic t cell activation [4] . this response could, if dysregulated, cause an autoimmune encephalopathy [5] . secondary effects include cerebral hypoxia or metabolic dysregulation in association with failure of pulmonary or other organ systems, such as can be seen in a variety of other types of delirium [6] . environmental and iatrogenic factors such as prolonged mechanical ventilation, sedatives (especially benzodiazepines), and immobility also contribute heavily to the risk of icu delirium [7] and can contribute to its development in the context of acute covid-19 infection. in an early retrospective report from wuhan, mao et al. reported that only 7.5% had any chart documentation of "impaired consciousness," which was the only term approximating delirium [8] . underreporting of delirium is extremely common in retrospective chart reviews, and under 1 in 10 with delirium is likely a gross underestimation. the literature is very consistent that7 5% of occurrences of delirium are missed in patients unless objective delirium monitoring is being employed to detect this form of acute brain dysfunction [9] [10] [11] [12] [13] [14] [15] . in addition, in covid-19, the risk of complications such as acquired dementia and icu-acquired weakness (icu-aw) as well as depression and ptsd, the defining illnesses of post-intensive care syndrome (pics), and pics in family members (pics-f) [16] [17] [18] will be greatly exacerbated if we allow patients to suffer unmitigated delirium. this article will discuss how icu professionals (e.g., physicians, nurses, physiotherapists, pharmacologists) can use our knowledge and resources to limit the burden of delirium on patients by reducing modifiable risk factors despite the imposed heavy workload and difficult clinical challenges posed by the pandemic. for example, others have already stressed reasonable analgesia and sedation use with special attention to monitoring and mitigating delirium [19] . delirium, the most frequent clinical expression of acute brain dysfunction [20] , is especially important in the context of covid-19. it may be regarded as an early symptom of infection, as previously described in septic patients [21] . therefore, delirium should be actively screened for using dedicated psychometric tools, i.e., cam-icu [22] or icdsc [23] [24] [25] [26] . it is also plausible that delirium severity, which could be measured with cam-icu-7 or drs-r-98 [27, 28] , may be associated with covid-19 severity [25, 29, 30] . the sars-cov-2 virus causes pneumonia, especially in elderly patients [31, 32] . since advanced age is a well-described independent risk factor for delirium, it could be postulated that those who are at the greatest risk for severe pulmonary disease related to covid-19 are likely at the greatest risk for delirium as well. it has been reported that nearly 90% of covid-19 patients whose condition required admission to the intensive care unit need mechanical ventilation, either non-invasive (niv) (42%) or invasive requiring intubation (48%) [33] . currently, due to the reports of increased aerosolization of the viral load, niv is not recommended yet still being used when icu resources become limited [34] . the use of sedating medications in critically ill patients, especially sedative-hypnotics and anticholinergic agents is associated with the development of delirium [35, 36] . despite advances in care bundles, such as the abcdef bundle [37] [38] [39] , to reduce the incidence of delirium and improve the care of critically ill patients, recent reports from regions of the world hardest hit by covid-19 suggest that a flexible approach to management algorithms may be required, due to either a strained workforce or scarcity of resources [40] . highlighting the importance of covid-19-related morbidities it must be underlined that agitation associated with hyperactive delirium could theoretically be a source of intra-hospital disease spread in uncooperative patients in over-crowded settings with respiratory distress prior to intubation or awaiting admission to the icu. another potential factor contributing to the occurrence of icu delirium during the sars-cov-2 outbreak is social isolation created by "social distancing" strategies and quarantines, which may prove especially difficult in older adults, who have no or limited support from caregivers. in the age of covid-19, in an attempt to "flatten the curve" and slow the spread of the virus, many hospitals have instituted no-visitation or very limited visitation policy, which may propagate a sense of isolation, ultimately contributing to disorientation and lack of awareness in the patient. what is needed now, is not only high-quality icu care, concentrated on providing adequate respiratory support to critically ill patients, but an identification of the source and degree of mental and spiritual suffering of patients as well as their families to provide the most ethical and person-centered care during this humanitarian crisis. many patients, coming from different religious backgrounds, will need the support of religious services that are likely to be unavailable for an extended period of time. implementation of policies that prevent visitors from coming into the hospital should be followed by additional efforts to support patient-family interaction. this must include dedicated time and effort for phone and video conversations during busy icu time. moreover, hospital management should provide all possible novel technological options for communication, including teleconferences or portable speakerphones. all of these concepts are summarized in fig. 1 . this patient-centered approach is especially important for delirious patients, the majority of whom are elderly, may suffer from an evolving neurocognitive disorder, be hypoactive or aphasic and cannot express their emotional or spiritual needs, and would typically receive comfort from relatives, friends, and caregivers, during a medical crisis. during these strenuous and difficult times, an even deeper sense of humanity is required from healthcare professionals and hospital management to provide quality care to critically ill patients. the workload is already increased with the volume of new and deteriorating patients, but in order to provide maximum humanitarian care and preserve the sense of dignity, we must view the fulfillment of mental and spiritual needs as a medical intervention. yet it is obvious that during the covid-19 pandemic, the potential for nonpharmacological interventions encapsulated in the abc-def bundle (e.g., mobility outside the icu room, family engagement) may be extremely limited [26] . all of these issues factor into the type of survivorship that our covid-19 patients and their families will experience the months and years ahead as they face the burdens of pics and pics-f [16] [17] [18] . covid-19: neuro-invasive potential of sars-ncov-2 as cause of delirium acute brain dysfunction, symptomatically presenting as delirium (also called encephalopathy), may be a feature of the neuro-invasive potential of sars-cov-2. neurotropism of coronaviridae has been demonstrated during sars and mers epidemics [41] [42] [43] . during the 2002-2003 sars epidemic older subjects presented not only with respiratory symptoms and typical febrile response, but also with decreased general well-being, poor feeding, and delirium [44] . given the fact that sars-cov and sars-cov-2 are similar in terms of pathogenicity, it is quite likely that sars-cov-2 has a similar ability to cause delirium [45] . most covs share a common viral structure, infection potential, and neurotropism [46, 47] , covs are large, enveloped viruses with a large positive-sense, singlestranded rna genome [48] . human pathogenic covs include those causing recent epidemics, severe acute respiratory syndrome cov (sars-cov and sars-cov-2), middle east respiratory syndrome cov (mers-cov) hcov-229e, and other identified coronaviruses, i.e. hcov-oc43, hcov-nl63, and hcov-hku1 [49] [50] [51] . covs have been associated with cns diseases such as acute viral encephalopathy, acute disseminated encephalomyelitis, and multiple sclerosis and are increasingly recognized as presenting a neurologic crisis [3, 52, 53] . in one series of 183 children hospitalized with acute encephalitis, 12% were associated with coronavirus infection [54] . such propensity of covs has been documented for several of the beta-covs, including sars-cov and mers-cov [46, 48] . acute necrotizing encephalitis has also been described in one case of sars-cov-2. the patient presented with fever, cough, and altered mental status and was found to have hemorrhagic rim enhancing lesions in the deep gray matter of the cerebral cortex bilaterally [55] . animal studies suggest coronaviruses are delivered through the peripheral nerves and may access the central nervous system through retrograde synaptic transmission [43, 56, 57] . sars-cov spreads in the brains of intranasally inoculated mice primarily via the olfactory bulb with subsequent infection of the hypothalamus and brainstem [57] . such neuro-invasive potential of sars-cov-2 has been postulated to contribute to respiratory failure observed in infected patients [45] . the exact mechanism for neurotoxicity may depend on the brain entry route, which has not been fully elucidated [48] . the sars-covs enter human host cells mainly via a cellular receptor angiotensin-converting enzyme (ace2), expressed not only in the entire respiratory tract (which it destroys resulting in the leading cause of death), but also in the upper esophagus or enterocytes and showing very low expression level in the brain under normal conditions [45] . the virus entry route may be respiratory, via oro-fecal route, but also directly intranasal [42, 48, 58] . the possible brain entry routes for covs, including sars-cov-2, include either direct intranasal access to the brain via olfactory nerves (with anosmia as an early symptom) or indirect access to the brain by crossing the blood-brain barrier (bbb) via hematogenous or lymphatic spread [2, 41, 59] . there are several mechanisms of coronavirus-related brain damage. one of them is connected with the dysfunction of renin-angiotensin system in the brain. ace is the major component of the cerebral renin-angiotensin system and is localized in the endothelia of cerebral vasculature [60] . the use of ace inhibitors for treatment of blood hypertension reduces cognitive dysfunction through their anti-inflammatory actions [61] . circulating reninangiotensin components do not affect the brain with airtight bbb. however, general inflammatory response to virus infection impairs bbb integrity leading to massive infiltration of renin-angiotensin components to the brain [62] . uncontrolled infiltration of the brain with reninangiotensin components induces neuroinflammatory cascades resulting in extensive neurodegradation followed by cognitive dysfunction [63] . the sars-covs can enter the brain via the bbb angiotensin-converting enzyme receptors and induce neurodegeneration, astrogliosis, and neuroinflammation. it is noteworthy that sars-cov particles have been found in the brain [41, 42] . inflammatory response of the cns to viral infection seems to be another important reason for poor neurological outcome and occurrence of delirium. a few hours after infection, neutrophils and monocytes infiltrate cns, and neutrophils seem to be crucial in disruption of bbb permeability [64] [65] [66] the postmortem study documented a massive infiltration of the brain by immune cells, which was associated with neuronal edema and the scattered red degeneration [42] noteworthy, activated macrophages and microglia have been present in areas of demyelination and play a critical role in myelin destruction [66] . the hypomyelinated axons were found in experimental animals with short-and long-term memory deficit, and the degree of myelin disorders was associated with memory dysfunction and short-and long-term cognitive dysfunction [67, 68] . a large amount of damaged myelin following neuroinflammation is potentially immunogenic and activates macrophages again, which initiate a vicious cycle sustaining further inflammation. this prolonged inflammation may be responsible for the higher incidence of neuropsychological abnormalities in patients with severe infection and sepsis; however, this hypothesis should be confirmed in further studies. the median time from the onset of first symptoms to the diagnosis of respiratory compromise (dyspnea) is usually 5 days and 8 days from admission to the intensive care unit with severe respiratory failure requiring intubation and mechanical ventilation [45] . the latency period indicates that there might be sufficient time for the coronavirus to enter and destroy cns neurons. previous studies have shown that some patients infected with sars-cov-2 present with neurological symptoms such as headache (about 8% of cases) or centrally mediated nausea and vomiting (about 1% of cases) [50, 69] . a retrospective study performed by mao et al., reporting data from 214 covid-19 patients, showed that neurological symptoms were present in 45% of severely ill patients, with symptoms including both acute cerebrovascular disease and impaired consciousness [8] . possibly the neuro-invasive potential of sars-cov-2 may be associated with centrally mediated respiratory failure. as a hypothesis, early identification of patients with delirium, being an early symptom of cns involvement is critical in covid-19 patients, as it may indicate impending respiratory failure due to the neuro-invasive potential of sars-cov-2. historically, delirium rates among mechanically ventilated icu populations were consistently 70-75%, and the duration of delirium has consistently proven an independent predictor of longer lengths of stay, higher mortality, greater cost of care, and alarming rates of acquired dementia that lasts years following illness [70] [71] [72] [73] . given these facts, it is important to carry into the pandemic the knowledge that delirium in mechanically ventilated patients can be reduced dramatically to 50% using a culture of lighter sedation and mobilization via the implementation of the safety bundle called the abc-defs promoted by the society of critical care medicine (sccm) in their icu liberation collaborative [37, 38] . limitations in the ability to conform to this approach are a major component of the burden of the isolation required to limit the spread of covid-19, prompting us to discuss specifics related to bedside care that one might keep in mind in organizing busy triage units and routine icu care during the pandemic. delirium screening only takes 30 s. as such, delirium screening and treatment should follow well-established international guidelines, such as the ecash concept [74] and the sccm clinical practice guidelines [26] . although routinely used in clinical practice, some sedation-and delirium-associated issues may be especially important when using limited resources. standard nonpharmacological measures to treat or prevent delirium may not be possible in isolation environments, and these environments may themselves worsen delirium. pain management remains a priority for all patients and requires the widespread implementation of behavioral pain scales (cpot or bps) for sedated and mechanically ventilated patients. after pain control is adequately assured, we must focus on the intersecting issues that lead a person's brain to fail in critical illness, chief among them including overuse of powerful sedatives and undue immobilization. these and other potential problems regarding icu delirium management during the sars-cov-2 pandemic are identified in table 1 . during such harrowing times at the respiratory failure that is occurring with covid-19, it would be easy to disregard patients' brains as not being an essential concern. if we follow the critical care literature, this would be a grave error. evidence indicates that delirium is not only a robust prognostic indicator of worse survival immediately, but also of the cost of care and quality of survival [71-73, 75, 76] . thus, healthcare professionals should follow local guidelines and policies regarding the monitoring and management of delirium. implementation of easy screening methods for delirium is necessary especially in light of heavy workload because without validated assessment tools 75% of delirium will be missed [9] [10] [11] [12] [13] [14] [15] 24] during the covid-19 crisis. it is necessary to reduce the icu delirium risks using standard management approaches towards adequate pain management, avoiding urinary retention and gastro-intestinal problems (constipation), identification and treatment of nosocomial sepsis, and maintaining adequate oxygenation. non-pharmacological interventions such as regular orientation despite social separation and lack of contact with family and caregivers are going to prove vitally important. regarding pharmacological interventions, no drugs can be recommended for the prevention or treatment of icu delirium other than avoidance of overuse of potent psychoactive agents like sedatives and neuromuscular blockers (nmb) unless patients absolutely require such management [77] [78] [79] [80] . this component of the conversation is especially important given the early anecdotal recommendations to treat patients with covid-19 in the prone position [81] , which will be uncomfortable and thus likely be met with even higher than usual amounts of sedation, which could beget very high rates of delirium down the line in the management of these already high-risk patients. additionally, it is important to review previous medications to avoid withdrawal symptoms. the ease of covid-19 transmission and the risk of harm to others (healthcare workers, family, caregivers) may exceed risk of harm to the individual. this is an isolated example warranting earlier use of sedatives for hyperactively delirious patients who are proving harmful to self and others. icu beds and ventilators are valuable and needed resources so it will be important to consider ways to avoid unnecessary prolongation of ventilation time and icu length of stay that is associated with deeper sedation. table 1 provides an overview of abcdef bundle adaptations to meet the needs of covid-19. data regarding delirium in the sars-cov-2 pandemic era are thus far too limited. this virus destroys the respiratory tract and invades the cns, both of which will produce an extremely high-risk circumstance for both acute and long-term brain dysfunction in patients infected with the covid-19 virus. the further elements of human isolation, extended time away from family and other loved ones, and other elements of care all form what could be construed as a delirium factory that medical teams must address. in the patients with covid-19, delirium can be a manifestation of direct cns invasion, induction of cns inflammatory mediators, secondary effects of other organ system failure, and untoward medical and environmental factors including heavy use of sedatives for prone positioning of the patient and quarantining and social isolation during care. the focus during the covid-19 pandemic obviously lies within the dire necessity of organizational issues, i.e., lack of ventilators, shortage of personal protection equipment, resource allocation, prioritization of limited mechanical ventilation options, end-of-life care. it is precisely during such times that standardization of safety concerns encapsulated in the abcdef bundle can provide a framework to help us accomplish "whole person" care that will help with acute management success as well as improvement of long-term survivorship and reductions of pics and pics-f burden on individuals and society as a whole. at the heart of this safety bundle lies the brain, the most vital organ of the human body, and it has been shown now in over 25,000 patients [37, 39, 82, 83] that higher compliance yields better survival, less delirium and coma, shorter lengths of stay, less icu bounce-back, and lower cost of care. implementation at the bedside of excellent delirium prevention and management should be a priority during the covid-19 pandemic [84, 85] . although regarded as a priority, in intubated, deeply sedated patients, assessment and management require the use of behavioral pain scales that may at first glance seem burdensome for strained healthcare workers but which will ultimately provide the most humane care and help reduce ptsd. regular pain assessment (nrs, cpot/bps)-especially in prone position. provide adequate pain management, identify uncommon sources of pain. consider development of peripheral neuropathies from viral invasion of peripheral nerves and picsrelated complications. stopping both sedation and the ventilator to conduct daily spontaneous awakening trials and spontaneous breathing trials is essential. these will not be possible during paralysis in proned patients, which creates a serious risk-benefit choice of this modality of patient positioning that argues for the shortest duration possible. precautions for early extubation must be used to lower the spread of aerosol for patients who need nmbd infusion (paralyzed patients)-monitor nmb depth and shorten duration whenever possible. regularly assess patients with both sbt and sat daily. sometimes, deep sedation may be necessary, especially when using nmbd, when providing high peep, and when prone positioning is implemented. gaba-agonist propofol is likely the best choice during proning, but this can be shortened via daily questioning of the necessity of this management approach assess with rass/sas regularly. adjust sedation to ventilation needs-priority lies in effective ventilation (rass-4 for prone position). as soon as possible, discontinue potent sedatives or use those agents that do not suppress the respiratory drive such as intermittent use of antipsychotics or alpha-2 agonists. remember prolonged ventilation is associated with poor outcomes. hyperactive delirium and agitation can be a source of intra-hospital cross-infection, especially in agitated patients or during non-invasive ventilation (if used, not recommended). hypoactive delirium is likely to be missed if not monitored for using a validated instrument routinely. thus, patients may not receive appropriate attention to delirium prevention mechanisms. provide regular delirium screening (cam-icu, icdsc). provide usual non-pharmacological interventions: (1) orientation is a priority, because patients see healthcare wearing personal protective equipment; (2) support for senses (hearing aids/glasses); (3) monitor taste/ smell failure due to cov predilection to olfactory nerves (anosmia may be an early sign). limit the use of cns-active medications to agitated patients. when cam-icu or icdsc positive, use the dr. dre mnemonic to consider chief delirium risks: diseases (new nosocomial infections, acquired heart failure); drug removal, stop all unnecessary psychoactive medications, be on the lookout for withdrawal if the patient was on a prolonged course of sedatives; environment, maximize sleep, orientation to other humans, minimize sensory deprivation. e early mobility physiotherapy may be very limited due to heavy workload and epidemiologic precautions; infusion of nmbd may be necessary. physiotherapy must be adjusted to heavy workload and epidemiologic precautions. use passive physiotherapy interventions during the infusion of nmbd. limited or no family presence during the pandemic due to quarantine and social distancing. a major issue for elderly and as end-of-life problem. orientate both patients and family regularly, provide phone conversations and video conferences, use technology devices, headphones, and tele-medicine tools. provide visual and vocal contact with the family/ caregivers/friends, especially for all dying patients despite isolation, lack of time, and heavy workload. bps behavioral pain scale, cam-icu cognitive assessment method for intensive care unit, cns central nervous system, cov coronavirus, cpot critical pain 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affiliations key: cord-313914-m09lw0i4 authors: li, chenglong; hou, xiaotong; tong, zhaohui; qiu, haibo; li, yimin; li, ang title: extracorporeal membrane oxygenation programs for covid-19 in china date: 2020-06-08 journal: crit care doi: 10.1186/s13054-020-03047-6 sha: doc_id: 313914 cord_uid: m09lw0i4 nan the outbreak of coronavirus disease (covid-19) was first reported in wuhan, the capital city of hubei province, and may lead to severe pneumonia and acute respiratory distress syndrome (ards). extracorporeal membrane oxygenation (ecmo), as a temporary life support technique for refractory respiratory or cardiac failure, has been applied in covid-19 patients [1] . however, the impact of ecmo on outcomes from covid-19 was controversial. referring to the present case series and the covid-19 cohort in china, the mortality of patients undergoing ecmo ranged from 42 to 83% [2, 3] . the chinese society of extracorporeal life support (csecls) performed a survey of ecmo programs for covid-19 in china, aimed at investigating the program organization and the potential factors associated with outcomes during the pandemic. this voluntary survey was disseminated via e-mail and wechat to 365 ecmo programs registered with the csecls on march 23, 2020. through march 29, we had received 350 individual responses from 270 (74.0%) ecmo programs in total. when analyzing program characteristics, the program directors' or coordinators' responses were adopted. one hundred eleven individual responses from 79 ecmo programs (30 in hubei and 49 outside hubei) applied ecmo in patients with covid-19 pneumonia and ards were analyzed. respondents included those located in 25 provinces within china before covid-19 outbroke. twenty-seven respondents belonged to the medical assistance teams which were dispatched to aid hubei and 39 respondents aided other hospitals in their original province, while 45 respondents managed covid-19 patients with ecmo within their original hospitals. fifty-one of 79 ecmo programs (15 in hubei and 36 outside hubei) were organized temporarily in response to the crisis. thirty-two hospitals with temporary ecmo programs did not have any ecmo cases before. the geographic distribution of the 79 ecmo programs and responders' aid to hubei is shown in fig. 1 . patient management characteristics are illustrated in table 1 . compared with ecmo programs in hubei, more programs outside hubei initiated ecmo in older patients (36.7% vs 3.3% in age ≥ 75, p = 0.001; 55.1% vs 26.7% in age 65-74, p = 0.014). our findings provide evidence of the current condition of ecmo programs for covid-19 across china. fifty-one ecmo programs were newly organized. it was most efficient to rearrange medical workers and resources rather than starting new ecmo programs amid the crisis, given that inexperienced ecmo programs and hospitals might lead to unfavorable outcomes. since ecmo is a complicated and highrisk therapy, adequate training and high-volume experience are indispensable [4] . we also found a difference in age between ecmo patients in hubei and outside hubei. seventy-five percent of covid-19 cases in china were diagnosed in hubei [5] . with limited medical resources in hubei, patients with a higher likelihood of survival were chosen to receive ecmo, namely younger patients. however, medical resources were adequate outside hubei. that might be the main reason for more ecmo programs outside hubei applied ecmo in older patients (age > 65), aiming at minimizing the local mortality of covid-19. age is a key driver of mortality, helping clinicians to select the most appropriate candidates for ecmo among severe ards patients [6] . however, age should be reconsidered in the discussions of indications for ecmo in covid-19. to the limitation, the patient's detailed characteristic was not obtained in the present study. further multicenter registry on covid-19 patients receiving ecmo support would be performed. to summarize, our large national survey provided detailed information regarding the organization of ecmo programs for covid-19 in china. to improve outcomes with ecmo during the pandemic, it is key to provide information about ecmo experience, patient selection, and resource allocation to ecmo programs throughout the world. the datasets used in the present study are available from the first author and corresponding authors on reasonable request. ethics approval and consent to participate institutional ethics oversight was considered unnecessary since the present study was a voluntary survey. not applicable. preparing for the most critically ill patients with covid-19: the potential role of extracorporeal membrane oxygenation clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study prognosis when using extracorporeal membrane oxygenation (ecmo) for critically ill covid-19 patients in china: a retrospective case series association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. analysis of the extracorporeal life support organization registry characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-286963-rsmgx2xr authors: choi, yoon hee; lee, dong hoon; oh, je hyeok; wee, jung hee; jang, tae chang; choi, seung pill; park, kyu nam title: renal replacement therapy is independently associated with a lower risk of death in patients with severe acute kidney injury treated with targeted temperature management after out-of-hospital cardiac arrest date: 2020-03-23 journal: crit care doi: 10.1186/s13054-020-2822-x sha: doc_id: 286963 cord_uid: rsmgx2xr background: the effect of renal replacement therapy (rrt) on the outcomes of severe acute kidney injury (aki) after out-of-hospital cardiac arrest (ohca) is uncertain. this study aimed to evaluate the association of rrt with 6-month mortality in patients with severe aki treated with targeted temperature management (ttm) after ohca. methods: this was a retrospective analysis of a prospectively collected multicentre observational cohort study that included adult ohca patients treated with ttm across 22 hospitals in south korea between october 2015 and december 2018. aki was diagnosed using the kidney disease: improving global outcomes criteria. the primary outcome was 6-month mortality and the secondary outcome was cerebral performance category (cpc) at 6 months. multivariate cox regression analysis was performed to define the role of rrt in stage 3 aki. results: among 10,426 patients with ohca, 1373 were treated with ttm. after excluding those who died within 48 h of return of spontaneous circulation (rosc) and those with pre-arrest chronic kidney disease, our study cohort comprised 1063 patients. aki developed in 590 (55.5%) patients and 223 (21.0%) had stage 3 aki. among them, 115 (51.6%) were treated with rrt. the most common treatment modality among rrt patients was continuous renal replacement therapy (111 [96.5%]), followed by intermittent haemodialysis (4 [3.5%]). the distributions of cpc (1–5) at 6 months for the non-rrt vs. the rrt group were 3/108 (2.8%) vs. 12/115 (10.4%) for cpc 1, 0/108 (0.0%) vs. 1/115 (0.9%) for cpc 2, 1/108 (0.9%) vs. 3/115 (2.6%) for cpc 3, 6/108 (5.6%) vs. 6/115 (5.2%) for cpc 4, and 98/108 (90.7%) vs. 93/115 (80.9%) for cpc 5, respectively (p = 0.01). the rrt group had significantly lower 6-month mortality than the non-rrt group (93/115 [81%] vs. 98/108 [91%], p = 0.04). multivariate cox regression analyses showed that rrt was independently associated with a lower risk of death in patients with stage 3 aki (hazard ratio, 0.569 [95% confidence interval, 0.377–0.857, p = 0.01]). conclusion: dialysis interventions were independently associated with a lower risk of death in patients with stage 3 aki treated with ttm after ohca. acute kidney injury (aki) develops frequently after out-of-hospital cardiac arrest (ohca) and is associated with long-term mortality and poor neurological outcomes [1] [2] [3] [4] [5] [6] [7] [8] . similar to critically ill patients, increased aki severity is associated with increased mortality in ohca patients [2, 4, 9] . in contrast, recovery from aki was a potent predictor of survival and good neurological outcome at discharge [5] . mortality rates of patients with stage 3 aki after ohca are reported to be over 70% [2, 3] . although renal replacement therapy (rrt) is a treatment option for these patients, its impact on outcomes is uncertain. we hypothesised that applying rrt would be associated with better outcomes in patients who develop severe aki after ohca. two recent studies evaluated the effect of rrt on cardiac arrest outcomes [10, 11] . however, these studies did not show a risk reduction in patients receiving rrt. on the contrary, one of them reported a significant increase in mortality among patients receiving rrt [11] . the two studies did not consider aki stage in their comparison of outcomes in patients with and without rrt. because all patients who received rrt had stage 3 aki, the risk of death in the rrt group was higher than that in the non-rrt group. therefore, this study evaluated whether dialysis interventions had an impact on the outcomes of patients with stage 3 aki after ohca who were treated with targeted temperature management (ttm). this was a retrospective analysis of the prospectively collected multicentre observational cohort study. data were collected from the korean hypothermia network (korhn) prospective registry (korhn-pro) between october 2015 and december 2018. the korhn is a multicentre clinical research consortium for ttm in south korea. in total, 22 academic hospitals participated in the korhn-pro. all adult patients (≥ 18 years) with ohca, regardless of the cause of arrest, who were unconscious (glasgow coma scale score < 8) after the return of spontaneous circulation (rosc) and treated with ttm, were enrolled in the registry. patients with active intracranial bleeding, acute stroke, known limitations in therapy and do-notattempt resuscitation order, known pre-arrest cerebral performance category (cpc) 3 or 4, known disease making 6-month survival unlikely, and body temperature < 30°c on admission were excluded. enrolled patients received care for post-cardiac arrest syndrome (pcas) according to standard operating procedures regarding ohca at each hospital. the principal investigator of each participating hospital collected data from the hospital records of ohca survivors treated with ttm. using a telephone survey, the independent data input committee investigated the survival and neurological status 6 months after rosc. if patients died before 6 months, the death date was recorded. the primary outcome was 6-month mortality and the secondary outcome was cpc at 6 months. we examined the following variables: age, sex, body weight, medical history (hypertension, heart failure, diabetes mellitus), arrest location (home, workplace, street, public building, nursing home, unknown), witnessed arrest, bystander cardiopulmonary resuscitation (cpr), time from collapse to cpr, time from cpr to rosc, epinephrine dose, initial rhythm assessed by emergency medical service personnel in the field (ventricular fibrillation, pulseless ventricular tachycardia, pulseless electrical activity, asystole, unknown shockable, unknown non-shockable, unknown), arrest cause (medical or unknown, trauma, submersion, drug overdose, asphyxia, hanging), post-rosc lactate, post-rosc shock (cardiovascular sequential organ failure assessment score ≥ 1 on day 1), targeted temperature of ttm (33 or 36°c), duration of ttm (24 or [crrt] or intermittent haemodialysis), rrt initiation time, reasons for initiating/terminating rrt, dialysis dependence at discharge, and serum creatinine (scr). the korhn-pro required input of data on scr daily until 7 days after rosc. if the scr was checked twice or more in 1 day, the highest value was collected in the registry. we defined aki based on the diagnostic criteria stipulated in the kidney disease: improving global outcomes (kdigo) guidelines [12] . because we did not have data on patients' prior kidney function, we used the "modification of diet in renal disease study" formula for glomerular filtration rate (gfr) to estimate baseline scr using the lower end of the normal range of gfr [13] . after estimating baseline scr, we determined whether the patients had an aki and subsequently classified them into aki stages. a patient was defined as having aki if one of the scr measurements during the 7-day period was ≥ 150% of the baseline scr or if the scr increased ≥ 0.3 mg/dl within a 48-h interval during the 7-day period. once aki status was determined, aki staging was performed. a 150-199%, 200-299%, and ≥ 300% increase from baseline scr in one of the scr measurements during the 7-day period was defined as stage 1, 2, and 3 aki, respectively. regardless of fulfilling these criteria, patients were defined as developing stage 3 aki when scr increased ≥ 4.0 mg/dl or rrt was initiated. we could not use the criteria for hourly urine output because data on hourly urine output were not collected in the registry. descriptive statistics are reported as median (interquartile range) or mean ± standard deviation for continuous variables according to the normality of distribution. data normality was analysed using shapiro-wilk test or kolmogorov-smirnov test. categorical variables are reported as frequency (percentage). demographics and clinical differences between groups were assessed using pearson's chi-squared test, fisher's exact test, independent sample t-test, or mann-whitney u test, as appropriate. we performed multivariate cox regression analysis to calculate the hazard ratio (hr) and 95% confidence interval (ci) of rrt with respect to mortality and to find independent factors associated with risk of death. all variables were entered into a multivariate cox regression analysis. differences in kaplan-meier survival curves between rrt and non-rrt groups were compared using the log-rank test. a p value < 01.05 was considered statistically significant. statistical analyses were performed using ibm spss version 25.0 (ibm corp., armonk, ny, usa). out of 10,426 patients with ohca that were screened during the study period, 1373 were treated with ttm at 22 academic hospitals throughout south korea (fig. 1) . we excluded the patients who died within 48 h of rosc to minimise competing risk, those with pre-arrest chronic kidney disease or end-stage renal disease, and those with incomplete data such as scr, survival, or neurological status at 6 months. in total, 1063 patients were enrolled in the study cohort. the baseline characteristics of stage 3 patients with aki according to rrt status and outcomes are summarised in tables 1 and 2 . the time to achieve aki stage 3 in patients with rrt was 1 (1-2) day, and the time to achieve aki stage 3 in patients without rrt was 3 (2-4) days. average scr values from day 1 to 7 following rosc is provided in the supplementary material (see additional file 1, table s1 ). the overall 6-month mortality of all enrolled patients (entire cohort, n = 1063) was 541/1063 (50.9%). the 6-month mortality of the non-rrt group in the entire cohort was significantly lower than that of the rrt group (448/948 [47.3%] vs. 93/115 [80.9%], p < 0.001) (fig. 2) . in case of patients with aki (aki cohort, n = 590), 6-month mortality was 380/590 (64.4%). the 6-month mortality of the non-rrt group in aki cohort also was significantly lower than that of the rrt group (287/475 [60.4%] vs. 93/115 [80.9%], p < 0.001). however, in patients with stage 3 aki (stage 3 aki cohort, n = 223), the 6-month mortality of the non-rrt group was significantly higher than that of the rrt group (98/108 [90.7%] vs. 93/115 [80.9%], p = 0.04) ( table 2 ). the kaplan-meier survival curves differed significantly between the non-rrt and rrt groups in these cohorts (p = 0.003) (fig. 3 ). factors associated with 6-month mortality in patients with stage 3 aki in the multivariate cox regression analysis, four variables, namely, body weight, hypoglycaemia, re-arrest, and rrt, were independently associated with risk of death in patients with stage 3 aki (table 3 ). the hr of rrt was 0.569 (95% ci, 0.377-0.857, p = 0.01). the distributions of cpc (1-5) at 6 months for the non-rrt vs. rrt groups were 3/108 (2.8%) vs. 12 until recently, there was limited evidence on the use of rrt in ohca patients. although aki frequently occurs after ohca, the recent guidelines did not comment on the role of rrt during pcas because of insufficient data [1-8, 14, 15] . in this multicentre cohort of severe aki after ohca treated with ttm in south korea, we found that the 6-month mortality of the rrt group was significantly lower than that of the non-rrt group. moreover, dialysis intervention was associated with lower 6-month mortality in the multivariate cox regression analysis. in previous studies, the mortality of the rrt group was not lower than that of the non-rrt group [3, 4, 10, 11] . winther-jensen et al. reported that the 30-day mortality of a rrt group was significantly higher than that of a non-rrt group in the cohort of ohca patients [11] . however, beitland et al. reported that the 6-month mortality of a rrt group was not different from that of a non-rrt group in the cohort of patients with aki after ohca [4] , and geri et al. reported that there were no differences between the rrt and non-rrt groups in a cohort of patients with stage 3 aki [3] . considering those results, we compared the mortality between the non-rrt and rrt groups in the different cohorts (all enrolled patients, patients with aki, and stage 3 patients with aki). interestingly, although the 6-month mortality of the rrt group was significantly higher than that of the non-rrt group in the cohorts of all enrolled patients and patients with aki, the result was reversed in the cohort of patients with stage 3 aki (fig. 2) . this might be a promising result for nephrologists and intensive care practitioners and implies the need for rrt in patents with stage 3 aki after ohca treated with ttm. however, many factors should be considered in evaluating the results of the current study. first, there were differences in the baseline characteristics of the study cohorts between the present study and previous ones (e.g., age, male sex, witnessed arrest, bystander cpr, time from cpr to rosc, and shock after rosc) [3, 4, 10, 11] . second, there are insufficient data to determine absolute indications and the optimal timing for initiation of rrt. moreover, some clinicians tend to delay rrt when they suspect that patients may recover on their own and because of well-known risks of rrt itself, including hypotension, arrhythmia, membrane bioincompatibility, vascular access, and anti-coagulant administration [16] . as a result, the initiation of rrt is extremely variable and based primarily on empiricism and local institutional practice and resources [17] . therefore, it will be difficult to determine whether to provide rrt based only on whether the patient developed stage 3 aki after ohca. the aki network stated that the indications for rrt must be viewed within the context of the patient's entire clinical condition with most indications being relative; there are only a small number of absolute indications [17] . third, the 6-month mortality of those in the rrt group with stage 3 aki was extremely high in the present study. moreover, a longer cpr time, lower ratio of shockable rhythm, and higher ratio of shock may underlie the high mortality in our cohort. in addition, a longer cpr time and lower ratio of shockable rhythm may underlie the higher ratio of shock in our cohort. therefore, a large-scale multinational, multicentre study or randomised controlled trial will be needed to confirm the exact effect of rrt on the mortality after ohca because of extremely high mortality in those with stage 3 aki. in case of critically ill patients, the overall in-hospital mortality in patients with aki on dialysis consistently decreased, and the mortality of those with aki on dialysis was relatively lower than that of the rrt group with ohca; this is because outcomes associated with ohca remain poor [18] . contrary to the present study, some previous studies reported that the rrt was a risk factor for mortality even after correction for disease severity in case of critically ill patients, and the mortality of patients receiving rrt increased in the long-term follow-up over an 8year period [19, 20] . differences in disease severity, limits to defining disease severity accurately, and variability in selecting rrt could have contributed to the different results. additional data from well-designed table 3 factors associated with 6-month mortality in patients who developed stage 3 acute kidney injury after an out-of-hospital cardiac arrest observational studies will be needed to clarify the longterm mortality of rrt group after ohca. dialysis interventions were initiated within 48 h of rosc in most cases, and the most common modality was crrt. this may have been due to the high rate of shock after rosc. these results are compatible with current standards because crrt is recommended as the initial rrt modality [21] . a higher frequency of bleeding in the rrt group may have been caused by complications during the insertion of the dual-lumen haemodialysis catheter ( table 1 ). the ratio of dialysis dependence in our cohort was similar to that in a cohort of critically ill patients [20] . the distribution of cpc was significantly different according to the status of rrt (table 2) . although only 32 patients with stage 3 aki survived over 6 months, the high ratio of cpc 1 in the rrt group might suggest a beneficial effect of rrt. further studies will be needed to verify the role of rrt on neurological outcomes after ohca. although old age and initial non-shockable rhythm were risk factors for developing aki after ohca, age and differences in the initial rhythm between the non-rrt and rrt groups were not associated with 6-month mortality in the multivariate cox regression analysis [1] . instead, body weight, hypoglycaemia/re-arrest event within 7 days since rosc, and rrt were associated with 6-month mortality. interestingly, it was previously reported that overweight was associated with higher survival rate and a better neurological outcome after cardiac arrest [22] . overweight per se might act protectively after cardiac arrest because of a better nutritive state compared with that of underweight. however, obesity is a well-known risk factor for aki and mortality in critical illness [23] . as a result, an increase in body weight could act as a risk factor in our cohort of stage 3 aki. hypoglycaemia and re-arrest events were associated with poor outcome after cardiac arrest [24, 25] . therefore, our results are compatible with previous studies. the present study has several limitations. first, because we defined aki using only scr criteria, it is possible that we underestimated aki prevalence in our cohort. in the case of critically ill patients, the production of scr decreases. additionally, a decrease in scr could be potentiated by therapeutic hypothermia [26] . therefore, an exact judgement on aki status is difficult in the case of individuals treated with therapeutic hypothermia. in addition, differences in urine output and fluid balance are likely to have influenced the decision to start rrt. however, data on urine output at rrt initiation and fluid balance could not be evaluated in our cohort. second, the present study was a retrospective analysis of prospectively collected observational data that did not include information on standardised treatments or management protocols for rrt. therefore, the risk of selection bias could have been introduced. third, the initiation of rrt in our study was at the discretion of the physician responsible for the patient's care according to the kdigo guideline (e.g., severe hyperkalaemia, severe acidosis, pulmonary oedema, and uremic complication). there were no consistent protocols dictating when to initiate rrt, which might have led to inconsistencies in practices among the principal investigators of each institution. a randomised controlled trial of rrt on patients with stage 3 aki is needed to confirm the role of rrt. fourth, there was a possibility of failure to conduct rrt even if urgent rrt was indicated because of the decision on withdrawal of life-sustaining therapy according to the neurological prognostication. however, in south korea, the withdrawal of life-sustaining therapy depending on the neurological prognostication has not been used widely because of several reasons. for instance, the life-sustaining treatment decisions act was only applied recently in south korea (since february 2018). in addition, legal surrogates, including family members, could not determine withdrawal of lifesustaining therapy, especially stopping the ventilator or removing the endotracheal tube owing to traditional sentiment. therefore, we expect that decisions regarding withdrawal of life-sustaining therapy may not affect the initiation of rrt. however, there was a possibility that rrt may be stopped when a poor neurological outcome or death was expected through the treatment course, as the cost for rrt (especially continuous rrt) is quite expensive in south korea (approximately €400 per day). fifth, in the cohort of rrt (n = 115), 80 patients were diagnosed as achieving stage 3 aki by initiating rrt itself (group a) and 35 patients were diagnosed as achieving stage 3 aki based on scr (group b). although the initiation of rrt was not determined by conditions other than scr in most cases, daily scr of group b was significantly higher than that of group a (see additional file 1, table s2 ). therefore, it may be possible to compare patients reaching the aki stage 3 by non-creatinine criteria with patients reaching the aki stage 3 by creatinine criteria. the sixth limitation is that the results of the present study may have been affected by the characteristics of our study cohort. therefore, the results might not be reproducible in another cohort with different characteristics. fifth, although we excluded the patients who died within 48 h from the time of rosc initiation to decrease problems related to competing risk, excluding these patients itself may have introduced bias. dialysis interventions were independently associated with a lower risk of death in patients with stage 3 aki treated with ttm after ohca. acute kidney injury after cardiac arrest: a systematic review and meta-analysis of clinical studies korean hypothermia network i. association between acute kidney injury and neurological outcome or death at 6months in out-of-hospital cardiac arrest: a prospective, multicenter, observational cohort study acute kidney injury after out-ofhospital cardiac arrest: risk factors and prognosis in a large cohort impact of acute kidney injury on patient outcome in out-of-hospital cardiac arrest: a prospective observational study recovery from acute kidney injury as a potent predictor of survival and good neurological outcome at discharge after out-of-hospital cardiac arrest acute kidney injury after cardiac arrest impact of acute kidney injury on neurological outcome and long-term survival after cardiac arrest -a 10year observational follow up acute kidney injury and mild therapeutic hypothermia in patients after cardiopulmonary resuscitation -a post hoc analysis of a prospective observational trial epidemiology of acute kidney injury in critically ill patients: the multinational aki-epi study in-hospital survival and neurological recovery among patients requiring renal replacement therapy in post-cardiac arrest period use of renal replacement therapy after out-of-hospital cardiac arrest in denmark section 2: aki definition acute dialysis quality initiative w: acute renal failure -definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (adqi) group european resuscitation council guidelines for resuscitation 2015: section 7. resuscitation and support of transition of babies at birth american heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care section 5: dialysis interventions for treatment of aki timing of initiation and discontinuation of renal replacement therapy in aki: unanswered key questions temporal change in characteristics and outcomes of acute kidney injury on renal replacement therapy in intensive care units: analysis of a nationwide administrative database in japan devriendt j, investigators s: renal replacement therapy is an independent risk factor for mortality in critically ill patients with acute kidney injury long-term outcome in icu patients with acute kidney injury treated with renal replacement therapy: a prospective cohort study effects of renal replacement therapy on renal recovery after acute kidney injury association between body mass index and clinical outcomes of patients after cardiac arrest and resuscitation: a meta-analysis obesity, acute kidney injury, and mortality in critical illness factors associated with re-arrest following initial resuscitation from cardiac arrest adverse events associated with poor neurological outcome during targeted temperature management and advanced critical care after out-of-hospital cardiac arrest the effect of mild therapeutic hypothermia on renal function after cardiopulmonary resuscitation in men publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-2822-x.additional file 1: supplementary material. table s1 . average serum creatinine values from days 1 to 7 according to the cohort. table s2 .comparisons of daily serum creatinine values between patients who were diagnosed with stage 3 acute kidney injury by initiating renal replacement therapy itself (group a) and patients who were diagnosed with stage 3 acute kidney injury by serum creatinine value (group b) in patients undergoing renal replacement therapy. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. the study design and plan, including the informed consent form, were approved by the institutional review board of each hospital. in accordance with national requirements and the principles of the declaration of helsinki, written informed consent was obtained from all patients' legal surrogates. not applicable. the authors declare that they have no competing interests.author details key: cord-270298-zv0t3d0m authors: bouch, christopher; williams, gareth title: recently published papers: pulmonary care, pandemics, and eugenics in surviving sepsis? date: 2006-02-01 journal: crit care doi: 10.1186/cc4820 sha: doc_id: 270298 cord_uid: zv0t3d0m respiratory failure is one of the leading admission diagnoses on the critical care unit, and the journals have reflected this over the past few months. an understanding of the aetiology of pulmonary sepsis is important but your choice of ventilator gas humidification system is not. there are prophecies of more pandemics, but panic is futile because survival is all down to your genes. health-care-associated pneumonia (hcap) refers to a pulmonary infection that develops in individuals recently hospitalised, or undergoing renal replacement therapy or other long-term out-patient care. over the past few years it has been postulated that this reflects a distinct group of pathogens with consequent implications for therapy and also on outcome. however, no study had looked at the pathogens of both hcap and community-acquired pneumonia (cap) and compared them with those of hospital-acquired pneumonia (hap) and ventilator-associated pneumonia (vap). kollef et al. [1] have attempted to do this by retrospective analysis of a large usa database of culture-positive pneumonia, in 59 us centres over a 1-year period. the study defined 4,543 positive pneumonias, of which 2,221 were cap, 988 hcap, 853 hap and 499 vap. the results showed that patients with hcap were slightly older than those with cap but were broadly similar to those with hap. half of the patients with hcap came from nursing homes. illness severity was almost identical in both hcap and vap, but was higher than in hap and cap. bacterial pathogen identification showed a high rate of staphylococcus aureus infection in all types of pneumonia but this may be an artefact; however, also of interest was the low rate of pneumococcal infection in cap. overall, bacterial species in hcap were broadly similar to those in hap and vap; pseudomonas accounted for just over 25% and methicillin-resistant s. aureus 56%, with the rest made up of the usual gram-negative types. it was also noted that patient mortality for hcap was similar to that for hap but higher than that for cap and lower than that for vap. the authors suggest that hcap is a distinct entity from cap and should be treated as a hospital-acquired type of infection from first presentation; the paper certainly supports the recently published guidelines from the american thoracic society [2] . staying with the pulmonary sepsis theme, lacherade et al. [3] shed further light on the debate over which factors may influence the development of vap, in particular the use of differing humidification devices. this five-centre prospective trial randomised 369 unselected patients who had required ventilation for more than 48 hours, to receive treatment with either a heated humidifier or a heat and moisture exchanger during their stay. they showed no difference between the treatments in incidence of vap. given previous data on this subject it increasingly appears that the mode of respiratory gas humidification is not critical. the optimal specimen collection technique for the diagnosis of vap continues to be strongly debated. the paper by brun-buisson et al. [4] looked at 68 patients with clinically apparent vap and prospectively performed blinded endotracheal aspiration, blinded protected telescoping aspiration (ptc) and bronchoscopic aspiration. their results confirmed that bronchoscopic aspiration provides the best cultures with fewer false positives, with ptc being close behind. however, endotracheal aspiration produced more false positives. this means that the use of ptc can be used to obtain specimens for the diagnosis of vap and to guide therapy, and avoids the need for a more invasive procedure and expensive equipment. finally on the respiratory theme, the role of non-invasive ventilation (niv) makes another appearance [5] . this paper commentary compared the role of niv with mechanical ventilation for patients with acute respiratory failure from all causes who fulfilled defined criteria for conventional mechanical ventilation (cmv). a total of 64 patients were randomised, 31 to niv and 33 to cmv, with 18 in the niv group converting to cmv. the mortality rate in the niv group was 23%, compared with 39% in the cmv group; complication rates and durations of ventilation were similar. they also showed that patients who did not respond to niv did no worse overall than those who received cmv from the start, and of interest is the finding that all patients with pneumonia who underwent niv required cmv, a finding consistent with other studies. as identified in the accompanying editorial [6] , the study numbers are small, particularly given the all-cause inclusion criteria and as such interpretation of results should be cautious. the world recently seems to be an ever more dangerous place, with increasing reason to be troubled by apocalyptic nightmares. there is a superbug near you -be quite sure of itand it will probably try to kill you given half a chance. methicillin/vancomycin-resistant s. aureus, severe acute respiratory syndrome, pandemic and avian influenza have dominated both the medical and lay press. the antecedents of these organisms are well known to us, but it seems they have started taking steroids and going to the gym a lot. there is now mounting evidence that clostridium difficile has undergone a similar process. c. difficile, a spore-forming gram-positive anaerobic bacillus, has been recognised as the causative agent of an antibiotic-associated colitis since the mid-1970s. given appropriately altered colonic flora this bacterium will replicate and produce endotoxins (classically a and b) causing a spectrum of disease from troublesome watery diarrhoea to life-threatening pseudomembranous colitis, depending largely on host characteristics such as age and severity of underlying disease, therefore making its incidence on the intensive care unit particularly high. furthermore, outbreaks were largely isolated to individual wards or institutions. however, in recent years much larger outbreaks in both north america and europe have suggested increased prevalence, resistance and virulence of c. difficile. this raises the ugly spectre of an epidemic strain, and leads us to ask why this has occurred, whether it is spontaneous genetic mutation or a change in medical practice, and whether we can do anything about it. two recently published papers with an accompanying editorial address some of these issues [7] [8] [9] . the work of mcdonald et al. [7] consists of an impressively detailed microbiological survey of c. difficile outbreaks across six states in the united states. genetic and toxicological profiles were compared with those from a historical database of c. difficile obtained before 2001. in the second paper a research group in quebec [8] performed a prospective surveillance of 12 institutions to determine the incidence of hospital-acquired c. difficile-associated diarrhoea and its associated risk factors. isolates were also typed. the results from the two studies were largely corroborative: 1. a previously uncommon strain of c. difficile has markedly increased in incidence. 2. it is characterised by the production of a new toxin (binary toxin), a partial deletion of the tcdc gene, which normally downregulates toxin a and b production, and increased resistance to fluoroquinolones. 3. morbidity and mortality, particularly among the elderly, are increasing compared with outbreaks in the 1980s and 1990s. 4. risk factors include exposure to fluoroquinolones and cephalosprins. a precise scientific link between the suggested virulence factors (binary toxin and tcdc partial deletion) and severity of disease is yet to be made. but the emergence of this relatively new strain of c. difficile concomitant with increased severity and prevalence of disease must be a cause for concern. in answer to the question 'what can we do?' the accompanying editorial [9] suggests that the following are essential: 1. continued microbiological surveillance of disease outbreaks, along with early diagnosis and treatment. 2. scrupulous infection control practice, above and beyond the normal, by all in contact with at risk patients. 3. the use of soap and water for hand washing given spore resistance to alcohol preparations. 4. regular institutional review of antimicrobial stewardship, with early de-escalation of broad-spectrum antibiotics wherever possible. finally, presuming that you have kept up with the lancet recently, you will be hoping that your mitochondrial dna is of the haplogroup h variety. a group in newcastle analysed mitochondrial dna in 150 sequential adult admissions to the intensive care unit with a diagnosis of severe sepsis, the primary outcome measure being survival at 180 days [10] . using logistical regression analysis they demonstrated that haplogroup h was an independent predictor of survival, patients with haplogroup h being 2.12 (95% confidence interval 1.02 to 4.43) times more likely to be alive at 180 days. the authors propose that this finding might be explained by the enhanced respiratory chain activity associated with this haplotype, citing cellular dysoxia secondary to mitochondrial dysfunction as a key factor in sepsis-induced organ dysfunction. interestingly, haplogroup h patients generated significantly higher temperatures than patients with differing haplogroups. fortunately, h is the commonest haplogroup, accounting for about 44% of patients in this study. the authors suggest that mitochondrial dna haplotyping offers a new means of risk stratification in severe sepsis, although further work is clearly needed to identify possible therapeutic avenues. the author(s) declare that they have no competing interests. epidemiology and outcomes of health-care-associated pneumonia: results from a large us database of culture positive pneumonia guidelines for the management of adults with hospital acquired, ventilator associated and healthcare-associated pneumonia impact of humidification systems on ventilator associated pneumonia contribution of blinded, protected quantitative specimens to the diagnostic and therapeutic management of ventilator associated pneumonia noninvasive vs conventional mechanical ventilation in acute respiratory failure: a multicenter, randomised controlled trial non-invasive ventilation for acute respiratory failure: but how severe? chest an epidemic, toxin gene-variant strain of clostridium difficile a predominantly clonal multi-institutional outbreak of clostridium difficile-associated diarrhea with high morbidity and mortality the new clostridium difficile -what does it mean? mitochondrial dna and survival after sepsis: a prospective study key: cord-003870-hr99dwi7 authors: clohisey, sara; baillie, john kenneth title: host susceptibility to severe influenza a virus infection date: 2019-09-05 journal: crit care doi: 10.1186/s13054-019-2566-7 sha: doc_id: 3870 cord_uid: hr99dwi7 most people exposed to a new flu virus do not notice any symptoms. a small minority develops critical illness. some of this extremely broad variation in susceptibility is explained by the size of the initial inoculum or the influenza exposure history of the individual; some is explained by generic host factors, such as frailty, that decrease resilience following any systemic insult. some demographic factors (pregnancy, obesity, and advanced age) appear to confer a more specific susceptibility to severe illness following infection with influenza viruses. as with other infectious diseases, a substantial component of susceptibility is determined by host genetics. several genetic susceptibility variants have now been reported with varying levels of evidence. susceptible hosts may have impaired intracellular controls of viral replication (e.g. ifitm3, tmprs22 variants), defective interferon responses (e.g. gldc, irf7/9 variants), or defects in cell-mediated immunity with increased baseline levels of systemic inflammation (obesity, pregnancy, advanced age). these mechanisms may explain the prolonged viral replication reported in critically ill patients with influenza: patients with life-threatening disease are, by definition, abnormal hosts. understanding these molecular mechanisms of susceptibility may in the future enable the design of host-directed therapies to promote resilience. the normal response to infection with influenza a virus (iav) is to remain asymptomatic. during the 2009/2010 pandemic, serosurveillance studies revealed that a majority of volunteers who tested positive for antibodies to the new h1n1pdm09 virus did not report any symptoms [1] . the majority of people newly exposed to one of the most dangerous viruses to circulate in human populations in recent history, which in the same population created an overwhelming burden of critical illness [2] , did not notice any symptoms. wide variation in susceptibility is a general feature of human and animal populations exposed to any pathogen [3] . explaining the mechanisms of susceptibility may enable effective targeting of vaccine therapies, may reveal new therapeutic approaches [4, 5] , and, in theory, may contribute to future clinical risk prediction models. as with any infectious disease in a given host, the site of infection, the scale of the initial exposure, and the virulence, degree of pathogenicity, of the pathogen determine the nature of the disease in iav infection. although the alimentary tract is a common site of infection in other species (for example the natural hosts, water fowl [6] ), initial infection in humans is through the respiratory tract. the number of viable iav virions transmitted has a direct effect on the probability of symptoms, both in animal models [7] and human challenge studies [8] . this may explain a proportion of the variation in individual responses to the virus. the virulence of the virus itself varies greatly. perhaps fortunately, there is a general trend for the most virulent iav strains to be less transmissible; that is, those that cause the most severe disease are less likely to be passed on to others. while highly transmissible iav strains, such as h1n1pdm09, replicate well in the upper respiratory tract, viruses associated with higher rates of severe disease, such as h5n1 and h7n9 avian iav, exhibit tropism for the lower respiratory tract [9, 10] . within a given strain, not all iav viruses are the same. in fact, it is statistically unlikely that any two iav virus particles will have exactly the same genome sequence. small changes, such as a single amino acid change in the hemagglutinin protein, can significantly alter the tropism of the virus for example, increasing the likelihood of spread to the lower respiratory tract and establishing a more severe infection [11] . iav viruses change rapidly by two mechanisms: shift and drift. shift is the exchange of viral segments between strains, occasionally resulting in a new iav subtype to which a large proportion of the population does not have existing immunity. this shuffling of the viral genes contributes to the sudden and dramatic change in virulence that may occur from season to season, and to zoonoses, as iav jumps from its natural avian host to mammalian pig and human hosts. drift refers the accumulation of small mutations in the viral genome that occur on a continuum. because of the short genome (around 13,500 bases of rna are carried by a functional virion particle) and a very high error rate when this genome is replicated [12, 13] , viral quasispecies arise, leading to a heterogenous swarm of virions [14] . this variation enables iav to evolve extremely rapidly where a selective pressure exists. for example, it is likely that iav can evolve de novo resistance to antivirals during treatment of a single patient [15] [16] [17] . studies of viral whole genome sequence during outbreaks have failed to identify consistent viral factors associated with severe disease [18] . it is therefore likely that viral factors do not explain the vast spectrum of variation observed in the disease. variation attributable to the host previous exposure to iav due to the remarkable memory of the adaptive and innate immune systems, previous exposure to iav has a strong effect on future susceptibility. adaptive immune memory is highly strain-specific and provides targeted antibodymediated defence against iav [19] . the first iav strain to which a child is exposed has a profound effect on subsequent immunity-a concept known as original antigenic sin [20] . the host immune system is extensively programmed by this first iav exposure, such that the susceptibility of whole populations of adults can be predicted using the patterns of circulating iav in each patient's year of birth [21] . this has been proposed as one reason why the burden of mortality for the 2009/2010 outbreak was shifted towards patients younger than 65 years of age [22] -patients over 65 years old are more likely to have been exposed at a young age to an iav strain similar to the h1n1pdm09 strain, and were hence protected. interestingly, the lifelong immunity provided by this first iav exposure has broad protective effects against different iav strains [21] . cell-mediated immunity may play an important role in this protection. an iav challenge study in healthy volunteers found that preexisting cd4(+) t cell responses to iav nucleoprotein and matrix proteins were present prior to infection [23] . the magnitude of this cd4(+) t cell response when challenged correlated with reduced symptoms and reduced virus shedding. regardless of prior exposure, the most reliably quantified risk factors for life-threatening seasonal and pandemic iav are advanced age (> 65 years), obesity, immunosuppression, cardiovascular disease, and neuromuscular disease [24] . a number of well-recognised host factorsbest summarised by the broadly understood but poorly defined term, "physiological reserve"-increase the chance of organ failure and death following any severe injury or infection. these factors are extensively discussed elsewhere in the critical care literature; here, we focus on host factors that are thought to confer some element of specific susceptibility to iav (fig. 1) . studies dating back to the 1918-1919 pandemic have suggested that pregnancy, particularly in the third trimester, increases the risk of death from iav [25] . additionally, pregnant women have a higher rate of hospitalisation with seasonal iav [26] . however, in the largest systematic review of clinical risk factors for iav, pregnancy was not fig. 1 conceptual visualisation of variation in specificity of host susceptibility factors. factors predicted to confer more specific susceptibility to influenza are placed higher in the diagram independently associated with severe disease from either seasonal or pandemic iav [24] . the immunological changes that occur in pregnancy are theoretically compatible with increased severity of iav: in particular, an increase in innate immune activation and a decrease in the number and activity of cells associated with cytotoxic immunity-in which infected cells are killed to limit the dissemination of the virus [27] . these changes may lead to an increased propensity to develop ards [28] and a decreased ability to eliminate iav-infected cells, which is a core component of anti-iav immunity. some indices of severity used in epidemiological studies are themselves directly affected by pregnancy. the cardiovascular adaptations to pregnancy, combined with an increased metabolic rate, a decrease in functional residual capacity, and increased basal ventilation to perfusion mismatch, are expected to worsen hypoxaemic respiratory failure following any insult. in parallel, admission to hospital or critical care may be in part biased by elevated concern for a pregnant patient, and by the perception of high risk of severe iav [29] . obesity was identified as a risk factor for iav infection over a decade ago and confirmed during the swine flu pandemic [30, 31] when it was associated with an increased risk of death [32] . although comorbidities associated with obesity-specifically diabetes mellitus and cardiovascular disease-compromise pulmonary host defence and increase the chance of death following any severe systemic injury [33] , an independent association between obesity and severe iav is robust and replicated [24] . in parallel with the immune changes associated with pregnancy, obese patients are more likely to have impaired cell-mediated immunity and excessive chronic activation of the innate immune system [34] . this is reflected in a study which demonstrated that among vaccinated adults, those who are obese are more likely to suffer severe consequences of iav [35] . furthermore, it has been shown that obese adults have an impaired antibody response to iav vaccination [36] , and impaired cd4(+) and cd8(+) t cell responses iav in vitro [37] . obese patients have a prolonged period of viral replication and shedding, even in the absence of clinical disease [33] . extremes of age are well-recognised risk factors for severe disease. children under the age of 5 years, and particularly those under 2 years, have consistently been found to be at high risk for severe disease and serious complications following iav infection [38] [39] [40] . functional immaturity of the immune system, together with a failure to recognise iav-related antigens, may largely explain this effect. in industrialised countries, the group at highest risk of death from seasonal iav is those over 65 years of age [22, 41, 42] . senescence affects antiviral immunity in complex ways; it is difficult in clinical epidemiological studies to distinguish the effect of these immune changes from the effects of frailty and antigenic exposure. baseline markers of systemic inflammation are elevated [43] and circulating t cell counts are reduced. naive t cells, a key component of cell-mediated adaptive immunity, are lost from the circulation due to the process of thymic involution, which begins very early in life [44] . in mouse models of iav infection, aged mice exhibit slower antiviral and adaptive immune responses, and more severe disease [45] . expansion of clonal t cell populations, driven by cytomegalovirus (cmv), occurs in older adults and may impair t cell responses to new pathogens [46] . in contrast, in the young, a multi-omic systems analysis demonstrated that cmv infection is associated with an enhanced t cell mediated response to iav vaccination [47] . integrating systems studies of host response to iav infection with markers for genetic susceptibility (see below) may in the future reveal new biological pathways and patterns of disease [48] . as with pregnancy and obesity, ageing is associated with both an increase in the basal activation of the innate immune system (sometimes referred to as "inflammaging") and a decrease in cell-mediated immunity. this combination of mechanisms may explain the particularly strong effects on susceptibility. susceptibility to death from any infection is strongly inherited by children from their parents [49] . in iav, numerous genetic studies in humans and animal models have revealed specific genes associated with susceptibility, which are extensively reviewed elsewhere [50] [51] [52] . in addition to the specific genetic variants discussed below, there is direct evidence, from a study of death records in utah, that susceptibility to iav is heritable at a population level [53] . much of what is known about human genes associated with iav susceptibility has been discovered from lossof-function mutations in the immune system, which lead to loss of the gene product or a substantial reduction in gene function. these often lead to severe defects that are likely to present in childhood. such variants can reveal key components of the immune response to a specific infection. in considering the biological lessons from such discoveries, it is important to consider that, in most people, these components of the immune system function perfectly well and may not be suitable targets for therapy. secondly, there is little that can be inferred from the absence of any particular gene, or immune process, from the list of loss-of-function defects associated with susceptibility to iav. the conditions that must be met for such a gene to be discovered are not restricted to disease susceptibility. many variants that confer susceptibility to iav have broader pleiotropic effects that may be terminal in utero or in early life, or may lead to susceptibility to other infections or autoimmune conditions that obscure the clinical picture. alternatively, some variants may lead to strain-specific susceptibility and will only be detected following exposure to the right virus. the full range of genetic defects associated with susceptibility to iav in animal models is reviewed elsewhere [54, 55] . so far, three known human genes, all transcription factors active primarily in myeloid cells, have been found to have loss-of-function variants that increase susceptibility to iav. since transcription factors function as master regulators of large numbers of genes, functional deficiencies are expected to have broad, nonspecific effects. in 2015, ciancanelli et al. identified a patient with a mutation in the transcription factor interferon regulatory factor 7 (irf7) that led to severe infection and ards when she was 2.5 years old [56] . irf7 is a transcription factor and a key regulator of the type i interferon response. this was the first published example of a singlegene inborn error of immunity that was specific to iav. both parents were heterozygous for different loss-offunction alleles, but each had sufficient functional irf7 activity allowing them to avoid severe iav. the patient inherited these two different loss-of-function alleles (compound heterozygosity) leading to complete loss of functional irf7. leukocytes and plasmacytoid dendritic cells from this patient produced very little interferon type i (α/β) and iii (γ) in vitro indicating that expression and production of these interferons in these cell types is specifically irf7-dependent in iav infection in humans. whole exome sequencing of 20 children identified a variant in the gene encoding interferon regulatory factor 9 (irf9) in a 2-year-old child who had previously suffered from bronchitis and biliary perforation [57] . the child inherited a mutation on both alleles from consanguineous parents leading to a single change in the dna sequence (single nucleotide polymorphism, snp) in the irf9 gene. this snp occurs at an essential site leading to aberrant processing of the gene transcript and thus the expression of a truncated, functionally defective, protein product. in this case, irf9 was only partially defective. activation of interferon-stimulated gene 3 (isg 3) was impaired in response to iav infection or interferon α stimulation, but other irf9-dependent pathways remained intact. the consequence of this appears to be a global reduction in type i interferon responses, a key mechanism of early mucosal resistance to infection, in all cell types. unrestricted viral replication was observed in cells from the patient and was also shown for parainfluenza virus and respiratory syncytial virus. gata2 is a zinc finger transcription factor, part of the gata family, so named because they bind a g-a-t-a pattern (also called a motif) in dna sequence. transcription factor binding at sites bearing this motif alters the probability that a given gene will be transcribed, and ultimately controls the amount of the encoded protein that is made. gata2 deficiency results in primary immune cell deficiency and affects a wide range of cell types. decreased circulating counts of b lymphocytes, nk cells, monocytes and plasmacytoid dendritic cells have been observed, along with reduced t cell thymic output. in 2018, sologuren et al. published a case study of a father and son who contracted and subsequently died from severe iav [58] . both patients were heterozygous for a novel mutation in gata2 that led to a dysfunctional protein. despite the known effects of gata2 deficiency on primary immune development, the first, older patient had suffered few health problems prior to his 30th year, after which frequent respiratory illnesses and a single incidence of viral pneumonia is reported prior to his severe illness. the second patient had been hospitalised with pneumonia at 16 without recurrence until hospitalisation with severe iav at 31. the authors attribute protection from viral and bacterial infection observed in the lifetime of these patients to long-living memory t and b cells. genetic variants with less drastic effects on susceptibility can be detected by comparing flu-susceptible populations with control populations (table 1) . these studies generally look for candidate genes or take a genomewide approach. candidate gene association studies have a long but troubled history in human genetics. genes are selected because of some underlying hypothesis; single variants within these genes are then chosen because they are believed to have an effect on the expression or function of the gene. genotype frequencies (that is, the proportion of a population who have a given variant) at these genomic positions are then compared between a case and control group. this has the advantage of economy, since only one or two variants need to be genotyped for each participant, and has the superficial appearance of statistical efficiency, since fewer comparisons are made. the fundamental limitation is that, in a human genome composed of 3 × 10 9 bases, of which 4 − 5 × 10 6 are different between any random pair of people [59] , the probability of choosing the right base is very low. in the event that a given variant meets a nominal level of significance, the evidence for an association is easily misinterpreted. looking backwards from a single small p value, it is common to focus on the fact that probability of seeing such an association by chance alone is very low. what is easy to forget is that the probability of such an association existing is also very low. an understanding of this methodology is important for the interpretation of such studies. many of the positive studies reflect more the biases of well-informed investigators in the choice of target genes. the additional value of an unreplicated genetic association on this background is often small. lgals1 galectin-1 cell-cell interactions rs4820294 [82] rs2899292 [82] rs4820294 [82] st3gal1 (*) st3 beta-galactoside alpha-2, [85, 88] gene: gene symbol. gene name: gene name and alternate name. function: summary function of gene product. snp: snps associated with host susceptibility to influenza a associated with gene. (*) represents genes not addressed in the text nonetheless, candidate gene approaches in various forms detected numerous real and informative associations with disease before the advent of genome-wide genotyping technology [60] . we focus here on larger studies, those that have been replicated, and studies with particular relevance to the pathogenesis of severe iav. genome-wide approaches seek to eliminate the aforementioned bias. in the most widely used design, the genome-wide association study (gwas), hundreds of thousands of common variants are genotyped in each patient. this is expensive and requires correction for multiple comparisons. a widely used convention is to correct for 1 × 10 6 independent comparisons in each study, requiring a p value <5 × 10 −8 for significance. large numbers of patients are needed to detect associations at this level above the background noise of variation in human populations. however, genome-wide approaches use no preconceptions about the pathogenesis of disease. hence, such methods have the potential to teach us something that we did not already know. because of the stringent threshold for statistical significance, and the burden of multiple testing, statistical power to detect small effects is usually lacking unless many tens of thousands of patients are included. for this reason, the expected outcome is false-negatives. hence, we would caution against drawing any conclusion from the absence of significant associations within a given gene. genome-wide in vitro knockdown screens can also be used to limit bias and enable genome-wide discovery. in this approach, although a candidate gene is often selected from cell culture results and tested for genetic associations in patients, there is an important difference from single-gene candidate studies: the pool of genes from which the candidate is chosen comprises the entire protein-coding part of the genome. a role for interferon-induced transmembrane protein 3 (ifitm3) in iav replication was discovered in an in vitro genome-wide knockdown screen in cultured cells [61] . the protein product of this gene restricts iav entry by blocking the fusion of host and viral membranes [62] and acts as a restriction factor in viral infections, along with family members ifitm1 and ifitm2 [61] . ifitm proteins were also shown to inhibit the early replication of other virus types, for example the west nile virus [63] . based on this genome-wide knockdown screen, a candidate gene sequencing approach was conducted to test for an association with severe illness. the 2009/2010 pandemic provided a colossal natural experiment-a large proportion of the population were exposed to a new pathogen, but only a small minority developed lifethreatening illness requiring critical care. focusing on these previously healthy adults with life-threatening iav (in the genisis and mosaic studies) may have increased the effect size seen [64] . genotypes at every variant within the ifitm3 gene were compared with population controls, identifying a single variant (rs12252-c) associated with severe iav. this variant is rare in the european cohorts in which it was discovered, but is frequent in the han chinese cohorts hospitalised with severe h1n1pdm09 infection [65] . the association has been replicated in independent studies in different populations [66] . a second snp associated has been shown in populationlevel studies to regulate ifitm3 expression. rs34481144-a encourages the transcription factor ctcf to bind to the regulatory region of ifitm3 and repress gene expression in response to iav infection [67] . this snp can also disrupt the methylation pattern (a key modification of dna that usually silences genes) in the regulatory region leading to cell type-specific effects. ifitm3 expression in memory cd8(+) t cells in response to viral infection has been found to protect and encourage survival of these cells allowing for the establishment of adaptive immunity. loss of methylation at this site prevents ctcf from binding to the dna and inducing expression of ifitm3 in response to the pathogen, thus reducing cell survival. this is estimated to lead to a 2.6-fold increased risk of a severe outcome upon iav virus infection. ifitm3 has also been recently shown to have a protective effect on the heart during severe iav infection. myocarditis has been associated with iav infection since the 1918 pandemic [68] , and iav has been shown to lead to a sixfold increased risk of myocardial infarction in the 7 days post infection [69] . so far, ifitm3 is the only gene for which snps have been identified and independently confirmed in vivo and in vitro to restrict iav replication [70] . however, this gene is not specific to iav replication and the full extent of the antiviral actions remains to be discovered. unbound complement is rapidly inactivated in plasma. where this process is defective, uncontrolled complement activation can damage host cells. cd55 prevents the formation and accelerates the decay of c3 and c5 convertases. these proteases are part of the complement system and have roles in opsonisation and the release of inflammatory molecules. cd55 polymorphisms were associated with severe h1n1pdm09 infection (defined as requiring supplementary oxygen, admission to intensive care or death) [71] . this study found carriers of the rs2564978-t/t polymorphism had significantly lower levels of surface cd55 on their circulating monocytes compared to the more common c allele. further work identified a deletion in a nearby regulatory region as the element responsible for the specific effect on both protein and mrna levels of cd55 in monocytes. a more recent study of han chinese individuals that looked at several genes confirmed an association between cd55 rs2564978 t/t and death from severe iav infection [72] . the cumulative effects of multiple snps (ifitm3, cd55, and the immune cell receptors tlr3 and tlr4) on iav susceptibility have been examined in a targeted study [72] . this independently confirmed the association of the cd55 rs2564978 polymorphism with severity, and the ifitm3 rs12252-c and tlr3 rs5743313-cc genotypes were both over represented in fatal cases. in a small-scale pilot study, genome-wide genotypes of 42 patients with severe iav were compared to 42 controls with mild iav. the rs2070788-g allele of tmprs22 was significantly overrepresented in severe compared with mild cases of h1n1pdm09, with a > 2fold higher risk of severe infection. there was higher tmprs22 expression in human lung tissues with the high-risk gg genotype [73] . this was replicated in a targeted study of 162 severe and 247 mild iav patients. this genetic association in humans is highly biologically plausible: tmprs22 has been shown to play a role in haemagluttinin cleavage, an important step in iav replication. additionally, mice lacking this gene are strongly protected from iav infection [74] [75] [76] . this genome-wide array also identified a snp in pulmonary-surfactant-associated protein b (sp-b), rs1130866, as a potential association. this snp was genotyped in a targeted study of 111 severe and 185 mild iav patients to replicate the finding [77] . again, this is a plausible association with severe disease: sp-b forms a key part of pulmonary surfactant and is essential for lung function. a subset of the same protein family, sp-a and sp-d, have been shown to initiate and enhance immune cell ingestion and killing (opsonisation) of pathogens and play a role in the progression of iav in mice [78] . a polymorphism associated with sp-b, rs1130866 [77] , has also been associated with copd in several cohorts [79] . susceptibility to severe h1n1 infection was analysed in a recent genome-wide study (integrated with data on genetic variants associated with altered gene expression) which implicated an intronic snp of gldc, rs1755609-g [80] . the gldc gene encodes glycine decarboxylase, also known as the p protein of the glycine cleavage system, a pathway in glycine metabolism [81] . the association was replicated by targeted genotyping in a larger cohort of 174 patients suffering severe iav infection and 258 mildly infected controls. the risk variant corresponds to higher gldc expression in lymphoblastoid cell lines and human lung tissues. consistent with this effect, inhibition of gldc in cultured bronchial epithelium using sirna or a specific inhibitor, aminooxyacetic acid (aoaa), leads to an increased type i ifn response and a restriction of viral replication in vitro. this effect on viral restriction was seen with both h1n1 and h7n9, and the allele genotype was replicated in susceptibility cohorts for both viruses. the protective effect of aoaa against h1n1 was shown in mice to be comparable with that of zanamivir. susceptibility to severe h7n9 was examined in a gwas performed with 102 patients and 106 controls who worked with poultry. this study identified rs13057866, associated with galectin-1 (lgals1), as a potential susceptibility factor. lgals1 is a lectin that may have a role in modulating cell-cell and cell-matrix interactions. the study further demonstrated that genetic variants of lgals1, including rs4820294 and rs13057866, lead to higher expression of lgals1 protein in human cells, possibly leading to a protective effect. carriers of the rs4820294/rs2899292 gg haplotype were found to have higher lgals1 protein in lymphoblastoid cells and expression levels of lgals1 in human lung correlated with the rs4820294 snp [82] . the role of host factors in susceptibility suggests a clinically important conclusion: there is something unusual about the small minority of patients who develop critical illness following iav. therefore, extrapolating from human challenge and primary care studies of viral clearance is very likely to lead to error. viral clearance among critically ill patients is slow and incomplete [83] . hence, the critically ill population should be regarded-by 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otherwise healthy children publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors declare that they have no competing interests. key: cord-280129-a97rvtzl authors: honore, patrick m.; barreto gutierrez, leonel; kugener, luc; redant, sebastien; attou, rachid; gallerani, andrea; de bels, david title: liver injury without liver failure in covid-19 patients: how to explain, in some cases, elevated ammonia without hepatic decompensation date: 2020-06-16 journal: crit care doi: 10.1186/s13054-020-03088-x sha: doc_id: 280129 cord_uid: a97rvtzl nan liver injury without liver failure in covid-19 patients: how to explain, in some cases, elevated ammonia without hepatic decompensation patrick m. honore * , leonel barreto gutierrez, luc kugener, sebastien redant, rachid attou, andrea gallerani and david de bels we read with great interest the recent research letter by cardoso et al. who describe the liver injury seen with covid-19 [1] . we would like to provide some additional information. in our large cohort of covid-19 patients, we had several patients who did not regain consciousness as expected, even when sedation had been stopped for 4-5 days. electroencephalogram (eeg) in these patients demonstrated a metabolic pattern. in the process of working through the differential diagnoses, we measured serum ammonia levels and were surprised to see that in two patients the ammonia level was elevated 3 times above the normal limit. while those patients had liver injury but absolutely no sign of liver failure, nor were they receiving medications that could explain hyperammonemia, such as valproate or amiodarone [2] . both patients had experienced very severe diarrhea several days prior to admission. baseline glasgow coma score (gcs) was difficult to determine as both patients were intubated by an emergency team on site. ct scan of the brain was unremarkable. both patients were treated with classical medical therapy including lactulose, but, despite increasing doses of lactulose for 3 days, ammonia levels remained unchanged. we decided that if there was no progress within 72 h, continuous renal replacement therapy (crrt) would be started to remove ammonia. as the ammonia was below 200 mg/dl, there was no acute indication to start crrt to avoid brain edema. we were surprised to see that both patients regained consciousness 48 and 72 h later respectively, and ammonia levels normalized. retrospectively, we hypothesize that the pre-admission diarrhea may have resulted in secondary carnitine deficiency, as described in the literature [3] , leading to hyperammonemia unresponsive to medical therapy [4] . crrt dramatically reduces ammonia levels, but ultimately can worsen the situation by further reducing the level of carnitine [5] . as we did not measure serum carnitine levels and we did not supply the patients with carnitine supplementation, the diagnosis of carnitine deficiency in these cases remains only a hypothesis. clinicians should keep this diagnosis in mind in covid-19 patients with severe diarrhea. liver injury in critically ill patients with covid-19: a case series ould-nana i. hyperammonemic encephalopathy and lipid dysmetabolism in a critically ill patient after a short course of amiodarone clinical quiz. secondary carnitine deficiency due to celiac disease hyperammonemic encephalopathy caused by carnitine deficiency carnitine deficiency in children receiving continuous renal replacement therapy publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank dr. melissa jackson for the critical review of the manuscript.authors' contributions pmh, sr, and ddb designed the paper. all authors participated in drafting and reviewing. all authors read and approved the final version of the manuscript. key: cord-299650-lhphdjeu authors: whittle, john; molinger, jeroen; macleod, david; haines, krista; wischmeyer, paul e. title: persistent hypermetabolism and longitudinal energy expenditure in critically ill patients with covid-19 date: 2020-09-28 journal: crit care doi: 10.1186/s13054-020-03286-7 sha: doc_id: 299650 cord_uid: lhphdjeu nan covid-19 infection results in respiratory failure requiring icu care in a small, yet significant, number of patients [1] . the longitudinal metabolic phenotype and energy expenditure of this novel pandemic disease has yet to be described. as a marked and often prolonged, systemic inflammatory response (sirs) has been suggested to be a hallmark of severe covid-19 infection [1] , we hypothesized a prolonged hypermetabolic state would evolve over icu stay that would persist beyond the 7-10 day hypermetabolic phase described previously in other icu conditions [2] . further, understanding the energy expenditure of covid-19 icu patients is essential to help determine safe, optimal nutrition needs for the icu provider [3] , as both over-/underfeeding is associated with increased icu mortality [3, 4] . prediction of resting energy expenditure (pree) using standardized formulas or bodyweight calculations often correlates poorly with measured ree (mree) [3] . thus, our aim was to assess longitudinal mree via indirect calorimetry (ic) in intubated covid-19 patients. here, we report the first results from the leep-covid study (clinicaltrials.gov nct04350073) from march to may, 2020. following irb approval, ic was conducted every 72 h (q-nrg, cosmed/baxter, usa) [5] . prior to testing, patients were confirmed to be in stable condition with only steady-state measures for ≥ 20 min considered valid. mree was compared to pree, which was calculated at same timepoints via commonly utilized harris-benedict equation (hbe). for calculations, actual body weight (abw) was used for non-obese (bmi < 30) and both actual and adjusted body weight (adjbw) was utilized for obese subjects (bmi > 30) [3] . data from 22 covid-19 icu patients are summarized in table 1 and fig. 1 . during the 1st icu week, mree was observed to fall between 15 and 20 kcal/kg (for abw in bmi < 30 and adjbw in obese subjects [3] .). increasing hypermetabolism and wider variability in mree were observed post-1st icu week. unlike data from smaller studies in other icu populations [1] , observed hypermetabolism persisted, and in fact increased during 3rd icu week (mean mree = 150% pree in 3rd icu week). certain individuals exhibited metabolic rates greater than two-times predicted via hbe, which significantly underpredicted ree post-1st icu week. changes in mree may not be significantly related to severity of organ failure and only minorly affected by paralysis/ prone positioning, as these were not significantly different over the study period (table 1) . longitudinal ic data presented here demonstrate a progressive hypermetabolic phenotype beginning 1 week post-intubation in covid-19 icu patients, with significantly greater mree versus predictive equations or aspen-recommended 11-14 kcal/kg abw for obese subjects used currently to determine energy requirements. our data support use of standard predictive equations or~20 kcal/kg as a reasonable approximation of mree in 1st icu week in covid-19 patients. current espen/aspen icu guidelines suggest hypocaloric (~70% pree) feeding during acute phase to prevent overfeeding risk as it is believed icu patients have initial early endogenous nutrient production that we currently are unable to measure [3, 4] . to our knowledge, this is the first description of longitudinal mree in a covid-19 icu population. the covid-19 metabolic phenotype may be unique from previously described icu models of metabolic response [2] , with a more prolonged hypermetabolic phase that may be independent of severity of organ failure and, as previously published, may only be minorly affected by interventions such as paralysis [6] . further, it is one of the largest single-icu diagnosis cohorts with longitudinal ic measures for 21 days. in conclusion, we demonstrate progressive hypermetabolism and considerable variation in ree throughout icu stay. we hope this data assists icu clinicians in further understanding the effects of covid-19 on metabolism and in assessing nutrition care needs. these data suggest personalization of nutrition delivery, including ic use [3, 5] , should be considered to provide more accurate assessments of energy expenditure and help guide nutrition delivery in covid-19 icu patients. this study was funded in part by an investigator-initiated grant from baxter inc. (deerfield, il) to paul e. wischmeyer via duke university. the sponsor (baxter) did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. only the authors and investigators at duke university participated in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. all raw data available upon request ethics approval and consent to participate leep-covid study was approved by duke institutional review board. a waiver of consent was granted by duke irb due to minimal risk to patient from fda-approved qnrg indirect calorimeter assessment. all patients were provided an information sheet when able to be awake and oriented (if possible) and given option to withdraw from the study with no data retained. not applicable; all authors have seen and approved the final version of the manuscript. severe covid-19 components of energy expenditure in patients with severe sepsis and major trauma: a basis for clinical care espen guideline on clinical nutrition in the intensive care unit guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition the clinical evaluation of the new indirect calorimeter developed by the icalic project the effect of cisatracurium infusion on the energy expenditure of critically ill patients: an observational cohort study springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the primary authors acknowledge the commitment and many hundreds of hours spent conducting this trial by the study research coordinators, respiratory therapists, dietitians, critical care attendings, nurses, and other icu staff at duke university hospital that made the many daily measurements in critically ill coivd-19 patients possible. we also acknowledge the leep-covid study group co-authors who made this research possible: anthony sung md, marat fudim md, lindsie boerger rd, kathryn lessig rd, jessica lumbard bs, leslie c. murray rd, sue steves rd, jhana parikh bs, jacob ribet bs, rrt ldn, and melanie hollidge md. dr. wischmeyer reports receiving investigator-initiated grant funding related to this work from national institutes of health, canadian institutes of health research, baxter, and fresenius. dr. wischmeyer has served as a consultant to abbott, fresenius, baxter, cardinal health, and nutricia, for research related to this work. dr. wischmeyer has received unrestricted gift donation for nutrition research from musclesound. dr. wischmeyer has received honoraria or travel expenses for cme lectures on improving nutrition care from abbott, baxter, and danone-nutricia. key: cord-293766-vpfda3pd authors: ji, jingjing; zhang, jinxia; shao, ziyun; xie, qifeng; zhong, li; liu, zhifeng title: glucocorticoid therapy does not delay viral clearance in covid-19 patients date: 2020-09-21 journal: crit care doi: 10.1186/s13054-020-03287-6 sha: doc_id: 293766 cord_uid: vpfda3pd nan lower respiratory tract samples from confirmed patients were collected and tested by rt-pcr every 2 to 3 days. for the severe and critical patients, the interval between two tests was 4 to 5 days. to avoid false negative results, only patients with three continuously negative tests were considered that they have viral rna clearance. therefore, for the patients with negative rt-pcr result, two more samples were collected in the following 2 days, respectively. among the 684 cases, 202 (29.5%) cases had viral rna clearance within 14 days after illness onset and 210 (30.7%) cases had viral rna clearance between 14 and 28 days, and 272 (39.8%) cases had viral rna clearance over 28 days. there were no differences on the age, gender, and underlying diseases between different groups. the degree of decrease in cd4 t cell and b cell counts on admission was related with the prolonged viral rna clearance (table 1) . since gc therapy was usually employed in critically ill patients, we analyzed the effect of gc therapy separately for patients with different severity. patients were diagnosed as mild type, general type, severe type, and critical type according to the chinese recommendations for diagnosis and treatment of novel coronavirus (sars-cov-2) infection (trial 7th version) [4] . for the mild and general type patients, 30 (6.1%) cases received [4] . the results show that gc therapy increased hospital stay days but had no effect on the virus clearance time ( table 2) . for the severe and critical patients, the median viral rna clearance time in the gc group was 26 days (iqr 17-42 days), while the viral rna clearance time in the non-gc group was 25.5 days (iqr 13-39 days). in addition, the gc treatment had no effect on the peripheral lymphocyte counts, including cd4 t cells, cd8 t cells, nk cells, and b cells ( table 2) . the current multicenter cohort study demonstrates that gc therapy does not change viral clearance and peripheral lymphocyte counts in covid-19 patients. however, well-designed and large-scale randomized controlled trials are needed to further confirm the results derived from this observational study. the use of antiinflammatory drugs in the treatment of people with severe coronavirus disease 2019 (covid-19): the perspectives of clinical immunologists from china low-dose corticosteroid therapy does not delay viral clearance in patients with covid-19 persistence and clearance of viral rna in 2019 novel coronavirus disease rehabilitation patients national health commission of the people's republic of china. chinese recommendations for diagnosis and treatment of novel coronavirus (sars cov2) infection (trial 7th version) publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank the help from zheying liu and conglin wang during the data collection, and thank jie fan (university of pittsburgh, usa) for revising the manuscript. all authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. zhifeng liu was responsible for the study concept and design. jinxia zhang, ziyun shao, qifeng xie, and li zhong were responsible for collecting the data. jingjing ji, jinxia zhang, and ziyun shao were responsible for the statistical analysis. jingjing ji was responsible for drafting the manuscript. all authors commented on the previous versions of the manuscript. all authors read and approved the final manuscript. this work was supported by grants from the pla logistics research project of china [18cxz030, 17cxz008]. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.ethics approval and consent to participate the study was approved by the research ethics commission of general hospital of southern theater command of pla. the requirement for informed consent was waived by the ethics commission. all authors reviewed the manuscript and approved the publication. the authors declare that they have no competing interests. key: cord-310776-4iqu18gi authors: supady, alexander; duerschmied, daniel; bode, christoph; rieder, marina; lother, achim title: extracorporeal cytokine adsorption as an alternative to pharmacological inhibition of il-6 in covid-19 date: 2020-08-20 journal: crit care doi: 10.1186/s13054-020-03238-1 sha: doc_id: 310776 cord_uid: 4iqu18gi nan extracorporeal cytokine adsorption as an alternative to pharmacological inhibition of il-6 in covid-19 alexander supady 1,2,3* , daniel duerschmied 1,2 , christoph bode 1,2 , marina rieder 1,2 and achim lother 1, 2, 4 with great interest we read the article by convertino et al. discussing potential treatment targets for pharmacological immunomodulation in coronavirus disease 2019 (covid-19) with acute respiratory distress syndrome (ards) [1] . we would like to add to the debate some thoughts about cytokine adsorption, which was mentioned only in passing in this discussion. following initial reports describing interleukin-6 (il-6) as a predictive factor for a negative outcome, extracorporeal cytokine adsorption was discussed as a possible treatment option for severe covid-19 cases. initial experience at our center using the cytosorb® device (cytosorbents europe, berlin, germany) in combination with veno-venous extracorporeal membrane oxygenation (v-v ecmo) in severe covid-19 yielded promising results; cytokine adsorption resulted in a more pronounced decrease of il-6 after initiation of v-v ecmo as compared to patients treated without cytokine adsorption [2] . the use of the term "cytokine storm" in the context of covid-19 has been challenged, though. while elevated levels of il-6 are associated with poor outcome, absolute levels in these cases are rather moderately elevated in comparison to other forms of ards with extensive il-6 increases [3] . inflammatory dysregulation in severe cases is probably more complex and does not only go along with an upregulation of interleukins or tnf-α but also with an impaired interferon response [4] . a major advantage of extracorporeal cytokine adsorption over the other therapeutic approaches discussed in this debate is that it does not selectively block a specific receptor or signal transduction cascade, but it rather reduces particularly elevated concentrations of various inflammatory mediators such as interleukins, tnf-α, and also interferons; these factors have both pro-and anti-inflammatory functions. only mildly elevated, physiological, or even decreased concentrations are not relevantly altered; thus, oversuppression of the immune response may be prevented [5] . furthermore, cytokine adsorption can be better controlled than the other mentioned treatment options-it can be terminated at any time without any specific after-effect. these two aspects may be particularly relevant, e.g., in the case of bacterial superinfection in severe covid-19 when an adequate immune response is required. in conclusion, we recommend a cautious approach to intervention or "modulation" in the immune response in covid-19 patients as long as the pathophysiological background remains to be unveiled. all interventions discussed in this debate should be considered experimental and therefore applied and evaluated within clinical trials. exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in covid-19 patients cytokine adsorption in patients with severe covid-19 pneumonia requiring extracorporeal membrane oxygenation is a "cytokine storm" relevant to covid-19? impaired type i interferon activity and inflammatory responses in severe covid-19 patients cytokine clearance with cytosorb(r) during cardiac surgery: a pilot randomized controlled trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-284355-yb2t5ypa authors: xing, changyang; li, qiaoying; du, hong; kang, wenzhen; lian, jianqi; yuan, lijun title: lung ultrasound findings in patients with covid-19 pneumonia date: 2020-04-28 journal: crit care doi: 10.1186/s13054-020-02876-9 sha: doc_id: 284355 cord_uid: yb2t5ypa nan since december 2019, the outbreak of pneumonia caused by a new coronavirus [1] , which was later identified as coronavirus disease 2019 (covid19), has infected more than 410,000 patients globally according to the situation report of world health organization. lung ultrasound is an important tool for the diagnosis and follow-up of pneumonia in neonates, children, and adults [2] [3] [4] . recent ct reports demonstrated that most of the lesions were distributed peripherally in the lung, which facilitates detection by lung ultrasound [5, 6] . in this study, we characterize the lung ultrasound findings covid-19 pneumonia, and study the relationship between the ultrasound findings and clinical severity and the time-course of disease progress. bedside lung ultrasound was performed to detect b-lines, lung consolidation, and pleural line abnormalities at 5 areas in each lung. vascular ultrasound was also performed to detect potential deep vein thrombosis. a total of 20 patients of covid-19 pneumonia (12 males and 8 females) were categorized as 4 moderate, 5 severe, and 11 critical cases according to the current diagnosis and treatment program. all patients showed abnormal lung ultrasound findings, including 100% (20) pleural line abnormalities, 100% (20) b-lines, and 50% (10) consolidation. most of the moderate and severe cases could show both separated b-lines and confluent b-lines during admission. all critical patients showed confluent blines, and 18% (2) of them had compact b-lines. bilateral involvement was observed in all patients. the predominate involved areas in moderate patients were on the back, i.e., the interscapular and infrascapular areas. for severe and critical patients, all 5 areas could be involved. consolidations were not detected in moderate cases, and distributed mainly on the posterior areas in severe and critical cases. pleural effusion (18%, 2 cases), pericardial effusion (9%, 1 case), and deep vein thrombosis (64%, 5 cases) were only found in critical patients. (table 1) . a total of 36 ultrasound examinations were categorized to four groups based on the time interval between onset of symptoms and ultrasound examinations (1st to 4th week). all of the examinations showed abnormal lung ultrasound findings, including 100% (36) pleural line abnormalities, 100% (36) b-lines, and 64% (23) consolidation. the separate b-lines were found more than half of the examinations after the 2nd week. the majority of examinations during the 2nd and 3rd weeks showed confluent b-lines. the involvement of anterior areas with b-lines decreased along with the infected time course. the lateral and back areas were always involved in all stages for b-lines. consolidations were found in more than half examinations after the 1st week. most of consolidation lesions confined within unilateral lung except at the 2nd week. the anterior and lateral areas were not involved of consolidations during 1st and 4th week. consolidations were always found in the interscapular and infrascapular areas. pleural effusion was observed across all stages, but only in a few examinations. the deep vein thrombosis can be found since the 1st week and most prevalent at the 4th week (62.5%, 5 cases). (table 2 ). in summary, abnormal lung ultrasound findings, mainly b-lines, consolidation and pleural line abnormalities, were found in patients infected with covid-19 pneumonia. bilateral involvement was always observed with predominant distribution in the posterior part of the lungs. the composition of different density of b-lines and areas of consolidation showed parallel changes with the clinical severity. the extent of disease demonstrated by ultrasound findings seemed reaching the peak at the 2nd week and recovering gradually thereafter. collectively, lung ultrasound could serve as a valuable tool for the detection and follow-up of lung lesions in covid-19 pneumonia and also provide supplemental imaging information for current recommended radiological examination, with the advantages of radiation-free, flexibility, and cost effective. shaanxi province (2020zdxm-sf-003). changyang xing was supported by the grants from national postdoctoral program for innovative talents (bx20180377) and the eyas program of the fourth military medical university. all data generated or analyzed during this study are included in this published article. authors' contributions ly and jl contributed to the study concept and design. cx, ql, hd, and wk contributed to the acquisition, analysis, or interpretation of data. cx contributed to the drafting the manuscript. ql, jl, ly, hd, and wk contributed to the critical revision of the manuscript. all contributed to the final approval of the manuscript. all agree to be accountable for all aspects of the work. prof. ly and prof. jl were the guarantors of the paper. the authors read and approved the final manuscript. bilateral involvement 0 40% (2) 54% (6) anterior upper area 0 0 18% (2) anterior lower area 0 0 18% (2) lateral area 0 20% (1) 18% (2) interscapular area 0 20% (1) 64% (7) deep vein thrombosis 0 0 64% (7) data are presented as percentages (number of cases) bilateral involvement 100% (4) 100% (11) 100% (13) 87.5% (7) anterior upper area 100% (4) 91% (10) 85% (11) 87.5% (7) anterior lower area 100% (4) 91% (10) 77% (10) 75% (6) lateral area 100% (4) 100% (11) 100% (13) 100% (8) interscapular area 100% (4) 100% (11) 100% (13) 87.5% (7) infrascapular area 100% (4) 100% (11) 100% (13) 100% (8) consolidation 50% (2) 55% (6) 77% (10) 62.5% (5) bilateral involvement 25% (1) 55% (6) 36% (4) 25% (2) anterior upper area 0 9% (1) 0 0 anterior lower area 0 9% (1) 8% (1) 0 lateral area 0 18% (2) 8% (1) 0 interscapular area 50% (2) 55% (6) 54% (7) 62.5% (5) infrascapular area 25% (1) 55% (6) 77% (10) 62.5% (5) pleural effusion 25% (1) 9% (1) 15% (2) 12.5% (1) pericardial effusion 0 9% (1) 8% (1) 12.5% (1) deep vein thrombosis 50% (2) 46% (5) 46% (6) 62.5% (5) data are presented as percentages (number of cases) ethics approval and consent to participate this study was approved by the ethics committee of tangdu hospital, fourth military medical university. the requirement for informed patient consent was waived in light of the urgent need to collect clinical and imaging data. consent for publication was obtained from every patient. clinical features of patients infected with 2019 novel coronavirus in wuhan lung ultrasonography for the diagnosis of severe neonatal pneumonia lung ultrasound characteristics of community-acquired pneumonia in hospitalized children lung ultrasound in the diagnosis and follow-up of community-acquired pneumonia: a prospective, multicenter, diagnostic accuracy study time course of lung changes on chest ct during recovery from 2019 novel coronavirus (covid-19) pneumonia radiological findings from 81 patients with covid-19 pneumonia in wuhan, china: a descriptive study not applicable. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.received: 30 march 2020 accepted: 6 april 2020 key: cord-290741-y3lvewlz authors: zeng, yingchun; cai, zhongxiang; xianyu, yunyan; yang, bing xiang; song, ting; yan, qiaoyuan title: prognosis when using extracorporeal membrane oxygenation (ecmo) for critically ill covid-19 patients in china: a retrospective case series date: 2020-04-15 journal: crit care doi: 10.1186/s13054-020-2840-8 sha: doc_id: 290741 cord_uid: y3lvewlz nan prognosis when using extracorporeal membrane oxygenation (ecmo) for critically ill covid-19 patients in china: a retrospective case series yingchun zeng 1 † , zhongxiang cai 2 † , yunyan xianyu 2 † , bing xiang yang 3* , ting song 1* and qiaoyuan yan 4* the world health organization (who) has characterized the disease, coronavirus disease 2019 (covid-19), as a pandemic on march 11, 2020 (www.who.int). as of march 11, the who had recorded a total of 118,326 confirmed covid-19 cases, with 4292 death cases (www.who.int). while the cumulative mortality of covid-19 is 3.63%, covid-19 has resulted in more death cases than sars and mers combined [1] . within china, a total of 80,955 cases are confirmed, with 4257 severe cases in mainland china (www.nhc. gov.cn). in severe cases of covid-19, patients experience rapid disease progression and can quickly progress to acute respiratory distress syndrome (ards) [2] . based on this, when covd-19 patients develop ards and mechanical ventilation cannot be improved, extracorporeal membrane oxygenation (ecmo) can be used [3] . as mortality rates among critically ill covid-19 patients can be as high as 61.5% [4] , ecmo may play a role in reducing mortality rates [5] . the indications of using ecmo are "for patients with severe ards, it is recommended to perform lung expansion. in the case of adequate human resources, prone positioning should be recommended for at least 12 hours per day for protective ventilation. if severe respiratory failure persisted, then ecmo should be started as soon as possible." [6] worldwide data on prognosis when using ecmo to treat critically ill patients with covid-19 infection are not available, and whether ecmo plays a role in reducing patient mortality rates is currently unknown. this research letter provides the first evidence of prognosis in treating critically ill covid-19 patients with ecmo in china. these preliminary data were collected from two medical centers of wuhan, china (table 1) . these data could be of considerable value in judging whether ecmo should be recommended as a salvage therapy for critically ill covid-19 patients. to date, the role of ecmo in the management of covid-19 is unpromising. nearly half of the patients treated with ecmo died from septic shock and multiple organ failure. the observed late complications included bleeding and infection. while the world health organization (who) interim guidelines and china's national interim guidelines for the diagnosis and treatment of covid-19 infection (sixth version) have made general recommendations for the use of ecmo for ards and critical covid-19 infection [3, 5] , the preliminary evidence available in mainland china does not support this general recommendation. certainly, understanding the risk-to-benefit ratio of performing ecmo on critically ill covid-19 patients is dynamic as the course of this novel disease unfolds. the chinese government covers all costs to treat patients with the covid-19 infection, so the cost analysis of ecmo is to date unavailable in mainland china. however, an average ecmo procedure in the usa costs $73,122 usd, indicating that ecmo is a highly resource-demanding procedure [7] . therefore, a further, larger sample size study and a comprehensive analysis of the medical value of using ecmo on covid-19 patients are urgently required. based on the two cohort case series in this study, nearly half of the critically ill covid-19 patients with ecmo were dying from septic shock and multiple organ failure. as anticipated by maclaren et al. [3] , covid-19 is a pandemic; all healthcare resources are stretched so that ecmo is not a therapy to be rushed to the frontline. therefore, interim treatment guidelines [5, 6] of recommending ecmo for critically ill covid-19 patients should be taken cautiously. coronavirus: covid-19 has killed more people than sars and mers combined, despite lower case fatality rate chinese expert consensus on supportive treatment of extracorporeal membrane oxygenation novel coronavirus pneumonia preparing for the most critically ill patients with covid-19: the potential role of extracorporeal membrane oxygenation clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study preparing for covid-19: early experience from an intensive care unit in singapore diagnosis and treatment guideline for covid-19 infection cost of extracorporeal membrane oxygenation: evidence from the rikshospitalet university hospital publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations thanks to all the participants involved in this study. authors' contributions yz, manuscript writing; zc, yxy, bxy, data collection and analysis; ts, qyy, manuscript revision. the authors read and approved the final manuscript. none. the datasets used in the present study are available from the first author and corresponding authors on reasonable request. this study was approved by the institutional review board of wuhan university school of health sciences. informed consent was waived, as this study was conducted during a public health outbreak. not applicable. none. key: cord-275154-vwnpred5 authors: bermejo-martin, jesus f; ortiz de lejarazu, raul; pumarola, tomas; rello, jordi; almansa, raquel; ramírez, paula; martin-loeches, ignacio; varillas, david; gallegos, maria c; serón, carlos; micheloud, dariela; gomez, jose manuel; tenorio-abreu, alberto; ramos, maría j; molina, m lourdes; huidobro, samantha; sanchez, elia; gordón, mónica; fernández, victoria; del castillo, alberto; marcos, ma ángeles; villanueva, beatriz; lópez, carlos javier; rodríguez-domínguez, mario; galan, juan-carlos; cantón, rafael; lietor, aurora; rojo, silvia; eiros, jose m; hinojosa, carmen; gonzalez, isabel; torner, nuria; banner, david; leon, alberto; cuesta, pablo; rowe, thomas; kelvin, david j title: th1 and th17 hypercytokinemia as early host response signature in severe pandemic influenza date: 2009-12-11 journal: crit care doi: 10.1186/cc8208 sha: doc_id: 275154 cord_uid: vwnpred5 introduction: human host immune response following infection with the new variant of a/h1n1 pandemic influenza virus (nvh1n1) is poorly understood. we utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvh1n1. methods: we profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvh1n1 infected patients. severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). a group of healthy donors was included as control (n = 15). differences in levels of mediators between groups were assessed by using the non parametric u-mann whitney test. association between variables was determined by calculating the spearman correlation coefficient. viral load was performed in serum by using real-time pcr targeting the neuraminidase gene. results: increased levels of innate-immunity mediators (ip-10, mcp-1, mip-1β), and the absence of anti-nvh1n1 antibodies, characterized the early response to nvh1n1 infection in both hospitalized and mild patients. high systemic levels of type-ii interferon (ifn-γ) and also of a group of mediators involved in the development of t-helper 17 (il-8, il-9, il-17, il-6) and t-helper 1 (tnf-α, il-15, il-12p70) responses were exclusively found in hospitalized patients. il-15, il-12p70, il-6 constituted a hallmark of critical illness in our study. a significant inverse association was found between il-6, il-8 and pao2 in critical patients. conclusions: while infection with the nvh1n1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of th17 and th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. the exact role of th1 and th17 mediators in the evolution of nvh1n1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness. methods we profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvh1n1 infected patients. severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). a group of healthy donors was included as control (n = 15). differences in levels of mediators between groups were assessed by using the non parametric u-mann whitney test. association between variables was determined by calculating the spearman correlation coefficient. viral load was performed in serum by using real-time pcr targeting the neuraminidase gene. results increased levels of innate-immunity mediators (ip-10, mcp-1, mip-1β), and the absence of anti-nvh1n1 antibodies, characterized the early response to nvh1n1 infection in both hospitalized and mild patients. high systemic levels of type-ii interferon (ifn-γ) and also of a group of mediators involved in the development of t-helper 17 (il-8, il-9, il-17, il-6) and t-helper 1 (tnf-α, il-15, il-12p70) responses were exclusively found in hospitalized patients. il-15, il-12p70, il-6 constituted a hallmark of critical illness in our study. a significant inverse association was found between il-6, il-8 and pao2 in critical patients. conclusions while infection with the nvh1n1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of th17 and th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. the exact role of th1 and th17 mediators in the evolution of nvh1n1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness. the emergence of the new pandemic variant of influenza virus (nvh1n1) has brought renewed attention to the strategies for prevention, treatment and minimization of the social and human costs of the influenza disease [1] [2] [3] [4] [5] . the great majority of nvh1n1 infections are mild and self-limiting in nature [6] [7] [8] . nevertheless, a small percentage of the patients require hospitalization and specialized attention in intensive care units (icus) [9] [10] [11] [12] . many severe cases occur in healthy young adults, an age group rarely seriously affected by seasonal influenza [9] [10] [11] [12] [13] [14] . while pregnancy and metabolic conditions (including obesity and diabetes) have been identified as risk factors for severe nvh1n1 disease, 40 to 50% of fatal cases have no documented underlying medical condition [11, 12, 14] . the new virus causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than seasonal human h1n1 virus [15] . the role of host immune responses in clearance of nvh1n1 or the role, if any, of host immune responses in contributing to severe respiratory pathogenesis of nvh1n1 infections is not known at this time. we have previously identified specific host immune response chemokine and cytokine signatures in severe and mild sars cov, h5n1 and respiratory syncytial virus infections. in these studies, early host immune responses are characterized by the expression of systemic levels of chemokines, such as cxcl10, indicative of innate anti viral responses [16] [17] [18] [19] . severe and mild sars and rsv illness could further be defined by chemokine and cytokine signatures involved in the development of adaptive immunity. interestingly, de jong et al. have demonstrated that hypercytokinemia of specific chemokines and cytokines is associated with severe and often fatal cases of human h5n1 infections [20] . to determine if host immune responses play a potential role in the evolution of mild or severe nvh1n1 illness we performed an analysis of systemic chemokine and cytokine levels in serum from severe and mild nvh1n1 patients shortly following the onset of symptoms. interestingly, we identified cytokine signatures unique to mild and severe patients. both hospitalized and outpatients were recruited during the first pandemic wave in the months of july and august 2009 in 10 different hospitals within the national public health system of spain. inclusion criteria: critical patients with respiratory insufficiency, hospitalized non critical patients with respiratory insufficiency, and mild outpatients with no respiratory insufficiency attending to the participant centers with confirmed nvh1n1 infection by molecular diagnostic methods (see below) were asked to donate a serum sample for the study in the first contact with the participant physicians. initially we enrolled 35 hospitalized patients and 31 outpatients. to determine systemic levels of chemokines and cytokines in sera from nvh1n1 infected individuals, we analyzed sera from 20 hospitalized, 15 outpatients, and 15 control subjects for levels of 29 different mediators. the final number of patients used for analysis was based on exclusion and matching criteria listed in figure 1 . exclusion criteria: patients with signs of bacterial infection defined by the presence of purulent respiratory secretions, and/or positive results in respiratory cultures, blood cultures, and/or positive urinary antigen test to legionella pneumophila or streptococcus pneumoniae were excluded from the analysis ( figure 1 ). children under 16 years old and one patient older than 80 years old were also excluded in order to make groups comparable by age. pregnant women were also excluded to avoid confusion factors during the analysis of the immune response to the virus, since pregnancy induces physiological changes in the immune system ( figure 1 ). informed consent was obtained directly from each patient or their legal representative and also from the healthy controls before enrollment. approval of the study protocol in both the scientific and the ethical aspects was obtained from the scientific committee for clinical research of the coordinating center (hospital clinico universitario de valladolid, spain). sample collection and transport blood samples were collected by experienced nurses. a single serum sample was obtained from each patient or control. serum samples were obtained after proper centrifugation and were sent refrigerated to the national influenza center of valladolid (spain), where they were stored at -70°c until immune mediator profiling, haemagglutination inhibition activity (hi) and viral load evaluation. nasopharyngeal swabs preserved in virus transportation medium were sent to the world health organization (who) associated national influenza centers of valladolid, majadahonda and barcelona, spain for viral diagnosis purposes. viral rna from nasopharyngeal swabs was obtained by using automatic extractors (biomerieux ® (marcy l'etoile, france), roche ® (basel, switzerland) and viral presence was assessed by real time pcr based methods using reagents provided free of charge by the centers for disease control (cdc, atlanta, usa) or purchased from roche ® (basel, switzerland) (h1n1 detection set) on 96-well plate termocyclers (roche ® lc480 (basel, switzerland) and applied biosystems ® 7500 (foster city, ca, usa) viral load measurement viral load was measured and compared between groups by real time reverse transcription pcr on rna extracted from serum. briefly, an external curve was obtained by using a serial dilution of human rna extracted from cultured monocytic leukemia (thp-1) cells, and human gene gapdh was employed as reporter gene. nvh1n1 neuraminidase gene was amplified by qrt-pcr in each serum sample, and crossing points were extrapolated to the external curve. analysis of samples and standard curve was conducted by using the 7500 fast v2.0.3 software (applied biosystem™). results were given as relative comparisons in (pg rna/μl). 5'-3' sequences of primer pairs: (reverse); nvh1n1 neuraminidase: 5'-tcagtcgaaatgaatgccctaa-3' (forward) and n1r 5'-cacggtcgattcgagccatg-3'(reverse). serum chemokine and cytokine levels were evaluated using the multiplex biorad © 27 plex assay (hercules, ca, usa). this system allows for quantitative measurement of 27 different chemokines, cytokines, growth-factors and immune mediators while consuming a small amount of biological material. furthermore, this system has good representation of analytes for inflammatory cytokines, anti-inflammatory cytokines, th1 cytokines, th2 cytokines, th17 cytokines and chemokines, allowing for the testing of differential levels of regulatory cytokines in the serum of severe and mild patients. additionally, interferon α, adiponectin and leptin were measured by using an enzyme-linked inmuno adsorbant assay (elisa) from r&d © systems (minneapolis, mn, usa). hi assays were performed on a 100 μl aliquot of the samples at university health network (uhn), toronto, ontario, canada. the sera was treated with receptor-destroying enzyme (rde) of v. cholerae by diluting one part serum with three parts enzyme and were incubated overnight in a 37°c water bath. the enzyme was inactivated by a 30-minute incubation at 56°c followed by the addition of six parts 0.85% physiological saline for a final dilution of 1/10. hi assays were performed in v-bottom 96-well microtiter plates (corning costar co., cambridge, ma, usa) with 0.5% turkey erythrocytes, as previously described [21] , using inactivated pandemic influenza a/california/07/2009 (nvh1n1) antigens. data analysis was performed using spss 15.0. comparisons between groups were performed using the non parametric u-mann whitney test. data are displayed as (mean, standard deviation) for clinical and laboratory parameters and as (median, interquartile rank) for data on sample collection timing and the immune mediators levels. association between variables was determined by calculating the spearman correlation coefficient (r) and data shown as (r, p value). significance was fixed at p value < 0.05 all the patients showed symptoms of acute respiratory viral infection at disease onset. the most frequent initial symptoms were (% of patients in each group: critical, hospitalized non critical, outpatients): fever (100, 100, 80), cough (100, 90, 80), headache (90, 80, 40), tiredness (100, 80, 66) and myalgia (50, 80, 46) . hospitalized patients showed dyspnoea as the initial symptom in 90% of the cases and 100% developed respiratory insufficiency at the time of hospital admission (dyspnoea and/or hypoxemia defined as o2 saturation < 95% breathing at least two liters of oxygen). ten patients required admission to an intensive care unit (icu) due to their respiratory situation. the remaining 10 were admitted to other different specialized hospital services. outpatients had no difficulties with respiratory function, showing respiratory rates under 25×'. sex composition was the same for both critical and non critical hospitalized patients: 60% of the patients were male (n = 12) and 40% female (n = 8). fifty-three percent of the outpatients were male and 47% female (n = 8 and 7 respectively) ( table 1 ). average age was as follows: hospitalized patients (36.6; 11.5), outpatients (29.7; 8.0) and healthy controls, (29.5; 13.2). critical patients were slightly older than the other hospitalized patients (table 1) . seven patients with critical illness and four severe patients with non critical illness showed previous pathologies (table 1 ). ten out of 10 of the critical patients, and 6/10 of the severe non critical patients showed a pathological chest x-ray within 24 hours of onset of the symptoms (table 1) . outpatients had received just antipyretics (paracetamol) before sample collection (none of them had received oseltamivir). one hundred percent of the hospitalized patients (critical and non critical), had received oseltamivir at the time of sample collection (table 1) . lymphopenia was a common finding in the critical patients (mean; sd) (358.5; 267.1). ldh levels were increased over normal levels in hospitalized patients, mostly in those critically ill (table 1) . furthermore, critical patients also showed high levels of cpk, got, gpt and glucose in venous blood (table 1) . critical patients stayed longer at the hospital than the other hospitalized patients (table 1) . three critical patients ultimately died (five days after onset due to hypoxemia and septic shock; 69 days after onset by refractory hypoxemia complicated by systemic candidiasis; and the third after 75 days of supportive therapy by multiorganic failure). hi activity (a/california/07/2009) was present in serum from only two critically ill patients of 50 and 51 years old (titres 1/ 1280 and 1/160 respectively) and in one 25-year-old outpatient (titre 1/160). serum from those three patients showing hi showed also the ability to block viral replication, as assessed by microneutralization assay against a/california/07/2009 (data not shown). this data supports the notion that at the time of sampling the vast majority of the patients had yet to produce table 1 clinical and laboratory characteristics of the patients hospitalized, non critical illness (n = 10) antibodies against nvh1n1 and was in the early stages of disease. the virus induced in both mild and severe patients a systemic elevation of three chemokines that have been shown to be expressed early during viral infections, cxcl-10 (ip-10), ccl-2 (mcp-1) and ccl-4 (mip-1β), with no differences in the levels of these mediators between them (data on immune mediators profiling are shown in figure 2 and additional file 1). il-8, ifn-γ, il-13, il-10 levels were higher in the hospitalized patients than in outpatients and controls (p < 0.05). il-9 behaved in a similar way. while both critical and non-critical hospitalized patients showed higher levels of il-17 and tnf-α than controls, only severe non critical patients showed significant higher levels of il-17 and tnf-α than mild. on the other hand, il-15 and il-12p70 increased exclusively in critical patients, who in addition showed the highest levels of il-6 of the compared groups. to determine if systemic viral load plays a role in chemokine or cytokine expression levels we evaluated serum for nvh1n1 levels. fifty-seven percent of critical patients, 50% of hospitalized non critical patients, and 93% of mild patients showed positive virus in serum. for those with positive virus in serum, we found no differences in viral load between critical patients, hospitalized non critically ill, and mild outpatients (figure 3 ). we found significantly higher levels of il-13 and il-17 in those hospitalized patients with negative virus in serum compared to those with virus in serum (data not shown). similarly, inverse correlations were found between viral load and il-13, il-17 in patients requiring hospital admission (figure 4 ). when mediator levels were correlated with the clinical parameters, a significant inverse association was found between il-6 and pao2 in hospitalized patients (figure 4 ). exclusively in the critical patients group, il-8 inversely correlated with pao2 [-0.7; 0.028]. in the non critically ill hospitalized patients group, a negative association was observed between il-15 and pao2 [-0.7; 0.039]. in a first attempt to understand the role host immune responses play in the evolution of severe and mild nvh1n1 disease, we assessed systemic levels of chemokines and cytokines in the sera from hospitalized and outpatients. consistent with our previous studies on early elevated expression of cxcl10, ccl2 and ccl4 in sars cov and rsv infected patients [16] [17] [18] [19] , we found in the present study elevated expression of these chemokines in severe patients (critical and non critical) and mild patients. the early expression of these chemokines in all patients likely is indicative of innate antiviral host responses. one of the most intriguing observations in our present study is the dramatic increase of mediators which stimulate th-1 responses (ifn-γ, tnf-α, il-15, il-12p70) and th-17 ones (il-8, il-9, il-17, il-6) in the severe patients ( figure 5 ). th-1 adaptive immunity is an important response against intracellular microbes such as viruses [22] . th-17 immunity participates in clearing pathogens during host defense reactions but is involved also in tissue inflammation in several autoimmune diseases, allergic diseases, and asthma [23] [24] [25] [26] [27] . increase in ifn-γ il-8, il-9, il-13 and il-10 in both critical and non critical hospitalized patients compared to mild ones indicates that they constitute hallmarks of severe disease. ifn-γ and il-8 promote antiviral immunity but also respiratory tract inflammation by recruiting neutrophils and mononuclear cells to the site of the infection [28] [29] [30] . il-9 is a th2 cytokine that induces differentiation of th-17 cells [26] . il-10 and il-13 show immunomodulatory properties. il-13 attenuates th-17 cytokine production [31] . il-10 is known to be an anti-inflammatory cytokine. in a murine model, mckinstry et al.revealed that il-10 inhibits development of th-17 responses during influenza infection, correlating with compromised protection [32] . increase of il-17 and tnf-α in hospitalized patients over control indicated that they also parallel severe disease, but the significantly higher levels of il-17 and tnf-α in severe non critical patients compared to mild (difference not found for critical ones), could reflect a beneficial role of these cytokines in this particular subset of patients. the patient who died five days after disease onset showed high viral load and undetectable il-17 levels in serum. this could reflect a protective role of il-17 in severe patients. il-15, il-12p70, il-6 constituted a hallmark of critical illness in our study. these three cytokines also mediate both antiviral and pro-inflammatory responses. il-6 is a potent regulator switching immune responses from the induction of foxp3+ regulatory t cells to pathogenic th17 cells in vivo [33] . il-15 promotes cd8 t cells homeostatic proliferation [34] in response to infection. il-12 plays a key role in the switch from innate to adaptive immunity [17] . levels of immune mediators in the four groups levels of immune mediators in the four groups. *significant differences with control at the level p < 0.05. high levels of th-1 and th-17 related mediators could support the hypothesis of a th-1+th-17 inflammatory response in the origin of the severe respiratory disease caused by nvh1n1 infection. alternatively, an increase in th-1 and th-17 cytokines may reflect a vigorous antiviral host response necessary for clearance of virus during severe lower respiratory infections. while the ability of influenza a virus to induce the production of chemotactic (rantes, mip-1α, mcp-1, mcp-3, and ip-10) and pro-inflammatory (il-1β, il-6, il-18, and tnf-α) th1 related mediators is well know from previous reports on seasonal influenza [29, 35] , this is the first report evidencing th17 response as a signature of severe influenza disease in humans [36, 37] . since there are immunomodulatory drugs which have shown to down-modulate the activity of both th1 and th17 [38] , the results obtained here supports the development of further studies on animal models aimed to clarify the role of these mediators in the pathogenesis of the acute respiratory disease showed by severe nvh1n1 infected patients. analysis of the immune mediators involved in host responses to the virus in mild and severe cases revealed th1 and th17 cytokine responses as early distinctive hallmarks of severe respiratory compromise following infection with nvh1n1. the exact role of th1 and th17 mediators in the evolution of nvh1n1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness. the influence of th17-dominant conditions (autoimmune diseases) or th1 deficient ones (hiv infection) on disease outcome should also be explored. furthermore, the impact of other regulatory cytokines elevated in severe disease (il-10, il-13) on the evolution of host immune responses to nvh1n1 infections may represent alternative therapeutics for controlling severe illness. correlation studies correlation studies. from left to right: correlation between il-13 level and viral load in serum; correlation between il-17 level and viral load in serum; correlation between il-6 serum levels and pao2. • the great majority of infections caused by the new influenza pandemic virus are mild and self-limiting in nature. nevertheless, a small percentage of the patients develop severe respiratory disease. analysis of the immune mediators involved in host responses to the virus along with the evaluation of the humoral responses in mild and severe cases may help understand the pathogenic events leading to poor outcomes. • early response to the virus in both hospitalized and outpatients was characterized by expression of chemokines (cxcl10, ccl2 and ccl4), also observed in the response to sars cov, h5n1 and rsv, which previous literature describes to correspond to innate antiviral responses. • patients who develop respiratory compromise in the first days following infection with nvh1n typically showed th1 and th17 hyper-cytokinemia, compared to mild patients and healthy controls. these cytokine profiles have been previously reported to participate in both antiviral and pro-inflammatory responses. • increased systemic levels of il-15, il-12p70, il-6 constituted a hallmark of critical illness. these mediators are known to promote the development of adaptive responses and also pro-inflammatory ones in other viral infections. • our findings constitute a major avenue to guide the design of further works studying the beneficial or detrimental role of th1 and th17 responses in this disease. the following additional files are available online: predominant cytokine profiles paralleling early nvh1n1 disease by clinical severity predominant cytokine profiles paralleling early nvh1n1 disease by clinical severity. emergence of a novel swine-origin influenza a (h1n1) virus in humans lurie n: h1n1 influenza, public health preparedness, and health care reform swine flu. after delays, who agrees: the 2009 pandemic has begun a race against time to vaccinate against novel h1n1 virus the transmissibility and control of pandemic influenza a (h1n1) virus europe's initial experience with pandemic (h1n1) 2009 -mitigation and delaying policies and practices national public health service for wales, hpa northern ireland swine influenza investigation teams: epidemiology of new influenza a (h1n1) virus infection influenza a(h1n1)v in germany: the first 10,000 cases critical care services and 2009 h1n1 influenza in australia and new zealand hospitalized patients with 2009 h1n1 influenza in the united states critically ill patients with 2009 influenza a(h1n1) infection in canada león-gil c: intensive care adult patients with severe respiratory failure caused by influenza a (h1n1)v in spain severe respiratory disease concurrent with the circulation of h1n1 influenza epidemiology of fatal cases associated with pandemic h1n1 influenza in vitro and in vivo characterization of new swine-origin h1n1 influenza viruses gene expression analysis of host innate immune responses during lethal h5n1 infection in ferrets human immunopathogenesis of severe acute respiratory syndrome (sars) dj: interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome arranz e: persistence of proinflammatory response after severe respiratory syncytial virus disease in children fatal outcome of human influenza a (h5n1) is associated with high viral load and hypercytokinemia concepts and procedures for laboratory-based influenza surveillance. us department of health and human services the effector t helper cell triade interleukin-17 and systemic lupus erythematosus: current concepts il-17 and th17 cells development and function of th17 cells in health and disease il-9 induces differentiation of th17 cells and enhances function of foxp3+ natural regulatory t cells molecular mechanisms of cytokine and chemokine release from eosinophils activated by il-17a, il-17f, and il-23: implication for th17 lymphocytesmediated allergic inflammation both conventional and interferon killer dendritic cells have antigenpresenting capacity during influenza virus infection molecular pathogenesis of influenza a virus infection and virus-induced regulation of cytokine gene expression il-17 mrna in sputum of asthmatic patients: linking t cell driven inflammation and granulocytic influx? a functional il-13 receptor is expressed on polarized murine cd4+ th17 cells and il-13 signaling attenuates th17 cytokine production il-10 deficiency unleashes an influenza-specific th17 response and enhances survival against high-dose challenge oukka m: il-6 controls th17 immunity in vivo by inhibiting the conversion of conventional t cells into foxp3+ regulatory t cells loss of il-7r and il-15r expression is associated with disappearance of memory t cells in respiratory tract following influenza infection protective immunity to influenza: lessons from the virus for successful vaccine design tc17, a unique subset of cd8 t cells that can protect against lethal influenza challenge critical role of il-17ra in immunopathology of influenza infection confronting an influenza pandemic with inexpensive generic agents: can it be done? this work has been made by an international team pertaining to the spanish-canadian consortium for the study of influenza immunopathogenesis. the authors would like to thank lucia rico and verónica iglesias for their assistance in the technical development of the multiplex cytokine assays, to begoña nogueira for her technical support, and to nikki kelvin for language revision of this article. this work was possible thanks to the financial support obtained from the ministry of science of spain and consejería de sanidad junta de castilla y león, programa de investigación comisionada en gripe, gr09/0021, programa para favorecer la incorporación de grupos de investigación en las instituciones del sistema nacional de salud, emer07/050, and proyectos en investigación sanitaria, pi081236. cihr, nih and lksf-canada support djk. this sponsorship made possible reagent acquisition and sample transportation between participant groups. the authors declare that they have no competing interests. tp, jr and iml assisted in the design of the study, coordinated patient recruitment, analysed and interpreted the data, and assisted in writing the paper. pr, mcg, cs, dm, jmg, sh, es, mg, ac, bv, cjl, jad, ch, ig and pc supervised clinical aspects, participated in patient recruitment, assisted in the analysis, interpretation of data, and writing the report. at, mjr, mlm, vf, mam, mrd, jcg, rc, sr and jme performed viral diagnosis, assisted in the analysis, interpretation of data, and writing the report. ra performed cytokine profiling, and assisted in supervision of laboratory work and writing the report. nt collected clinical data, and assisted in writing the report. tr, db performed the hai assays and assisted in writing the report. dv and al designed and performed the quantitative pcr method for viral load measurement. jfbm, djk and rol were the primary investigators, designed the study, coordinated patient recruitment, supervised laboratory works, and wrote the article. key: cord-310561-67kp743f authors: shah, akshay; frost, joe n.; aaron, louise; donovan, killian; drakesmith, hal title: systemic hypoferremia and severity of hypoxemic respiratory failure in covid-19 date: 2020-06-09 journal: crit care doi: 10.1186/s13054-020-03051-w sha: doc_id: 310561 cord_uid: 67kp743f nan coronavirus disease 2019 (covid-19) caused by severe acute respiratory coronavirus 2 (sars-cov-2) was declared a pandemic on march 11, 2020 [1] . risk factors associated with respiratory failure in patients with covid-19 include older age, neutrophilia and elevated inflammatory and coagulation markers [1] . inflammation is often accompanied by systemic hypoferremia and low iron levels may impair hypoxia sensing and immunity [2] , and increase the risk of thromboembolic complications [3] -which are all of significant concern in covid-19. however, the iron status of covid-19 patients is unclear. therefore, we sought to characterise iron parameters, including serum iron, in covid-19 intensive care unit (icu) patients and relate these to disease severity. we retrospectively evaluated any serum iron profiles that were measured in critically ill patients with covid-19 within 24 h of admission to the icu, john radcliffe hospital, oxford, uk, between march 31, 2020, and april 25, 2020. relevant clinical and laboratory data were extracted from routine datasets. the number of patients who had died, had been discharged, and were still in icu as of may 12, 2020 was recorded. we stratified patients according to severity of hypoxemic respiratory failure on admission to icu-severe (pao 2 /fio 2 ratio < 100 mmhg) versus non-severe (pao 2 /fio 2 ratio 100-300 mmhg). all patients with severe hypoxemia required invasive mechanical ventilation and prone positioning. mann-whitney rank sum test was used to compare nonparametric continuous variables between these two groups. all statistical tests were 2-tailed, and statistical significance was defined as p < .05. analyses were performed using prism version 8 (graphpad software). a total of 30 patients were included. table 1 shows the demographic, clinical and laboratory characteristics of the included patients. overall, 17 (57%) patients were male. the median (interquartile range (iqr)) age was 57 (52-64) years. compared with patients with non-severe hypoxemia, patients with severe hypoxemia had significantly lower levels of serum iron (median 2.3 (iqr, 2.2-2.5) vs 4.3 (iqr, 3.3-5.2) μmol/l, p < 0.001) and lymphocyte counts (mean (sd) 0.50 (0.2) vs. 0.87 (0.4), p = 0.0152). there were no statistically significant differences in transferrin saturation and serum ferritin levels between groups (fig. 1a) . the area under the curve for receiver operating characteristic curves for serum iron to identify severe hypoxemia was 0.95; the optimal youden index for distinguishing between severe and non-severe hypoxemia was a serum iron concentration of 2.9 μmol/l (sensitivity 0.9, specificity 1.0) (fig. 1b) . by linear regression, serum iron was associated with lymphocyte count and pao 2 /fio 2 ratio (fig. 1c, d) . the proportion of patients with pulmonary emboli was numerically higher in patients with severe hypoxemia, but this was not statistically significant. this is the first study describing iron status in covid-19. our data suggest that serum iron may be a useful biomarker for identifying disease severity in covid-19, whilst also being a potential therapeutic target. serum iron was lower when compared with other cohorts of non-covid-19 icu patients reported previously, including those with sepsis [4] . the association of serum iron with lymphocyte counts could reflect the requirement of the adaptive immune response for iron [5] and may contribute to possible t cell dysfunction reported in covid-19 [6] . hypoferremia is likely to be due at least in part to inflammation-driven increases in hepcidin concentrations [2] . anti-inflammatory drugs such as tocilizumab will likely suppress hepcidin synthesis through inhibition of interleukin-6 (il-6) [6] and so increase serum iron. other potential therapeutic strategies include hepcidin antagonists and hypoxia-inducible factor inhibitors. additionally, unlike hepcidin and il-6, serum iron is measured widely and so could assist with identification and monitoring of severity of disease. our results support performing a larger study to better characterise these patterns. icu length of stay, median (iqr), days 8 (4-11) 7 (4-9) 9 (4-12) abbreviations: apacheii acute physiology and chronic health evaluation ii, crp c-reactive protein, icu intensive care unit, iqr interquartile range, sd standard deviation fig. 1 associations between markers of iron status, lymphocyte count and severity of hypoxemia. a boxplots show the 25th, 50th and 75th percentiles (box); 10th and 90th percentiles (whiskers); and data points (circles) of serum iron, transferrin saturation (tsat) and serum ferritin, stratified by severity of hypoxemia. b receiver operating characteristic (roc) curve and youden index for serum iron in distinguishing severe and non-severe hypoxemia. c correlation serum iron and pao 2 /fio 2 ratio. d correlation between serum iron and lymphocyte count clinical course and outcome of 107 patients infected with the novel coronavirus, sars-cov-2, discharged from two hospitals in wuhan iron metabolism: an emerging therapeutic target in critical illness low serum iron levels are associated with elevated plasma levels of coagulation factor viii and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia iron parameters determine the prognosis of critically ill patients a missense mutation in tfrc, encoding transferrin receptor 1, causes combined immunodeficiency covid-19: room for treating t cell exhaustion? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the dataset used and analysed for this study are available from the corresponding author on reasonable request. research ethics committee approval was not required for this study as per the uk health research authority decision tool (http://www.hra-decisiontools.org. uk/research/). due to the retrospective nature of the study, the local institutional board (oxford university hospitals nhs foundation trust research and development) approved ethical oversight and waiver of consent. no direct patient identifiable data were collected. none.author details key: cord-260215-gsnjlhjd authors: dhanani, jayesh; fraser, john f.; chan, hak-kim; rello, jordi; cohen, jeremy; roberts, jason a. title: fundamentals of aerosol therapy in critical care date: 2016-10-07 journal: crit care doi: 10.1186/s13054-016-1448-5 sha: doc_id: 260215 cord_uid: gsnjlhjd drug dosing in critically ill patients is challenging due to the altered drug pharmacokinetics–pharmacodynamics associated with systemic therapies. for many drug therapies, there is potential to use the respiratory system as an alternative route for drug delivery. aerosol drug delivery can provide many advantages over conventional therapy. given that respiratory diseases are the commonest causes of critical illness, use of aerosol therapy to provide high local drug concentrations with minimal systemic side effects makes this route an attractive option. to date, limited evidence has restricted its wider application. the efficacy of aerosol drug therapy depends on drug-related factors (particle size, molecular weight), device factors, patient-related factors (airway anatomy, inhalation patterns) and mechanical ventilation-related factors (humidification, airway). this review identifies the relevant factors which require attention for optimization of aerosol drug delivery that can achieve better drug concentrations at the target sites and potentially improve clinical outcomes. the main goal of aerosolization is to achieve high drug concentrations in lung tissue. aerosol therapy has been used as part of the treatment for a variety of respiratory diseases [1] . indeed, there is also significant interest in the utilization of the respiratory system as a portal for systemic therapy [2] of conditions that are not purely respiratory in nature. factors such as a large surface area, thin air-blood barrier and vascular epithelium coupled with low first-pass metabolism and enzymatic activity could achieve high bioavailability for aerosolized drug therapy [3] . the possibility of achieving very high local drug concentrations at the therapeutic site for respiratory pathology, rapid onset of action and lower systemic side effects [4] has thus led to a renewed interest in the field of aerosolized drug therapy in intensive care. datura administration in india, tobacco in ancient south america and smoking pipes from north american indians are some of the early uses of airways as a route for systemic drug delivery [5, 6] . vaporized opium was used as a treatment for cough. anticholinergic properties of inhaled herbal preparations were used to treat asthma and inhaled epinephrine was first used around 1910 [7] . aerosolized therapy is used for many therapies now including bronchodilators and corticosteroids, with a particular interest in antibiotic administration reemerging recently. although there are references to the use of inhaled penicillin as early as 1946 [5] , the first randomized controlled trial of inhaled antibiotics was first reported in cystic fibrosis (cf) patients in 1981. in critical care, endotracheal antibiotic administration was first reported in the 1970s [8] , when klastersky et al. reported that endotracheal polymyxins were effective for prevention of ventilator-associated pneumonia in tracheostomized patients [9] [10] [11] . following these and other studies it was noted that there were adverse effects such as bronchospasm and poor tolerance [9] as well as concerns regarding emergence of drug resistance associated with prolonged (>3 weeks) endotracheal administration and pharyngeal aerosolization [12] . this led to a reduction in the use of inhaled antibiotics. even so, some investigators continued to prescribe intratracheal antibiotics in the critically ill patient, often successfully, especially in drug-resistant pneumonias [13, 14] . antibiotic instillation practices were used in some early studies, but this practice was largely abandoned in the 1980s. subsequent use of bench models enabled an improved understanding of the aerosolization factors such as optimal ventilator parameters, device position in the circuit and effects of humidity to enable optimal therapy [15] [16] [17] . this work was then supplemented with antibiotic studies in experimental pneumonia that demonstrated higher lung tissue concentrations of antibiotics [18] . the later development of 'new generation' devices such as the ultrasonic nebulizer and the vibrating mesh nebulizer (vmn) encouraged further study and application of aerosol therapy in critical care because of the ability of these devices to consistently generate desired aerosol particle sizes which are considered optimal for deep lung penetration [17, 19, 20] . previously, the formulation of drugs used for aerosolization was the reconstituted form of compounds developed for parenteral administration. these were poorly tolerated by patients due to hyperosmolarity and added preservatives (i.e. phenols), which induced bronchial irritation and bronchospasm, leading to abandonment of this route of therapy. these formulation issues were particularly problematic for antibiotics until the 1990s, when aerosolized tobramycin was evaluated in patients with cf chronically infected with increasingly resistant pseudomonas aeruginosa [21, 22] . a number of highquality studies using preservative-free and iso-osmolar formulations of tobramycin showed improvements in lung function, a decreased exacerbation rate and reductions in sputum bacterial load [21] [22] [23] . these results have encouraged further developments in the application of aerosolized antibiotics in non-cf patient populations such as critical care. in the critically ill patient, certain anatomicophysiological changes can significantly affect the pharmacokinetics (pk)-pharmacodynamics (pd) characteristics, thus causing dosing difficulties [24] . mechanically ventilated patients pose a challenge for the effective delivery of aerosolized drugs [25] . these various factors need to be considered and optimized to achieve desired therapeutic outcomes with aerosolized drug therapy [25] . the research interest in aerosol drug therapy in critically ill patients is not yet reflected in the bench-to-bedside transfer of knowledge. one report mentions that up to 95 % of intensivists are routinely prescribing aerosol medications [26] . this report also highlighted the lack of application of scientific principles during therapy and indicated the need for education and research in the bench-tobedside transfer of knowledge [26] . in another study, every fourth critically ill patient and every fifth ventilated patient received aerosol therapy [27] . a recent international survey performed in europe, asia, australasia and north america showed that although 45 % of icus practice antibiotic nebulization, very few actually follow the recommendations [28] . given the commonness of use of aerosolization in critical care, yet the uncertainty over the optimal approach for administration, this article aims to discuss the essential concepts related to aerosolized drug therapy in critical care. an aerosol is defined as a suspension of liquid or solid in a gaseous medium [29] . for successful aerosolization, consideration of the aerosol system is required. the aerosol system includes the drug, the aerosol device, the disease (i.e. the target site) and the patient's respiratory system, with the ventilator being an additional factor in mechanically ventilated patients. the aim of the aerosol system is to produce aerosols with characteristics suitable for drug delivery to the lungs. drug deposition, absorption, metabolism and elimination are essential determinants of the pharmacokinetic profile resulting from the aerosol system. key expressions used to evaluate the aerosol system performance include [30] the following: emitted dose (ed)-the amount of drug exiting the delivery device. fine particle fraction (fpf)-the mass of particles below a cut-off diameter [31] . the overall efficiency of the aerosol system is a composite of the ed, the dose delivered to the lung (fpf as a surrogate marker) and lung bioavailability. the ed and fpf are normally determined in vitro and are governed by particulate properties and device design. the bioavailability of the drug is influenced by patient factors such as airway and lung anatomy, drug permeability across membranes, metabolism of the drug and phagocytic clearance in the lung [32] as well as fpf. the efficacy of the aerosolized drug depends on the dose deposited at the target site of action as well as its distribution in the lungs [33] . deposition in the airways can occur by inertial impaction, gravitational sedimentation or diffusion (brownian motion) (fig. 1) . because of the turbulence and high air velocity associated with aerosolization, an inertial impaction method is predominant in the first 10 branchings of the airway [34] . this proximal region is the target for aerosol therapy for diseases such as copd, asthma and ventilatorassociated tracheobronchitis. in the distal five to six airway generations, however, sedimentation predominates due to lower air velocity [34] . at the alveolar level, minimal air velocity means no effect of impaction will occur and a combination of sedimentation and diffusion will influence drug deposition [34] . most aerosolized particles for therapeutic purposes are in the range of 2-5 μm and diffusion is the predominant mechanism for lung deposition. the optimal technique for aerosolization is important to achieve distal airway and alveolar deposition. factors affecting aerosolized drug delivery in the critically ill patient drug concentrations in lung tissue are affected by the aerosolized dose administered, patient factors, device factors and the formulation of the drug. mechanical ventilation (mv) introduces additional elements such as the circuit and the ventilator and associated factors. for the purposes of describing the factors affecting aerosol therapy, critically ill patients could be classified into two groups: ventilated patients and non-ventilated patients [35] [36] [37] [38] . figure 2 shows the factors conducive for effective aerosol drug delivery in the critically ill mechanically ventilated and non-mechanically ventilated patient groups. airflow and tidal volume influence the effect of airway anatomy on aerosol deposition. patients suffering from airway obstruction such as asthma or copd have impaired mucociliary clearances and mucous retention [39] . for drugs with poor trans-mucous permeability (e.g. aerosolized aminoglycosides) this could mean reduced drug delivery and hence impaired efficacy, although this is yet to be confirmed in clinical studies [40] . chronic inflammation may result in airway remodelling, which changes the dynamics of airflow [33, 35] , and impaired mucociliary clearance, thus reducing the pulmonary drug deposition [33, 41] . these changes lead to a proximal shift in the airway deposition pattern of the aerosols [42] . significance-abnormal airways and impaired mucociliary clearance serve as a barrier to effective aerosolized drug therapy when the target site is the lung parenchyma. the airflow is not homogeneous throughout the lungs even in health. the result in an upright patient is that the apical portions of the lungs receive lung deposition of the order of a 2:1 higher ratio compared with the basal regions [43] . this difference is significantly reduced in the supine position [44] . moreover, most lung diseases are regional which adds to the heterogeneity to regional airflow, an important determinant of aerosol deposition [45] . for example, it has been shown that there is lower deposition in areas of poor air flow (i.e. atelectatic lungs) [46] . in the area of antibiotics, there is a large body of work with experimental pneumonia models which have demonstrated that lung tissue concentrations of nebulized amikacin, using a ultrasonic nebulizer, was significantly higher than the concentrations resulting from administration via the intravenous route [47, 48] . indeed, even though deposition of nebulized drug decreased with more severe pneumonia, it still resulted in higher lung tissue concentration than that achieved from intravenous administration. figure 3 illustrates this phenomenon. the same group also demonstrated that nebulized amikacin resulted in greater bactericidal activity leading to greater sterility rates compared with the intravenous route [49] . when compared with continuous intravenous [19, 20, 25, 29, 31, 38, 45, 51, 81, 82, 91, 93, 130] . niv non-invasive ventilation, hme heat and moisture exchanger, pmdi pressurized metered dose inhaler, aad adaptive aerosol device, vmn vibrating mesh nebulizer, dpi dry powder inhaler, peep positive end-expiratory pressure fig. 3 effects of regional lung aeration and pneumonia on drug concentration in lungs. a relationship of lung aeration (%) to pulmonary concentration of amikacin (μg/g) for different routes of administration. b relationship of route of drug administration to pulmonary concentration of amikacin (μg/g) for different severities of pneumonia. pulmonary concentrations derived from homogenized lung tissue specimens measured by an immunoenzymatic method. figure derived from elman et al. [47] infusion of ceftazidime, frequent nebulization achieved higher lung tissue concentrations with better bactericidal effects in an experimental model of pseudomonas pneumonia [50] . significance-differences in regional lung aeration may explain some of the variability in therapeutic outcomes amongst different lung diseases. in a critically ill, spontaneously breathing patient, air flow is likely to be turbulent leading to impaction in the proximal airway. for drugs dependent on lung deposition for their effect, this results in a decreased pharmacological effect. in contrast, laminar flow patterns are considered to enable optimal lung deposition [51] . in the critically ill patient, certain mv settings (e.g. square wave airflow pattern) enable generation of laminar airflow to improve drug deposition in the lungs. on the other hand, lower flows may reduce the ed when dry powder inhalers (dpis) are used [52] . using pressurized metered dose inhalers (pmdis) with valved holding chambers (vhcs) or spacers could mitigate this effect. significance-whilst a laminar flow pattern would be beneficial for aerosolized drug delivery, mechanistic data need to be confirmed using clinical trials. diseases such as pneumonia and other inflammatory lung diseases result in deficiencies of lung surfactant both in content and/or effect [53, 54] . drugs with high solubility will probably have a uniform dispersion compared with insoluble drugs. inferentially the soluble drugs are likely to have longer and more effective lung residence times, thus improving drug potency [55] . surfactant deficiency is associated with atelectasis, which in turn impairs drug deposition [42] . studies on surfactant replacement therapy in acute lung injury and ards, however, have failed to demonstrate benefit and may even be deemed harmful [56, 57] . aerosolized surfactant therapy has been studied as a mucokinetic agent in specific conditions [58] . its application for this purpose in critically ill patients needs further study. significance-uncertain benefits requiring further studies to demonstrate effects of surfactant. a major fraction of the aerosolized drug is entrapped in the mucous in the conducting airways. factors such as particle size, solubility, lipophilicity and charge govern the ability of the drug to penetrate this mucous barrier. for example, steroids and antimicrobial agents are seen to have reduced trans-mucous transport [39, 40] . atelectasis is a common occurrence in the majority of critically ill patients. this may have adverse effects on drug deposition and may result in heterogeneous distribution in the lung [59] . significance-both, mucous and atelectasis serve as a barrier to effective aerosolized drug therapy. a detailed discussion on the effect of device-related factors has been reviewed elsewhere [20, 60] . appropriate particle sizes are important to enable adequate concentrations at the target site. particle size also determines the mechanism of deposition in the respiratory system [31] . particles that distribute deep in the smaller airways (<5 μm) are reported to have up to 70 % deposition efficiency [33, 61] . smaller particles (1-3 μm) are considered to have the optimal droplet size for efficient deposition in the alveolar airspaces, for systemic delivery [62] . in this regard, the efficiency of the aerosol device can be defined to be the ability to generate the aerosol in the desired particle size range. pmdis with spacers or vhcs have demonstrated superior deposition efficacy over nebulizers in various studies [63] [64] [65] , although the vhcs cannot be used for mechanical ventilators due to their inability to trigger/ activate the device. dpis have no propellant, are inherently breath-synchronized/activated and produce little variation in particle size. these features may make dpis the preferred delivery device. in critically ill patients, however, poor respiratory reserve and diminished patient efforts are barriers to achieving the desired respiratory pattern for effective use of dpis. the dpis also vary widely in their efficacy [66] and their use in mechanically ventilated patients is not typically possible with a standard set up [67] . thus, dpis are presently used in stable and unventilated patient groups. both pmdis and dpis are limited by the formulations available to be delivered by these devices. nebulizers are different devices that are used to transform liquid formulations and suspensions into an aerosol form. these devices can be used to deliver larger volumes of a drug as an aerosol either intermittently or continuously, for prophylaxis or treatment purposes. depending on their mechanism of operation, there are three types of nebulizers: jet, ultrasonic and smns. jet nebulizers are the cheapest and simplest, albeit being inefficient in drug delivery [68] . their drawbacks are noise, poor dosing control and the requirement for changes in the ventilator settings such as airflow and tidal volume; although improvements have been made in the form of reservoirs and new baffles that ensure more optimal particle sizes. breath-enhanced versions of the jet nebulizers could increase fpf, improve drug delivery and reduce drug loss. there are limited studies evaluating the efficiency of these newer jet nebulizers and data are certainly lacking in critical care settings [69] . newer ventilators have in-built nebulization systems which improve the efficiency by synchronizing nebulization with the respiratory cycle. ultrasonic nebulizers are infrequently used and also have limitations [19, 70] . they are expensive, large in size, increase concentration of the drug during nebulization and can cause thermal inactivation of the nebulized drug. mesh nebulizers are the result of improvement in nebulizer technologies. although more efficient and with significant advantages, there is a dearth of human studies using mesh nebulizers. despite major improvements in the technology there is a need to reduce the cost of these devices. table 1 compares and contrasts the principles, advantages and disadvantages of different nebulizers. significance-where possible, pmdis with spacers should be used. dpi use is likely to be limited in critical care. for nebulizers, the device should be selected according to the formulation used and the desired site of deposition and effect. the rate and extent of absorption of the aerosolized substances is dependent on the molecular weight, ph, electrical charge, solubility and stability. macromolecules < 40 kda are observed to be better absorbed (in minutes) in the bloodstream following inhalation in the airways (e.g. insulin, molecular weight (mw) 5.7 kda) [71] . however, macromolecules > 40 kda are absorbed slowly over hours (e.g. albumin, mw 68 kda) [72] . molecules with mw > 30 kda may need an absorption enhancer for absorption in the alveoli [73] . significance-depending on the desired site of action, appropriate drug formulations should be used alongside delivery devices that would generate a suitable particle size. a combination of helium and oxygen (heliox) reduces gas density and increases aerosol deposition, particularly in the peripheral lung [74] . with pmdis, heliox has been reported to increase aerosolized drug delivery during mv [75] . however, with jet nebulizers heliox also increases the nebulization time, requiring higher gas flows to compensate for the low-density gas [76] . in an experimental study, there was no increase in lung deposition of nebulized ceftazidime in bronchopneumonic lungs compared with healthy lungs [77] . significance-further investigations and large-scale trials are needed to evaluate the effect of heliox in critical illness. because of a variety of proposed mechanisms, patient sputum is thought to cause aminoglycoside inactivation resulting in 'sputum antagonism' [78] . significance-uncertain, therefore the effect of sputum antagonism requires further in-vivo investigation. current data from cf patients support use of inhaled aminoglycosides [79, 80] . aerosol therapy is routinely used in mechanically ventilated patients, both invasive and non-invasive, and is inherently challenging due to the interplay of a variety of factors [25] . however, not all nebulization techniques are comparable. the patient position, formulation, temperature, endotracheal tube size, presence of airway obstruction or ventilatory asynchrony, flow pattern, respiratory rate, dose and frequency applied or position of the nebulizer in the circuit are important factors that influence delivery to the lung. the higher the turbulence, the lower the drug deposition in the distal airways. optimal settings of nebulization are not tolerated by many patients (such as those with severe hypoxemia, associated with ards or pneumonia) and require the addition of deep sedation and relaxation, which prolongs the duration of mv. disposition in unilateral pneumonia might be imbalanced. currently, nebulizers and pmdis, with and without spacers, are two types of devices available for use in mechanically ventilated patients. depending on the site of action, devices producing an appropriate particle size should be used [81] . nebulizers take a considerably longer time to deliver a standard dose as compared with other devices. there is also a variation in efficiency between nebulizer types and between nebulizers in different batches [20] . this effect is accentuated when coupled with the effects of different ventilator modes and lung mechanics [82] . inadequate cleaning and disinfection of the nebulizer increases the risk of nosocomial pneumonia [83] . compared with jet nebulizers, vmns could increase the drug delivery by 2-4-fold [19] , although as discussed previously the nebulizer choice is dependent on the formulation and the desired delivery site. pmdis are easy to administer, require less staff time, provide reliable dosing and have minimal risk of bacterial contamination when compared with nebulizers. when used with a collapsible spacer in the circuit, the circuit does not need to be disconnected [25] . pmdis are also more cost-effective than nebulizers [84] . although only bronchodilators and anti-inflammatory agents are available for this device, it is seen that using pmdis significantly reduces overall costs of care and could be equally effective in the treatment of inflammatory airways disease such as asthma and copd [20, [84] [85] [86] [87] [88] . in-vitro studies have shown improved aerosol delivery with large spacers compared with that with small spacers for pmdis and vmns [89] . published recommendations for the correct methods of their use are available [25] . others have shown modest improvement in the aerosol delivery [90] . significance-pmdis are possibly more effective than nebulizers. vmns appear superior to other nebulizer types although the choice should be dependent on the drug formulation properties and the desired deposition site. at this time, there is insufficient evidence to support the use of either delivery method over the other [91] . the use of spacers with pmdis needs further clinical trial to test the efficacy. in-vitro studies [92] using adult ventilators have shown that, when using vibrating mesh and ultrasonic nebulizers as well as the pmdi, a position 15 cm from the y-piece in the inspiratory limb of the circuit yields the highest drug delivery. in a constant flow pattern of ventilation, the vmn connected to the endotracheal tube could be as effective [93] . however, jet nebulizers seem to perform better when positioned closer to the ventilator, possibly due to the effect of the continuous gas flow 'charging' the circuit, which functions as an aerosol reservoir [92] . for non-invasive ventilation (niv), using the vmns position after the exhalation port is more efficient for drug delivery compared with that before the exhalation port [94] . significance-the best position for the aerosol generator may be 15 cm from the y-piece in the inspiratory limb. invivo studies are required to make definitive conclusions. although the endotracheal tubes and tracheostomy tubes present certain similarities, the tracheostomy tube is shorter and more curved than an endotracheal tube. in patients who are not mechanically ventilated, a tpiece interface between the tracheostomy tube and the nebulizer has been demonstrated to be more effective than a tracheostomy mask [95, 96] .preferably, the inner cannula should be removed before nebulization particularly for the smaller sized tubes [97] because smaller diameter airways lead to an increase in the resistance to airflow, resulting in increased drug deposition in the artificial airways and tracheobronchial region [98, 99] . significance-for aerosolized drug delivery, larger size artificial airways are better. in mechanically ventilated patients, a temperature of 34-41°c (average 37°c) and relative humidity of 95-100 % are required to prevent heat loss [100] . humidification also prevents drying of secretions, mucous plugging and consequently atelectasis. there are two major methods of humidification-active and passive. active methods include a heated humidifier (hh) and passive methods include a heat and moisture exchanger (hme). humidification is thought to have a significant effect on aerosol drug delivery. because of the hygroscopic effects of humidification, there may be a 2-3-fold growth in particle size as they pass through airways. this increase in size may reduce peripheral lung drug deposition and hence pharmacological efficacy [101] . compared with humidified conditions, drug delivery can be doubled in non-humidified conditions [92] . it is recommended that hh should be ceased for the duration of therapy. of interest, in an in-vitro non-mechanically ventilated model, using the excipient enhanced growth (eeg) of sub-micrometre particles, one group has demonstrated increased aerosol deposition in the airways and lungs [102, 103] . further investigations of this method are required to harness its effect in mv. the hme is a physical barrier and should not be placed between the delivery device and the patient. the particulate air filter in the expiratory limb, used to protect the ventilator and the flow meter, could get saturated resulting in airflow obstruction. it is recommended that the filter should be changed after every nebulization treatment [18, 26, 28] . significance-using hme or a particulate air filter with nebulization could result in air flow obstruction. awareness and routine changing of air filters after each nebulization should be performed. ventilator breath characteristics have an important effect on the efficacy of aerosol delivery. slower inspiratory flows, long inspiratory times [104] and tidal volumes > 500 ml (using a pmdi) [105] correlate well with improved aerosol delivery. higher bias flow is seen to reduce the delivery efficacy of nebulizers [19] . decelerating flow pattern is considered inferior to constant flow pattern for drug delivery [93] . the effect of ventilation mode is negligible for pmdis [16] . the delivery efficiency in patients on niv is seen to be comparatively less [106] . however, it must be remembered that specific techniques of ventilation may in themselves produce a greater benefit than the relative detriment of drug delivery (e.g. in niv and asthma). hence, in acute asthma, niv plus nebulization is more effective than nebulization alone [107] . a prescribed ventilatory pattern may not be practical in the critically ill patient. the most effective combination of tidal volume, flow and other ventilator parameters for aerosol delivery can be calibrated to the drug and delivery device using in-vitro models [108] . significance-tidal volumes > 500 ml may enhance aerosolized drug delivery. niv results in effective therapy despite reduced drug delivery in conditions like asthma. ventilator settings optimal for nebulization, however, could lead to patient-ventilator dyssynchrony in severely hypoxemic patients (e.g. due to severe pneumonia)-thus requiring deep sedation, which may increase the duration of mv. positive end-expiratory pressure (peep) is a commonly used ventilator setting as part of the lung protective ventilatory strategy in severe lung diseases [109] . peep has significant effects on regional ventilation and perfusion [110] and hence could influence the pk of an aerosolized drug. in an animal model using radiotracers, peep was found to enhance aerosol clearance. this could be due to the stretching of the alveolar epithelium and enhancing the distribution of aerosol into the bloodstream [111] . significance-peep is potentially beneficial, although further data are needed to quantify the effect on aerosolized drug delivery. the choice of one antimicrobial against another should consider efficacy data, costs, local antimicrobial resistance patterns and drug availability. aminoglycosides require tissue concentrations >10-fold higher than the mic to be maximally effective. because airway inflammation could increase systemic absorption and the molecular weight is low, serum aminoglycoside concentrations should be monitored to avoid systemic toxicity. beta-lactams are rapidly cleared from airways, requiring frequent administration. colistin is administered in its anionic (methanesulfonated) form-colistimethate. despite high doses (up to 1 million units of colistimethate every 8 hours (80 mg of colistimethate, equivalent to 33 mg of colistin base)) as administered in colonized patients with bronchiectasis, lung epithelial lining fluid concentrations are not above 4 mg/l after 8 hours (upper threshold of eucast mic breakpoint for pseudomonas) or even above 2 mg/l after 8 hours in many patients (eucast mic breakpoint for klebsiella sp. and acinetobacter baumannii). therefore, high doses (5 million units every 8 hours) should be considered in pneumonia. despite delivery of drugs via the inhaled route, significant extrapulmonary drug losses may mean that the actual amount of drug delivered might be less than 60 % of the ed into the trachea and even less will reach the alveolar space [112] . this factor should be taken into account when calculating dosing regimens. a number of animal studies have been useful to better understand the mechanistic principles of aerosol therapy. guillon et al. [113] showed effective teicoplanin nebulization during mv with good pk properties compared with the intravenous route. others successfully nebulized ceftazidime to achieve high local concentrations [77, 114] . further studies are required to quantify the exact dosing amount and schedule using pk studies. doses should be different in patients with colonization, tracheobronchitis or pneumonia. increasing doses (e.g. 5 million units of colistin) require longer periods of nebulization (~1 hour) which is not well tolerated by patients suffering from ards. significance-the inhaled drug dose is likely to be significantly higher than expected due to concerns about drug losses. further pk-pd studies are required to guide inhaled drug dosing. most of the drug losses occur in the exhalation phase of ventilation. to minimize this loss, the actuation of the inhaler or nebulizer could be matched with inspiration [17] . however, the use of the spacer-pmdi combination negates the effect of lack of breath synchronization [105] . the effect of breath synchronization on aerosol deposition is unproven. using radiolabelled aerosols, dubus et al. [115] showed that there is no significant increase in aerosol deposition in neonatal ventilation with breath synchronization. further investigations are thus needed to evaluate the effects of breath synchronization on aerosol deposition. in any event, devices which introduce synchronization of drug delivery facilitate tolerance. significance-breath actuation of the drug delivery devices has the potential to improve drug delivery. however, trial-based data are required to establish efficacy in aerosolized drug deposition. high-flow nasal oxygen therapy is becoming a widely prevalent therapy in intensive care [116] . a number of factors influence the nebulization therapy in patients using high flow, which was studied recently in an invitro model [117] : 1. position of the nebulizer-a position distant from the humidifier (closer to the patient) improved delivery of the drug upstream. 2. nebulizer type-vmns demonstrated improved delivery as compared with jet nebulizers, although the nebulizer choice is dependent on the formulation and desired site of action. 3. airflow-the delivery of respirable mass is lower with higher airflow and improves at a lower airflow. 4. patient efforts-converse to the effect of airflow with a high-flow oxygen system, in situations mimicking respiratory distress (i.e. increased patient inspiratory airflow) the delivery was in fact better. an open mouth, on the contrary, had no significant difference to closed mouth with respect to drug delivery. significance-limited data suggest better drug delivery using vmns at a lower airflow even in patients with respiratory distress. further in-vivo studies need to be performed using high-flow oxygen therapy devices. contemporary applications of aerosol therapy in critical care: focus on antibiotics table 2 summarizes the common applications of aerosol therapy in critical care. aerosolized bronchodilators and corticosteroids have been effectively utilized in critical care. aerosolized antibiotics are quickly gaining more data to support their position in the critical care armamentarium. with improvements in drug formulation and delivery devices, more is now known about the optimal conditions required for effective aerosolized therapy as summarized in fig. 2 . despite these developments there are concerns that best evidence for administration is not being applied, particularly for aerosolized antibiotic therapy [118, 119] . clinical and experimental study data for aminoglycosides and colistin are perhaps most numerous for antibiotics in critical care [28] . aminoglycosides are concentrationdependent antibiotics whereby the bactericidal effect is best described by the c max /mic ratio. studies have shown that intravenous aminoglycosides penetrate poorly into the epithelial lining fluid [48, 120] . in an escherichia coli inoculation pneumonia model, aerosolized amikacin was seen to achieve significant lung concentrations [48] . figure 4 is an illustration of this phenomenon. on the other hand, with repeated administration, there was no accumulation effect and hence no toxicity concerns with aerosolized amikacin [46] . in experimental studies, the serum concentration of amikacin was higher when aerosolized amikacin was used in a pneumonia model [48] compared with that of healthy lungs [46] . moreover, a combination of intravenous and aerosolized aminoglycosides has not been shown to increase cure rates compared with that of aerosolized antibiotic alone. thus, for the treatment of ventilator-associated pneumonia, aerosol therapy alone may be adequate without the need for intravenous therapy, decreasing the risk of systemic toxicity [121] . colistin, also a concentration-dependent antibiotic, is another antibiotic used widely in aerosolized form. colistin aerosolization is not approved by the fda and is not licensed for human use in china. like aminoglycosides, colistin has poor lung penetration when given intravenously. experimental studies have shown that a rapid and high bactericidal effect can be achieved with aerosolized colistin [112] . figure 5 illustrates this phenomenon. as demonstrated by lu et al. [112] , with low serum concentrations resulting from aerosolized colistin in an inoculation pneumonia model, the risk of toxicity is minimal. in a prospective observational study, lu et al. [121] demonstrated similar clinical cure for patients with vap where susceptible p. aeruginosa or a. baumannii were treated with only intravenous colistin and mdr strains were treated with nebulized colistin. combined intravenous aminoglycoside and aerosolized colistin has not been shown to be superior to aerosolized colistin alone although implemented worldwide. the benefit from the use of aerosolized colistin instead of systemic colistin is to avoid nephrotoxicity, and this was further confirmed in one randomized clinical trial [122] . observational cohort studies report less adverse events than randomized clinical trials. indeed, there is potential to cause systemic toxicity (e.g. nephrotoxicity by aminoglycosides) or local toxicity in the form of airway irritation, cough and often bronchospasm [123] , worsening hypoxemia (and secondary arrhythmias) as well as pulmonary injury when using aerosol therapies [124] . ventilator malfunction and obstruction of expiratory filters have been reported and contraindicate the use of drugs with lipid components or lactose sugar in the formulation (such as zanamivir or lipid-based amphotericin formulations), and careful monitoring of the potential increase of airway pressure and oxygen saturation is required to anticipate severe adverse events [125] . modification of ventilator parameters for appropriate jet nebulizer use (table 3) is not tolerated by some patients, increasing the work of breathing and ventilator dyssynchrony (requiring additional sedation). poor tolerance may preclude the use of aerosolized antibiotics in patients with pao 2 /fio 2 < 200 mmhg or high peep requirements. initial concerns regarding drug resistance as a result of intratracheal or nebulized use of antibiotics (polymyxin b) have been investigated and do not appear to be supported, with aerosolized antibiotics using newer devices no more likely than intravenous therapy to confer bacterial resistance [126] . this was probably linked to previousgeneration nebulizers and the technique of administration (instillation, pharyngeal aerosolization, etc.). however, this finding must be interpreted reservedly because no longterm follow-up has been performed. tolerance of aerosolization is different when drugs are nebulized for different durations of time. as a consequence, this might limit use of aerosolization in patients with ards or severe hypoxemia, such as severe pneumonia (in contrast to ventilator-associated tracheobronchitis), who often have poor tolerance. when high doses of colistin are nebulized, the infusion volume may represent an hour of nebulization and many patients require added sedatives or relaxation (with potential increased risk of myopathy or hypotension). this requirement would be associated with a prolonged mv period and extra length of stay [125] . further clinical trials should therefore use pre-defined outcome parameters (rather than surrogates), control by hypoxemia and careful recording of adverse events. environmental contaminations resulting from aerosolization of drugs in an open circuit system pose a small but significant risk to the caregivers. using expiratory filters with valves in the aerosol delivery devices could minimize this. this occupational risk exposure should be assessed and interventions to mitigate the risks should be implemented [127] . when using aerosolized antibiotics, it is recommended to change the filter after every therapy. optimizing the aforementioned factors could lead to effective drug delivery. however, it is important to realize that aerosolization of medications does not automatically lead to beneficial drug effects and may in fact be harmful, as shown in some studies [128, 129] . aerosol therapy provides effective drug delivery in the critically ill patient. careful consideration of the various elements that affect pharmacological effect of aerosolized therapies is essential to derive optimal therapeutic benefit. effective drug delivery alone does not ensure successful aerosol drug therapy. it is crucial that the drug in its aerosolized form should have efficacy in the specific disease condition to derive clinical benefit. good quality data and clinical experience support use of bronchodilators such as salbutamol, anti-infectives such as tobramycin, aztreonam and colistin, and antiinflammatory agents such as budesonide. although with application of principles it is possible to provide aerosol drug delivery, the effectiveness of the therapy in disease conditions is yet to be proven. this is because there is a scarcity of high-quality trial-based data in this area to quantify how effective these agents are in the critically ill patient. given the challenges of effective treatment of the critically ill patient, it is necessary to optimize as many factors as possible for effective drug delivery. hence, it is important that guidelines for aerosol therapy are developed. it is envisaged that as the technologies become mature through rigorous evaluation, a diverse range of aerosol therapies with unique advantages (i.e. controlled release/sustained release or direct targeting) and or for specific indications may be possible. table 3 optimization of ventilator parameters required for aerosolization of antibiotics modified from lu et al. [121] • nebulizer placement-in the inspiratory limb 10 cm proximal to y-piece • expired aerosolized particles collected in a filter hme heat and moisture exchanger, rr respiratory rate, i:e inspiratory: expiratory ratio, vt tidal volume fig. 5 comparison of lung concentration (measured by hplc) and bacterial burden of colistin between aerosolized and intravenous administration. samples taken 1 hour after the third aerosol in the aerosol group and the fourth infusion in the intravenous group and 49 hours after the bacterial inoculation. diagram derived from data of lu et al. 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surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant authors' contributions jd conceptualized the article, collected data, drafted, revised and submitted the manuscript. jff participated in the initial design and edited the manuscript. h-kc helped in the final editing of the manuscript. jr helped in the final editing of the manuscript. jc helped with design of figures and tables and in the final editing of the manuscript. jar participated in the design, drafting, editing and submission of the manuscript. all authors read and approved the final manuscript.competing interests jr has received funding for consulting from bayer. none of the other authors have any competing interests, of a financial or non-financial nature.author details 1 key: cord-321440-sts3re6p authors: klein, sebastian j.; fries, dietmar; kaser, susanne; mathis, simon; thomé, claudius; joannidis, michael title: unrecognized diabetes in critically ill covid-19 patients date: 2020-07-09 journal: crit care doi: 10.1186/s13054-020-03139-3 sha: doc_id: 321440 cord_uid: sts3re6p nan since the first discovery of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and description of the coronavirus disease 2019 (covid-19), a pandemic has evolved. due to winter tourism, tyrol, a federal province of austria with 750,000 inhabitants, has emerged as an epicenter in austria being faced with a surge of critically ill covid-19 patients reaching its peak on april 8, 2020. we retrospectively analyzed the incidence of diabetes in all critically ill patients admitted to the four dedicated covid-19 intensive care units (icu) at the university hospital in innsbruck, tyrol, austria, which covers 180,000 inhabitants as primary hospital and also functions as a tertiary referral center for the whole region of tyrol. patients were included in the analysis if they were 18 years of age or older, had confirmed covid-19, and were admitted to an intensive care unit from march 11 to april 29, 2020. covid-19 was confirmed by reverse-transcriptasepolymerase-chain-reaction assays of nasopharyngeal swab specimens. data were abstracted manually from electronic and paper-based health records. glycated hemoglobin (hba1c) was measured on admission by high-performance liquid chromatography (hplc-uv/ vis). of 47 covid-19 patients admitted to our icus, hba1c was measured in 44, which were included in the analysis ( table 1 ). the median age of patients was 61.5 (iqr 53.0-68.0). thirty-five (80%) patients required invasive mechanical ventilation (imv). additionally, 4 patients (9%) required veno-venous extracorporeal membrane oxygenation (vvecmo). at the time of writing this article, 11 patients (25%) have died in the hospital, 25 (56.8%) have been discharged alive from the icu, 20 patients (45.5%) were discharged alive from the hospital, and 13 patients (29.5%) are still hospitalized. median hba1c was 6.5% (iqr 6.1-6.7%). when categorizing patients according to hba1c [1] , 24 (54.5%) were considered to have diabetes mellitus (hba1c ≥ 6.5%), 16 (36.3%) were considered to have prediabetes (hba1c ≥ 5.7% < 6.5%), and only 4 (9%) had no diabetes (hba1c < 5.7%). interestingly, only 7 (15.9%) patients showed a medical history of diabetes mellitus. five (11.4%) patients had previously been treated with antidiabetic medication, and no patient had required insulin prior to hospitalization. patients with increased hba1c levels developed higher maximum crp and il-6 levels during their icu stay. there was a trend to higher in-hospital mortality with increasing hba1c. the median body mass index (bmi) was 29.4 kg/m 2 (iqr 26.2-32.7), which is slightly higher than a previously studied sample of critically ill patients in austria [2] , with a median bmi of 26 kg/m 2 . bmi did not differ significantly between diabetic and non-diabetic patients (fig. 1) . in conclusion, 85% of covid-19 treated in our intensive care units had prediabetes and diabetes which appear to be predisposing factors for severe manifestations of covid-19, potentially impairing outcome. this is in line with previous observations from the first sars-cov epidemic [3] . hyperglycemia may alter the response of the innate immune system through several mechanisms. it may induce toll-like receptor expression and inhibit neutrophil function, decrease vascular dilation, and increase permeability [4] . furthermore, it can cause direct glycosylation of proteins, thereby altering the structure of complement, and may cause a cytokine storm [4, 5] . recent data demonstrating viral particles in endothelial cells of several organs suggest "endotheliitis" as a possible mechanism of organ dysfunction leading to critical illness in covid-19 patients which may be aggravated by endothelial abbreviations: iqr interquartile range, bmi body mass index, hba1c glycated hemoglobin, crp c-reactive protein, il-6 interleukin-6, copd chronic obstructive pulmonary disease, sars-cov-2 severe acute respiratory syndrome coronavirus 2 *if specified in the patients' health records dysfunction associated with prediabetes and diabetes [6] . more pronounced peak levels of inflammation observed in our patients with abnormal hba1c may support such an assumption. in conclusion, we recommend routine measurement of hba1c in hospitalized covid-19 patients for additional risk stratification, because most patients of our cohort were previously not diagnosed with having impaired glucose tolerance. use of glycated haemoglobin (hba1c) in diagnosis of diabetes mellitus: abbreviated report of a who consultation p002 -atemwegsmanagement an einer von internisten geführten notaufnahme plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with sars the effect of short-term hyperglycemia on the innate immune system o-glcnac transferase promotes influenza a virus-induced cytokine storm by targeting interferon regulatory factor-5 endothelial cell infection and endotheliitis in covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank romuald bellmann, robert breitkopf, christoph hochhold, andreas peer, christian preuß hernández, and mathias ströhle for their support in conducting this analysis. received: 11 june 2020 accepted: 1 july 2020 authors' contributions sjk, sk, and mj collected data and wrote the manuscript. df, sm, and ct collected data for this study. the author(s) read and approved the final manuscript. no funding was received for this study. no data is publicly available at this time. this study was approved by the ethics committee of the medical university innsbruck (# 1099/2020). not applicable-the manuscript contains no individual patient data. none of the authors have any conflicts of interest to declare. key: cord-280233-avmisu31 authors: chase, j. geoffrey; chiew, yeong shiong; lambermont, bernard; morimont, philippe; shaw, geoffrey m.; desaive, thomas title: safe doubling of ventilator capacity: a last resort proposal for last resorts date: 2020-05-14 journal: crit care doi: 10.1186/s13054-020-02945-z sha: doc_id: 280233 cord_uid: avmisu31 nan the best way to ventilate two patients on a single ventilator is simply not to do it: the authors in light of the covid-19 pandemic, this commonsense approach was recently clarified in a sccm-asa-aarc-aacn-aspf-chest consensus statement on the society of critical care medicine (sccm) website [1] : 'we recommend that clinicians do not attempt to ventilate more than one patient with a single ventilator while any clinically proven, safe, and reliable therapy remains available (ie, in a dire, temporary emergency)' [1] . the current situation in several european countries and states in the usa is a 'dire emergency'. physicians have been, or may be, asked to make difficult choices in the face of ventilator shortages [2] . nevertheless, if you are faced with a decision to ventilate two patients at once, or deny care to one, we believe we can propose the next best way. the sccm recommendation [1] addresses a series of popular internet concepts with multiple patients breathing in-parallel [3, 4] . in-parallel is a critical point, as inspiration and expiration all take place at the same time, so there is thus no change to respiratory rate (rr) and tidal volume or driving pressure are adjusted for the number of patients. all of these add risk over over-/ under-ventilating patients and causing harm [1] . instead, we recommend a multiplex in-series breathing approach to double (2-for-1) the patients on a ventilator (fig. 1) . in-series breathing means only 1 circuit volume (split between patients) is active at a time, but each patient's inspiratory effort is singular. this approach addresses the limitations of shared, in-parallel breathing in the sccm statement, where table 1 addresses in detail each consensus statement concern [1] . instead of the same rr and higher tidal volume or driving pressure, in-series breathing doubles the rr and keeps the other ventilator settings the same. one patient breathes in, while the other breathes out. with typical i:e ratios around 1:3, there is also shared expiration time when neither is breathing in (fig. 1) . as with other proposals [3] , driving pressure can be modified by added resistors in the inspiratory circuit, and peep can be customised with in-line expiratory peep valves (table 1) . this in-series approach ensures breath-by-breath ventilation parameters of each patient are displayed to ensure monitoring and safety are maintained. staff can thus be assured more (or less) compliant patients are not over-(under-) ventilated, both of which could result in harm if ventilated in-parallel, where monitoring individual patients is not possible. finally, one-way expiratory valves and filters prevent rebreathing and cross-contamination. clinically, we would suggest pressure-control modes, where driving pressures are easily customised perpatient with resistors, and are more commonly used, currently. this choice allows customised peep and driving pressure for each patient effectively as if they were ventilated separately. this setup requires an active valve to switch between patients ( fig. 1) , comprising a pressure sensor at the single end of a y-splitter on the inspiration circuit, and two active valves at the outlet. it uses measured inspiratory pressure to switch the inspiratory circuit from one patient to the other after inspiration (as pressure drops). the active ysplitter valve thus allows flow down only one inspiratory path per ventilator-supplied breath (at 2xrr). the components, sensors, and computation are low-cost and easily 3d printable by hospital bioengineers or others. however, nothing is perfect. this approach is not suited for spontaneous, triggered breathing, which cannot be synchronised nor limited. in addition, it cannot be used if i:e < 1, or if a patient's respiratory mechanics are such they will receive inadequate minute ventilation within the time for each allocated breath. volumes would go to the most compliant lung segments. serial breathing ventilates a single lung at a time, and thus, using a volumecontrolled (vc) mode, lung compliances are not 'mixed' and do not create this same, critical problem. a pressure controlled (pc) mode will also be separated. critically, in all modes, each lung responds individually to the inputs. positive end-expiratory pressure, which is of critical importance in these patients, would be impossible to manage. peep can be individually set using peep valves on the expiratory circuit and putting peep = 0 on the ventilator. these valves are commonly available and some come with multiple settings. thus, peep may also be individualised monitoring patients and measuring pulmonary mechanics would be challenging, if not impossible. patients are split in serial breathing so inspiration does not overlap, and any monitoring present would monitor each inspiratory portion (at least) separately. monitoring mechanics would depend on the ventilator interface and monitoring algorithms used, thus the displayed patient-specific parameters would be averaged. however, clinicians could still examine breath by breath waveforms or pv loops. pip or vt alarm limits could still be used as these are based on safety settings determined for a population of patients, rather than individual patients. again, these outcomes are enabled by separating inspiration for both patients. alarm monitoring and management would not be feasible. see above, again by separating patient inspiration segments in serial ventilation this issue is mitigated. individualised management for clinical improvement or deterioration would be impossible. pc driving pressure and vc tidal volume would have to be the same as ventilators currently do not have the capability to enable alternating breath settings. clinical judgement would determine which one of the ventilation is most appropriate for this situation. where there are significant differences in compliance, a volumecontrolled mode may be preferable. however, peep would be individualised via separate peep valves. these peep valves could also be made active if desired, or set manually similarly to changing peep on a ventilator, but for each patient. in the case of a cardiac arrest, ventilation to all patients would need to be stopped to allow the change to bag ventilation without aerosolizing the virus and exposing healthcare workers. this circumstance also would alter breath delivery dynamics to the other patients. in this case, the patient still on the ventilator can be restored to a 1 patient, 1 ventilator standard use, after the other patient is disconnected. alternatively, a rubber bag (test lung) could be swapped in while the arrested patient is being hand ventilated during cpr. this would not involve having to make changes to the ventilator settings, which would create cognitive overload in the event of a cardiac arrest. the added circuit volume defeats the operational self-test (the test fails). the clinician would be required to operate the ventilator without a successful test, adding to errors in the measurement. self-testing can be carried out in the usual manner. there is no added circuit volume as individual breaths are within usual physiological limits and therefore not vulnerable to errors of extrapolation created by connecting patients in parallel. additional external monitoring would be required. the ventilator monitors the average pressures and volumes. in serial breathing, each breath would be presented. the clinician would have to know to identify each patient by examining their breathing directly, to know which waveform or pv loop corresponds to a particular patient. even if all patients connected to a single ventilator have the same clinical features at initiation, they could deteriorate and recover at different rates, and distribution of gas to each patient would be unequal and unmonitored. the sickest patient would get the smallest tidal volume and the improving patient would get the largest tidal volume. since each patient is separated, there is less need for matching compliance or resistance, the latter of which would be similar. specifically, for the following: pc: driving pressure would have to be the same. however, a resistor with known pressure drop can be added to one of the two inspiratory circuits to reduce driving pressure for one patient. tidal volume alarming would still be feasible and ventilator controlled to avoid injury or damage. vc: tidal volume would be the same for both patients, where we would recommend setting tidal volume for the smaller of two patients in ml/kg; however, a vast difference could be problematic requiring some light matching by approximate size. pip alarms and limits would still be applicable and ventilator controlled. the greatest risks occur with sudden deterioration of a single patient (e.g. pneumothorax, kinked endotracheal tube), with the balance of ventilation distributed to the other patients. patients are ventilated separately so changes in patient condition, resulting in tidal volume changes (during pc) or peak pressure changes (during vc) would be notable on the monitor and ventilator set limits and alarms would still work be useful. finally, there are ethical issues. if the ventilator can be lifesaving for a single individual, using it on more than one patient at a time risks life-threatening treatment failure for all of them. the best way to ventilate 2 patients on 1 ventilator is not to do it! given the exigency of no other alternative, we propose this method is currently the next best way. consensus statement on multiple patients per ventilator. sccm website the toughest triage -allocating ventilators in a pandemic a better way of connecting multiple patients to a ventilator differential multiventilation international working group. differential multiventilation. differential multiventilation publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions jgc and td developed the idea and led the writing. ysc, bl, pm and gms provided additional input and contributions to the development and writing. the authors read and approved the read manuscript. none key: cord-297062-dmiplvt2 authors: almekhlafi, ghaleb a.; albarrak, mohammed m.; mandourah, yasser; hassan, sahar; alwan, abid; abudayah, abdullah; altayyar, sultan; mustafa, mohamed; aldaghestani, tareef; alghamedi, adnan; talag, ali; malik, muhammad k.; omrani, ali s.; sakr, yasser title: presentation and outcome of middle east respiratory syndrome in saudi intensive care unit patients date: 2016-05-07 journal: crit care doi: 10.1186/s13054-016-1303-8 sha: doc_id: 297062 cord_uid: dmiplvt2 background: middle east respiratory syndrome coronavirus infection is associated with high mortality rates but limited clinical data have been reported. we describe the clinical features and outcomes of patients admitted to an intensive care unit (icu) with middle east respiratory syndrome coronavirus (mers-cov) infection. methods: retrospective analysis of data from all adult (>18 years old) patients admitted to our 20-bed mixed icu with middle east respiratory syndrome coronavirus infection between october 1, 2012 and may 31, 2014. diagnosis was confirmed in all patients using real-time reverse transcription polymerase chain reaction on respiratory samples. results: during the observation period, 31 patients were admitted with mers-cov infection (mean age 59 ± 20 years, 22 [71 %] males). cough and tachypnea were reported in all patients; 22 (77.4 %) patients had bilateral pulmonary infiltrates. invasive mechanical ventilation was applied in 27 (87.1 %) and vasopressor therapy in 25 (80.6 %) patients during the intensive care unit stay. twenty-three (74.2 %) patients died in the icu. nonsurvivors were older, had greater apache ii and sofa scores on admission, and were more likely to have received invasive mechanical ventilation and vasopressor therapy. after adjustment for the severity of illness and the degree of organ dysfunction, the need for vasopressors was an independent risk factor for death in the icu (odds ratio = 18.33, 95 % confidence interval: 1.11–302.1, p = 0.04). conclusions: mers-cov infection requiring admission to the icu is associated with high morbidity and mortality. the need for vasopressor therapy is the main risk factor for death in these patients. electronic supplementary material: the online version of this article (doi:10.1186/s13054-016-1303-8) contains supplementary material, which is available to authorized users. middle east respiratory syndrome coronavirus (mers-cov) is a novel betacoronavirus that was first reported in september 2012 [1] . by january 6, 2016, a total of 1626 laboratory-confirmed cases of infection with mers-cov, including at least 586 related deaths, had been reported to the world health organization [2] . although mers-cov infections have been reported from 26 countries around the world, the majority of cases have originated in saudi arabia, south korea, the united arab emirates, jordan and qatar [3] . interhuman mers-cov transmission occurs in community and healthcare settings [4] [5] [6] [7] [8] . the exact source and mode of transmission of mers-cov to humans remains uncertain. however, mers-cov circulates among dromedary camels in africa and the middle east with occasions of documented camel-human inter-transmission [9] . there have been several reports outlining the clinical features and outcomes of patients with mers-cov infection [7, [10] [11] [12] [13] [14] [15] . however, very few have focused on critically ill patients in intensive care units (icu) [16] [17] [18] . there is therefore a need for more data to understand the various clinical and prognostic aspects of this potentially lethal disease, particularly for the most severe cases that require admission to the icu. we performed a retrospective study to describe the clinical features and outcomes of patients admitted to our icu with laboratory-confirmed mers-cov infection. the study was approved by the institutional review board of prince sultan military medical city (11159 riyadh, saudi arabia), a large tertiary-care referral center in riyadh, saudi arabia. informed consent was waived due to the retrospective, anonymous nature of data collection. we included all patients aged 18 years or more with confirmed mers-cov infection who were admitted to our 20-bed mixed medico-surgical icu between october 1, 2012 and may 31, 2014. all icu patients with a confirmed diagnosis of mers-cov were registered in a special logbook. for the purpose of the current study, all patients' records were reviewed by a senior intensivist (s. hussain, a. alwan, a. abudayah, s. altayyar, m. mustafa, t. aldaghestani, a. alghamedi, a. talag or m. malik). clinical data and laboratory parameters from confirmed cases of mers-cov were transcribed onto specially developed case record forms. these included the initial manifestations of respiratory infection, the clinical picture on admission to the icu, laboratory indices of organ failure, radiographic findings, interventions during the icu stay, treatment modalities, and final outcome. the acute physiology and chronic health evaluation ii (apache ii) score was calculated from the data obtained within 24 hours of admission to the icu [19] . the sequential organ failure assessment (sofa), score, calculated daily by the physician in charge of the patient, was also noted [20] . since the first reported cases of mers-cov in saudi arabia in september 2012, all suspected cases in our institution are strictly isolated and nasopharyngeal swabs are obtained for initial screening. deep respiratory samples (tracheal aspirates or bronchoalveolar lavage fluid) are obtained from all patients admitted to the icu with suspected respiratory infections, in addition to blood samples to perform cultures and polymerase chain reaction for common respiratory viruses and atypical microorganisms. urinary samples were obtained to detect legionella antigens in only two patients (legionella infections are not common in saudi patients). cultures of tracheal aspirates are analyzed quantitatively and bacterial counts of at least 10 5 colony-forming units are considered positive. these investigations are repeated in the icu whenever secondary infections are suspected. clinical specimens aimed at detecting possible mers-cov infection are processed and analyzed at the national reference laboratory of the saudi ministry of health. mers-cov infections are identified using real-time, reverse transcription polymerase chain reaction (rt-pcr). the standard assays target amplifications of the upstream e protein (upe gene) and open reading frame (orf)1a; both need to be positive to confirm infection, otherwise another sample is required to confirm the diagnosis [21] . the sample requires 2 days of processing for the final results to be available. routine laboratory testing in our icu includes complete blood counts, coagulation profile, electrolytes, renal function, liver profile and arterial blood gases. these parameters are measured on admission to the icu and at least once daily thereafter (at 6:00 am) throughout the icu stay. all patients with suspected or confirmed mers-cov infection were isolated in single rooms, either on the hospital floor or in the icu. patients were admitted to the icu according to the guidelines of the society of critical care medicine for icu admission, discharge, and triage [22] . patients were classified into four categories according to their icu admission priority: priority one comprised critically ill patients who were unstable and need intensive treatment and monitoring, with significant likelihood of recovery; priority two were stable patients who required intensive monitoring because of the possibility of decompensation; priority three were unstable patients who had a low likelihood of recovery because of the severity of acute disease or because of comorbidities; priority four were those who had little or no anticipated benefit from icu admission. patients classified as priority one and two and most of those classified as priority three were admitted to our icu or full critical care services were mobilized and provided for in the isolation ward until a bed was available in the icu. priority four patients were not admitted to the icu and remained in the isolation ward. general ward patients with mers-cov infection were transferred to the icu if their condition deteriorated or organ failure developed. the infection control precautions recommended by the saudi ministry of health guidelines were strictly implemented to prevent possible transmission of mers-cov to other patients or to the healthcare staff [23] . supportive treatment was provided according to our standard operating procedures and in accordance with the surviving sepsis campaign guidelines [24, 25] . antiviral therapies, such as oseltamivir, and ribavirin/interferon alfa-2a, were prescribed at the discretion of the attending physician. protective lung ventilation was applied in mechanically ventilated patients. prone positioning was considered in some patients with severe refractory hypoxemia. extracorporeal membrane oxygenation (ecmo) and high-frequency oscillation were also available as a last resort, when considered necessary by the attending physician. statistical analyses were performed using spss statistics 19 for windows (ibm corp., armonk, ny, usa). the kolmogorov-smirnov test was used to verify whether there were significant deviations from the normality assumption of continuous variables. nonparametric tests of comparison were used for variables evaluated as not normally distributed. difference testing between groups was performed using student's t test, mann-whitney test, chi-square test and fisher's exact test, as appropriate. friedman's test was used to assess the time course of organ function. to identify the risk factors for death in the icu, we performed multivariable logistic regression analyses. due to the relatively small number of deaths in our study, we adjusted only for the severity of illness on admission to the icu (apache ii score) and the degree of organ dysfunction as assessed by admission sofa score. potential risk factors for icu mortality were selected among the demographic characteristics, comorbidities, mode of acquisition of mers-cov, initial manifestations, procedures and therapies, and superimposing infections. variables yielding p <0.2 in the univariate analysis, apa-che ii score and sofa score were included in a multivariable logistic regression analysis. these variables were introduced separately into multivariable models including apache ii and sofa scores on admission to the icu. adjusted odds ratios (or) and 95 % confidence of interval (ci) were computed. none of the covariates simultaneously introduced in a multivariable model were collinear. data are presented as mean ± standard deviation (sd), median value (25th-75th interquartile range [iqr]) or number (%), as appropriate. all statistics were two-tailed and a p < 0.05 was considered statistically significant. during the observation period, 70 cases with confirmed mers-cov infections were diagnosed in our institution [11] (fig. 1) ; 21 patients were managed in the hospital ward, 18 patients were admitted to other icus or received critical care service in the ward, and 31 patients were admitted to our icu (12 between october 1, 2012 and december 31, 2013 and 19 between january 1 and may 31, 2014). patients were admitted to our icu because of respiratory failure (pao2/fio2 < 250 mmhg). the mean age of the patients admitted to our icu (n = 31) was 59 (sd 20) years and 22 (71 %) were males. the characteristics of these patients on admission to the icu are shown in table 1 . eighteen (58.1 %) patients had community-acquired mers-cov infection, while for 13 (47.9 %), including two healthcare staff, infection was acquired in the hospital. twenty-seven patients (87.1 %) had at least one comorbidity. the median number of concomitant comorbid conditions was three (iqr: 2-4). initial clinical manifestations had occurred at a median of 2 days (iqr: 2-4) prior to hospital admission. patients had been treated for a median of 5 days (iqr: 2-9) in general hospital wards before their admission to the icu. only four patients (12.9 %) were admitted to the icu on arrival at the hospital. cough and tachypnea were reported in all patients. other common initial symptoms were fever (87.1 %), abdominal pain (29 %), sore throat (25.8 %), and fatigue (25.8 %) (additional file 1). crackles (93.5 %), tachycardia (67.7 %), and rhonchi (32.3 %) were the most commonly identified initial physical signs. bilateral pulmonary infiltrates were present in the chest x-rays of 24 (77.4 %) patients and lobar infiltrates in six (19.4 %). only one patient had a normal chest x-ray at the time of admission to the icu. on admission to the icu, no patients had microbiologically proven co-existing bacterial pneumonia. secondary infections, as evident from positive quantitative cultures of deep tracheal aspirates, occurred in 18 (58.1) patients within a median of 3 days (iqr: 3-8) after admission to the icu. the most commonly isolated microorganisms were acinetobacter baumannii (25.8 %), only four (12.9 %) patients had positive blood cultures; acinetobacter baumannii (n = 2), escherichia coli (n = 1), methicillin-resistant staphylococcus aureus (n = 1), and vancomycin-resistant enterococcus species (n = 1). invasive mechanical ventilation was applied in 27 (87.1 %) patients during the icu stay; 18 (58.1 %) within 24 hours of admission to the icu, and 14 (45.5 %) patients received noninvasive ventilation (table 2) . eleven (35.5 %) patients were treated with high-frequency oscillation and five (16.1 %) with prone positioning. only one patient received ecmo. the ventilatory parameters are presented in additional file 3. vasopressor therapy using norepinephrine was initiated in 25 (80.6 %) patients (table 2) . oseltamivir was administered to 20 (64.5 %) patients for a median of 5 days (iqr: 3-5). combined ribavirin plus interferon alfa-2a therapy was used in 13 (41.9 %) patients ( table 2 ). all patients received at least one antimicrobial agent during the icu stay (additional file 2). antifungal therapy was only used in four of the five patients with positive cultures for candida but the necessity of this therapy is uncertain. the overall icu mortality rate was 74.2 % (n = 23). the median icu and hospital lengths of stay were 9 (iqr: 4-16) and 12 (iqr: 4-16) days, respectively. the major causes of death were hypoxemic respiratory failure (52.2 %) and refractory septic shock (26.1 %). one patient died from sudden cardiac arrest after icu discharge but while still in the hospital. furthermore, one patient died within 1 year after discharge from the icu because of septic shock related to an infected wound. only one patient was lost to follow-up after hospital discharge. the sofa score and glasgow coma scale (gcs) increased markedly over the first 2 weeks in the icu in the whole cohort, while other parameters of organ function remained largely unchanged (additional file 3). compared with those who were discharged alive from the icu, nonsurvivors were older, had higher apache ii and sofa scores on admission to the icu, and were more likely to require invasive mechanical ventilation and vasopressor therapy and to have been ventilated using highfrequency oscillation (tables 1 and 2 , and additional files 1 and 2). nonsurvivors had a persistently low pao2/fio 2 throughout the first 2 weeks in the icu, whereas survivors showed a slight increase over time (fig. 2) . after adjustment for the severity of illness and the degree of organ dysfunction, the need for vasopressors was the only independent risk factor for death in the icu (or 18.33, 95 % confidence interval 1.11-302.1, p 0.04) (additional file 4). the 31 critically ill patients with confirmed mers-cov infection in our cohort frequently had organ failure with an overall mortality rate greater than 74 %. comorbidities were common in this cohort of patients. not surprisingly, mortality in the icu was associated with older age, severe disease and organ failure. the need for vasopressor therapy was an independent risk factor of death in the icu. since the first reported case of mers-cov infection in 2012, several authors have described various cohorts of patients with this serious infection [8, 10-12, 14, 15, 26] . [16, 18] . our facility is a large tertiarycare medical center in riyadh, central saudi arabia. we herein provide a detailed account of the largest single cohort of critically ill mers-cov infected patients reported thus far. in agreement with previous reports from saudi arabia, comorbid conditions were common in our patients with mers-cov infections with a median of three comorbidities per patient [10, 11, 15, 17] . in contrast, only 54.8 % of the 186 individuals involved in the recent mers-cov outbreak in south korea had any preexisting chronic medical conditions [8] . however, only 29.6 % of patients in the korean outbreak were aged 65 years or older and nearly half (46.2 %) were caregivers or healthcare personnel [8] . the differences in the demographic characteristics of our cohorts and the mode of acquisition of mers-cov infection may explain, at least in part, the discrepancy in the patterns of associated comorbidities between the saudi and korean cohorts. the respiratory manifestations of mers-cov infection in our cohort were similar to those observed in previous reports from saudi patients [10, 11, 14, 15, 17] . cough and tachypnea occurred in all patients and 77 % of cases had bilateral pulmonary infiltrates, denoting severe respiratory illness, which required a median of 5 days to reach the peak of clinical deterioration such that icu admission and organ support therapy were required. gastrointestinal manifestations, such as abdominal pain, diarrhea, vomiting, and abdominal tenderness, were relatively common in our cohort. this was also a common finding in the previous literature in patients with mers-cov infection as well as those with severe acute respiratory syndrome (sars) [10, 11, 15, 17, 28, 29] . our data confirm previous studies that reported a high prevalence of nonrespiratory organ failure in critically ill patients with mers-cov [16, 17] . the mechanisms of organ dysfunction and failure in these patients are yet to be determined. cytokine dysregulation has been suggested to be involved in the pathophysiology of mers-cov-related organ failure. direct viral invasion may also occur as the virus was recovered from urine and stool in one patient [30] . in agreement with the results of the previous reports on critically ill patients with mers-cov infection [16] [17] [18] , more than 80 % of our patients received vasopressor support, underscoring the high prevalence of cardiovascular dysfunction in these patients, and suggesting that disturbances in tissue perfusion may also have been involved in the pathophysiology of the organ failure. lower rates of vasopressor support have been reported in patients with sars [10, 11, 15, 17, 28, 29] with, as a result, lower mortality rates than those reported in patients with mers-cov infections. even though overall mortality rate was high in our cohort, it is still comparable with rates reported in previous studies (58.3-64.3 %) [16] [17] [18] . in all studies, almost all patients had significant comorbidities and median apache ii scores of 25 or higher. we observed significantly higher apache ii and sofa scores in icu nonsurvivors compared to those who survived severe mers-cov infection, underscoring the strong association between mortality and the severity of disease. epidemiological analyses have suggested that mers-cov is unlikely to trigger sustained human epidemics at present [31, 32] . nevertheless, nosocomial outbreaks have resulted in considerable morbidity and mortality, in addition to disruption of medical services and substantial economic losses [9, 33, 34] . the most severe infections usually require icu admission, necessitate major resource utilization and result in high fatality rates. identifying possible risk factors for poor prognosis in patients with mers-cov infection is therefore crucial to enable appropriate allocation of healthcare resources and early transfer of high-risk patients to the appropriate medical facilities. our data show that the need for vasopressor therapy was an independent risk factor for death in the icu. indeed, the major causes of death in our study were hypoxemic respiratory failure and refractory septic shock, which confirm the role of respiratory and cardiovascular system failures as determinants of outcome in this population. this was also evident from the persistent hypoxemia observed in the nonsurvivors. to date, published data on the risk factors for poor prognosis specific to critically ill patients with mers-cov infection are lacking. in cohort studies of patients with any degree of severity of mers-cov infection, older age, diabetes, chronic renal failure, chronic respiratory disease, high viral load in lower respiratory tract samples, shorter incubation period and mers-cov viremia have all identified as independent predictors of mortality [11, 14, [35] [36] [37] . secondary respiratory infections occurred commonly in this cohort, predominantly with gram-negative bacteria. although candida species were frequently isolated, these are probably not relevant as respiratory pathogens and the necessity of antifungal therapy is uncertain. interestingly, acinetobacter baumannii, which is an emerging fatal infection in icu patients worldwide, was isolated from deep tracheal aspirates in one in four patients. this may explain, at least in part, the relatively high mortality rates in this cohort. specific therapeutic options for mer-cov infections are limited and their efficacy is not well established [38] . all patients in this report received antiviral treatment with either oseltamivir or combined ribavirin/interferon alfa-2a therapy; two patients received both. although a previous study from the same institution showed that combined ribavirin/interferon alfa-2a therapy was associated with significant improvement in survival at 14 days, this benefit was not maintained at 28 days after the onset of the disease [39] . the retrospective and observational nature of this study does not allow precise assessment of the efficacy of these therapies. in the absence of a vaccine or a specific treatment, prevention of viral transmission through adequate infection control methods is the mainstay in the management of mers-cov outbreaks. appropriate isolation of patients with suspected or proven infections is crucial. in view of the high fatality rates of these patients in the icu, it may be reasonable to closely monitor patients with suspected infections in the general wards for early signs of organ dysfunction to prevent unnecessary delay in the provision of intensive care services and reduce mortality rates in these patients. our study has some limitations. we included patients with confirmed mers-cov infection from one icu of a large medical center. possible variations in the geographic distribution of the disease and in local practice may hinder extrapolation of these data to other cohorts in saudi arabia and other countries. the relatively low number of patients may have biased the statistical comparisons presented in this report and overestimated mortality rates. multivariable adjustment was also limited to the variables included in the models. collaborative efforts are needed to provide an insight into the risk factors for poor prognosis in these patients. isolation of a novel coronavirus from a man with pneumonia in saudi arabia middle east respiratory syndrome coronavirus (mers-cov european centre for disease prevention and control. epidemiological update: middle east respiratory syndrome coronavirus ?id=1278&list=8db7286c-fe2d-476c-9133-18ff4cb1b568&source=http%3a%2f%2fecdc%2eeuropa%2eeu%2fen% 2fpress%2fepidemiological%5fupdates%2fpages%2fepidemiological%5f updates%2easpx. accessed 23 a family cluster of middle east respiratory syndrome coronavirus infections related to a likely unrecognized asymptomatic or mild case community case clusters of middle east respiratory syndrome coronavirus in hafr al-batin, kingdom of saudi arabia: a descriptive genomic study hospital outbreak of middle east respiratory syndrome coronavirus mers-cov outbreak in jeddah-a link to health care facilities middle east respiratory syndrome coronavirus outbreak in the republic of korea middle east respiratory syndrome coronavirus (mers-cov): what lessons can we learn? epidemiological, demographic, and clinical characteristics of 47 cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study clinical aspects and outcomes of 70 patients with middle east respiratory syndrome coronavirus infection: a single-center experience in saudi arabia hospital-associated outbreak of middle east respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description middle eastern respiratory syndrome corona virus (mers cov): case reports from a tertiary care hospital in saudi arabia ifn-alpha2a or ifn-beta1a in combination with ribavirin to treat middle east respiratory syndrome coronavirus pneumonia: a retrospective study middle east respiratory syndrome coronavirus: a case-control study of hospitalized patients characteristics and outcomes of middle east respiratory syndrome coronavirus patients admitted to an intensive care unit in jeddah, saudi arabia clinical course and outcomes of critically ill patients with middle east respiratory syndrome coronavirus infection acute management and long-term survival among subjects with severe middle east respiratory syndrome coronavirus pneumonia and ards apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine assays for laboratory confirmation of novel human coronavirus (hcov-emc) infections guidelines for intensive care unit admission, discharge, and triage. task force of the american college of critical care medicine, society of critical care medicine infection prevention and control guidelines for patients with middle east respiratory syndrome coronavirus (mers-cov) infection surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 multifacility outbreak of middle east respiratory syndrome in taif, saudi arabia middle east respiratory syndrome: an emerging coronavirus infection tracked by the crowd middle east respiratory syndrome in the shadow of ebola middle east respiratory syndrome coronavirus: another zoonotic betacoronavirus causing sars-like disease clinical features and virological analysis of a case of middle east respiratory syndrome coronavirus infection interhuman transmissibility of middle east respiratory syndrome coronavirus: estimation of pandemic risk transmission scenarios for middle east respiratory syndrome coronavirus (mers-cov) and how to tell them apart spread of mers to south korea and china mers coronavirus: diagnostics, epidemiology and transmission mortality risk factors for middle east respiratory syndrome outbreak, south korea association of higher mers-cov virus load with severe disease and death, saudi arabia association between severity of mers-cov infection and incubation period therapeutic options for middle east respiratory syndrome coronavirus (mers-cov) infection: how close are we? curr treat options infect dis ribavirin and interferon alfa-2a for severe middle east respiratory syndrome coronavirus infection: a retrospective cohort study we would like to thank dr. hassane nijimi (free university of brussels) for the statistical revision of this study and dr. karen pickett for editorial assistance with the manuscript. the study was supported only by institutional funds. mers-cov infections requiring admission to the icu are associated with high morbidity and mortality rates. the need for vasopressor therapy is the main risk factor for death in these patients. this report describes the clinical features and outcomes of 31critically ill patients with confirmed middle east respiratory syndrome coronavirus (mers-cov) infection. patients with mers-cov infections frequently had organ failure, and mortality rates were greater than 72 %. the need for vasopressor therapy was an independent risk factor for death in the icu. the authors declare that they have no competing interests.authors' contributions gaa, ym, aso, mma, and ys conceived the study. sh, aal, aab, sa, mm, ta, aalg, at, and mkm participated in data collection. ys processed the data and performed the statistical analyses. ys and gaa drafted the manuscript. all authors read, revised, and approved the final manuscript.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord-290392-kpjp0sx4 authors: li, xu; ma, xiaochun title: acute respiratory failure in covid-19: is it “typical” ards? date: 2020-05-06 journal: crit care doi: 10.1186/s13054-020-02911-9 sha: doc_id: 290392 cord_uid: kpjp0sx4 in december 2019, an outbreak of coronavirus disease 2019 (covid-19) was identified in wuhan, china. the world health organization (who) declared this outbreak a significant threat to international health. covid-19 is highly infectious and can lead to fatal comorbidities especially acute respiratory distress syndrome (ards). thus, fully understanding the characteristics of covid-19-related ards is conducive to early identification and precise treatment. we aimed to describe the characteristics of covid-19-related ards and to elucidate the differences from ards caused by other factors. covid-19 mainly affected the respiratory system with minor damage to other organs. injury to the alveolar epithelial cells was the main cause of covid-19-related ards, and endothelial cells were less damaged with therefore less exudation. the clinical manifestations were relatively mild in some covid-19 patients, which was inconsistent with the severity of laboratory and imaging findings. the onset time of covid-19-related ards was 8–12 days, which was inconsistent with ards berlin criteria, which defined a 1-week onset limit. some of these patients might have a relatively normal lung compliance. the severity was redefined into three stages according to its specificity: mild, mild-moderate, and moderate-severe. hfno can be safe in covid-19-related ards patients, even in some moderate-severe patients. the more likely cause of death is severe respiratory failure. thus, the timing of invasive mechanical ventilation is very important. the effects of corticosteroids in covid-19-related ards patients were uncertain. we hope to help improve the prognosis of severe cases and reduce the mortality. in december 2019, an outbreak of coronavirus disease 2019 (covid19) , which was caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), broke out in wuhan, china [1] [2] [3] . the world health organization (who) declared it a significant threat to international health [4] . covid-19 was of clustering onset and mainly affected the respiratory system with some patients rapidly progressing to acute respiratory distress syndrome (ards); other organ functions were less involved [5, 6] . these patients were likely to be admitted to the intensive care unit (icu) and might die. the elderly and those with comorbidities are at highest risk of death. the death appeared to be related to ards [7] . although several studies have reported the clinical features of covid-19 [1, [8] [9] [10] [11] [12] [13] , our understanding about it remains limited [14] . can we consider all the cases of acute respiratory failure associated with covid-19 as ards? the answer is probably no. based on current reports and our experience in the management of covid-19-related ards patients, we realized that there are many differences between covid-19-related ards and ards caused by other factors as defined by berlin criteria, and therefore differences in treatment. thus, we aimed to describe the characteristics of covid-19-related ards and to elucidate the differences (fig. 1 ). ards occurs as a result of an acute systemic inflammatory response, which can be caused by insults to the lung, either direct or indirect. the early exudative stage presents diffuse alveolar damage with destruction of epithelial and endothelial cells. covid-19 mainly affected the respiratory system with minor damage to other organs. studies reported that acute myocardial injury (7.2-17%) and acute renal injury (2.9-15%) could occur in severe patients. the reported incidence of ards was 15.6-31%, higher than that of other organ injuries [1, [8] [9] [10] [11] . the most common respiratory symptom of covid-19 is dry cough (59.4-82%) [1, [8] [9] [10] [11] . sputum production was less. it suggested that injury to the alveolar epithelial cells was the main cause of covid-19-related ards, and endothelial cells were less damaged with therefore less exudation. endothelial cells line the inner surface of blood vessels in all organs. it was possible that due to less damage to the endothelial cells, other organ functions were less involved in covid-19 patients. the respiratory system was mainly involved in covid-19 patients as mentioned above. some patients had a low oxygenation index, indicating severe respiratory failure. chest imaging findings suggested the involvement of both lungs. chest computed tomography (ct) scans usually showed multifocal bilateral patchy shadows and/ or ground-glass opacities; some patients showed a mixed pattern of ground-glass opacities and consolidation [15] . the ct results indicated diffuse and severe lung injury. however, the clinical manifestations were relatively mild in some patients. these patients might have no complaint of dyspnea, no significant increase in respiratory rate, and no respiratory distress. hemodynamics and indexes of tissue perfusion such as lactate were also relatively stable. the clinical symptoms were inconsistent with the severity of laboratory and imaging findings. however, these patients may deteriorate rapidly and need to be monitored closely. blood carbon dioxide levels may be a meaningful indicator for invasive mechanical ventilation. timing of onset the ards berlin criteria defined that for a patient to be diagnosed as having ards, the onset must be within 1 week of a known clinical insult or new or worsening respiratory symptoms [16] . the reported onset of covid-19-related ards was similar in different studies. huang et al. [1] first reported 41 cases of covid-19 in which the median time from onset of symptoms to ards was 9.0 days (8.0-14.0). subsequently, wang et al. [9] reported 138 cases of covid-19 in which the median time from the first symptom to ards was 8.0 days (6.0-12.0). zhou et al. [11] reported the median time from illness onset to ards was 12.0 days (8.0-15.0). studies by chen et al. [8] and guan et al. [10] did not report the onset of ards. as the onset time of covid-19-related ards was 8-12 days, it suggested that the 1-week onset limit defined by ards berlin criteria did not apply to covid-19-related ards. it reminded us to pay more attention to the development of ards in patients with the course of more than a week, so as to treat timely. not all the cases of acute respiratory failure caused by covid-19 were ards. the typical ct findings of covid-19 showed bilateral ground-glass shadow with a peripheral lung distribution [15] . although there was consolidation and exudation, it was not a "typical" ards image. ards is a condition associated with many disease processes, resulting in reduced lung compliance and severe hypoxemia [16] . lung compliance might be relatively normal in some covid-19-related ards patients who met ards berlin criteria. this was obviously inconsistent with ards caused by other factors. in addition, the lung compliance was relatively high in some covid-19-related ards patients, which was inconsistent with the severity of hypoxemia. according to the berlin definition, ards is divided into three stages based on oxygenation index (pao 2 /fio 2 ) on positive end-expiratory pressure (peep) ≥ 5 cmh 2 o: mild (200 mmhg < pao 2 /fio 2 ≤ 300 mmhg), moderate (100 mmhg < pao 2 /fio 2 ≤ 200 mmhg), and severe (pao 2 / fio 2 ≤ 100 mmhg) [16] . ards classification determines both the severity of the disease and choice of treatment protocol. a previous study reported that more than 50% of patients with moderate and severe ards according to the berlin definition did not show diffuse alveolar damage [17] . in fact, the specific ranges under which the hypoxemia is evaluated differ among clinicians. from the perspective of therapy, the intensity of adjunctive treatment varies according to the degree of hypoxemia. thus, we need a more suitable classification of ards severity that can accurately identify patients for a specified therapy. till now, the clinical features of covid-19-related ards are still unclear. there are no specific monitoring and implementation protocols. under the current situation, a number of designated hospitals and dozens of medical teams from different provinces have participated in the treatment. the unified ards treatment standard is needed in order to improve the uniformity and thus reduce the mortality. therefore, experts from the national health commission of china developed a standard treatment protocol for covid-19 based on their experience. covid-19-related ards was divided into three categories based on oxygenation index (pao 2 /fio 2 ) on peep ≥ 5 cmh 2 o: mild (200 mmhg ≤ pao 2 /fio 2 < 300 mmhg), mild-moderate (150 mmhg ≤ pao 2 /fio 2 < 200 mmhg), and moderate-severe (pao 2 /fio 2 < 150 mmhg) [18] . the new stratification for covid-19-related ards determines personalized treatment for different patients. in fact, a number of ards treatments, including prone positioning and neuromuscular blockers, are recommended for patients with pao 2 /fio 2 less than 150 mmhg. this indicates that berlin classification is not suitable to define the severity of ards and accurately guide the corresponding treatments. hypoxemic respiratory failure in ards generally results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation. compared to standard oxygen therapy, high-flow nasal oxygen (hfno) reduces the need for endotracheal intubation in ards patients [19] . who recommended that hfno should only be used in selected patients with hypoxemic respiratory failure [20] . studies indicated that hfno is more suitable for patients with mild ards. however, according to clinical situations, hfno can be safe in both mild and mild-moderate covid-related ards patients, and even some moderate-severe patients. some patients with an oxygenation index of 100 mmhg can remain relatively stable with the support of hfno. this is clearly inconsistent with the stratified treatment strategies of ards caused by other factors. although covid-19 may be associated with myocardial injury and arrhythmia as reported [8, 9, 11] , there is currently no evidence that myocarditis is the cause of death. the respiratory system is the most commonly involved for covid-19, and some cases can rapidly progress to ards, which requires venous-venous extracorporeal membrane oxygenation (v-v ecmo) in the most severe cases. to date, no patients with severe arrhythmia or acute heart failure due to acute myocarditis have been reported to require venous-arterial ecmo (v-a ecmo) treatment. cardiac injury was diagnosed by elevation of cardiac biomarkers in serum or new abnormalities in electrocardiography and echocardiography. however, serum lactate dehydrogenase (ldh) and creatine kinase-mb were elevated more commonly than hypersensitive troponin i in covid-19 patients as reported [1, 9] . the pathological findings of a covid-19-related ards patient by xu et al. [21] indicated that there were no obvious histological changes seen in heart tissue. therefore, the diagnosis of acute myocardial injury needs further consideration. thus, the more likely cause of death is severe respiratory failure. therefore, the timing of invasive mechanical ventilation is very important. since severe covid-19 patients may deteriorate rapidly, patients receiving hfno should be closely monitored and cared for by experienced personnel capable of endotracheal intubation at any time. currently published studies did not report the proportion of different respiratory support according to covid-19-related ards classification. further research is expected to provide more evidence for the use of hfno in covid-19-related ards patients. corticosteroids are considered a potential treatment for ards because of their role in reducing inflammation and fibrosis. although the use of corticosteroids in ards patients remains controversial, treatment with corticosteroids is currently the only pharmacological intervention that may reduce morbidity and mortality. it is reported that treatment with high-dose corticosteroids for a prolonged period of time could accelerate the improvement of ards [22] . furthermore, methylprednisolone shortened periods of need for invasive mechanical ventilation and lowered mortality in ards patients [23] . however, who recommended that systemic corticosteroids should not be routinely administered to covid-19 or covid-19-related ards patients [20] . studies reported that less than half of the covid-19 patients were given systemic corticosteroids, mostly in severely ill patients with ards [1, 9, 11] . low-to-moderate dosage was administered depending on the severity of the disease, for as short time of treatment as possible. although it has been reported that treatment with methylprednisolone may be beneficial for covid-19-related ards patients [24] , the effect of corticosteroids in such patients is still uncertain and needs to be further evaluated. in particular, the use of corticosteroids may affect virus clearance in covid-19 patients. further evidence is needed to evaluate the role of systemic corticosteroid therapy and its impact on long-term prognosis in this group of patients. covid-19 is highly infectious and can lead to fatal comorbidities especially ards. there are currently no recommended specific anti-covid-19 treatments, so supportive treatment is important. fully understanding the characteristics of covid-19-related ards is conducive to early identification and precise treatment. we hope to help improve the prognosis of severe cases and reduce the mortality. clinical features of patients with 2019 novel coronavirus in wuhan genomic characterization and epidemiology of 2019 novel coronavirus: implications of virus origins and receptor binding a novel coronavirus from patients with pneumonia in china world health organization. coronavirus disease (covid-19) outbreak a familial cluster of pneumonia 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coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention ct imaging features of 2019 novel coronavirus (2019-ncov) acute respiratory distress syndrome: the berlin definition comparison of the berlin definition for acute respiratory distress syndrome with autopsy respiratory treatment procedures in patients with severe novel coronavirus infected pneumonia: an expert opinion. chin j crit care intensive care med effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials clinical management of severe acute respiratory infection when novel coronavirus (2019-ncov) infection is suspected: interim guidance pathological findings of covid-19 associated with acute respiratory distress syndrome prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ards risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. both authors had their substantial contributions to the conception or design of the work or the acquisition and interpretation of data. xl drafted the work. xcm revised it critically for important intellectual content. both authors read and approved the final manuscript. the authors declare that they have no competing interests.received: 23 march 2020 accepted: 21 april 2020 key: cord-316829-wm6y6uwm authors: vargas, maria; de marco, giuseppe; de simone, stefania; servillo, giuseppe title: logistic and organizational aspects of a dedicated intensive care unit for covid-19 patients date: 2020-05-18 journal: crit care doi: 10.1186/s13054-020-02955-x sha: doc_id: 316829 cord_uid: wm6y6uwm nan logistic and organizational aspects of a dedicated intensive care unit for covid-19 patients maria vargas 1* , giuseppe de marco 1 , stefania de simone 2 and giuseppe servillo 1 dear editor, on 31 march, the world health organization (who) reported 750,890 confirmed globally confirmed cases of covid-19 [1] . covid-19 cases are dramatically increasing in several countries with heterogenous and unpredictable distributions [2] . patients with covid-19 have resulted in high rates of hospitalization and icu admissions [3] . on 6 april, the worldwide icu admission rate of covid-19 patients was 3% ranging from 1% of total cases in africa to 4% of total cases in europe [4] . according to this heterogenous and unpredictable geographic distribution of covid-19, several countries are increasing their icu capacity response by converting general icu in dedicated covid-19 facilities [5] . dedicated icus for covid-19 patients were suddenly created on the whole italian territory [5] . based on the high contagiousness of the 2019 novel cov virus [6] , the logistics and the staff organizations are the fundamental principles to avoid the in-hospital spread of the virus while creating dedicated covid-19 facilities. from 10 march, our icu is completely dedicated to covid-19 patients, and actually, it is one of the largest cohorted icu in the south of italy admitting 12 positive critically ill patients (fig. 1 ). the icu is divided into green, yellow, and red areas (fig. 1) . each icu bed is equipped with a full monitoring of vital parameters and a mechanical ventilator. each monitor is duplicated in the centralized control unit equipped with microphones and glasses to allow the communications between the staff. inside the icu, we have a laboratory section including two dedicated ultrasound machines, disposable fiberoptic bronchoscopes, video laryngoscopes, point-of-care arterial blood gas and coagulation analyses, transport ventilator, and emergency cart with a defibrillator. during the 12-h shift, the nursing and medical working is organized as follow: 1. the most experienced icu physician is the work shift coordinator and stays in the green area to control the compliance of the staff with the procedures and to check the patients from the centralized monitoring area. 2. medical staff review the medical records of each patient, and then a briefing with the whole staff is made to plan the actions of the shift. 3. all the therapies are prepared in a dedicated area outside the icu boxes to minimize the time spent inside. 4. the nursing and medical staff performed the first entry in the icu boxes and stay inside for 4 h. after that, only two nurses and one medical doctor continue to stay inside for an additional 2 h while the other personnel rest themselves and fulfill the medical records. 5. after that, the nurses and the medical doctor are replaced by other 3 colleagues for another 2 h. 6. the transition from the red to the green area must be preceded by the staff decontamination in the yellow area. 7. the disinfection of the different areas is performed three times during the shift. according to our experience, a simple logistic project and clear organizational plan may be the keys to the success of surging the icu capacity with dedicated facilities during the covid-19 outbreak. fig. 1 upper box-organization of icu before covid-19 outbreak. before the outbreak of covid-19, our icu was equipped with two main boxes including 5 beds each and one box with two beds for the infected patients. we also had several offices for medical and nursing staff. lower box-organization of icu dedicated to covid-19 patients. the red area is a zone where the full ppe is mandatory. the yellow areas are the zone of decontamination while the green area is a clean one. the entrance of the first icu box was the only entry point for covid-19 patients. the green area inside the icu is a clean zone where the medical and nursing staff may stay during the 12-h shift. the green area outside the icu, equipped with shower facilities, clean scrubs, and clean supplies, is dedicated to the staff wash at the end of shift. the yellow areas are the filter of decontamination where the staff must change their scrubs, wash their body with disinfectants, and clean their shoes in the bowls with sodium hypochlorite 0.1 to 0.5 before accessing the green areas. inside the red area, we set up two contamination filters, equipped with waste management material, mirror, and supply to wash the body and the hand, for doffing after the exiting from the icu boxes coronavirus disease 2019 (covid-19) situation report -71 worldmeters data source aseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region situation update worldwide critical care utilization for the covid-19 outbreak in lombardy, italy early experience and forecast during an emergency response insights into the recent 2019 novel coronavirus (sars-cov-2) in light of past human coronavirus outbreaks publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions mv, gds, sds, and gs planned the manuscript, collected the data, wrote the manuscript, and approved the final version. none key: cord-286771-77hs34jm authors: cruces, pablo; retamal, jaime; hurtado, daniel e.; erranz, benjamín; iturrieta, pablo; gonzález, carlos; díaz, franco title: a physiological approach to understand the role of respiratory effort in the progression of lung injury in sars-cov-2 infection date: 2020-08-10 journal: crit care doi: 10.1186/s13054-020-03197-7 sha: doc_id: 286771 cord_uid: 77hs34jm deterioration of lung function during the first week of covid-19 has been observed when patients remain with insufficient respiratory support. patient self-inflicted lung injury (p-sili) is theorized as the responsible, but there is not robust experimental and clinical data to support it. given the limited understanding of p-sili, we describe the physiological basis of p-sili and we show experimental data to comprehend the role of regional strain and heterogeneity in lung injury due to increased work of breathing. in addition, we discuss the current approach to respiratory support for covid-19 under this point of view. severe acute respiratory syndrome coronavirus 2 (sars-cov2) pandemic has pushed health systems' response to its maximum capacity. in many countries, the surge of cases has exceeded the facilities, technological, and human resources availability at all levels of care. intensive care units have been overcrowded due to swarming of severe cases in a few weeks, where acute respiratory failure (arf) and acute respiratory distress syndrome (ards) are the main cause of admission. protective lowtidal volume (vt) mechanical ventilation (mv), including delivering a physiologic low vt adjusted by ideal body weight, is currently the standard of care for patients requiring invasive respiratory support, like moderate and severe ards. the surge of patients presenting with sars-cov2 has led to an unprecedented demand of mechanical ventilators, surprising the whole world with a shortage of equipment unthinkable just 6 months ago. due to high demand of invasive mv in many hospitals, mechanical ventilators have become a scarce or nonexistent resource, and other respiratory support strategies have been used, including high flow nasal cannula (hfnc), non-invasive ventilation (niv), and other alternative devices. specific indications for their use are not well defined, consensus guidelines are controversial and frequently they are not followed in clinical practice. the risk of healthcare professional's infection due to aerosolization was suggested as a strong contraindication for hfnc and niv at the beginning of pandemic, contributing in some degree to the shortage of invasive mechanical ventilators. as pandemic reached peak of cases, use of non-invasive devices became widespread. cohort studies form china, italy and north america [1] [2] [3] , showed niv use between 10 and 30% of patients, but when considering single center and small case series it ranges from 0 to 69%. although non-invasive respiratory support may prevent invasive mv, failure of this approach may lead to morbidity and mortality [4] [5] [6] [7] [8] [9] [10] [11] [12] . some patients will remain dyspneic, breathing spontaneously, with or without respiratory support. currently, indirect information suggests that vigorous and dysregulated respiratory effort may be a promoter of lung injury, a phenomenon known as "patient self-induced lung injury" (p-sili) [13] [14] [15] . biomechanical framework for amplification of lung damage: stress and strain the lung can be described as a pre-stressed network of viscoelastic tissue elements deformed by surface tension and the action of respiratory musculature. this characteristic allows deformation in a time-dependent manner upon applied pressure and return to its initial configuration once the pressure is relieved [16] . breathing produces a phenomenon of continuous cyclic strain deformation throughout life, where the applied pressure is inspiratory pressure. in biomechanical terms, deformation in the lung is measured in terms of strain, defined as the relative change in volume normalized by a reference volume. this biomechanical property can be defined for the whole lung (global strain) as the ratio between the vt and a reference volume, usually the volume of air at the end of passive expiration, and the functional residual capacity (frc). correspondingly, the force acting on a surface unit, producing its deformation, is the stress. the transpulmonary pressure corresponds to the stress in the lung. strain and stress in the lung tissue are closely related to each other through a constitutive relation (stress = tissue elastance*strain). both are considered to play an important role in the onset and development of ventilator induced lung injury (vili). high values (non-physiological) of strain, measured as pulmonary tissue deformation relative to volume change, are known to be harmful to the lung and to increase mortality in ards patients under mv [17] . indeed, improved clinical outcomes observed in ards patients due to lower vt corresponds to a reduction of the lung deformation because of mv [18] . these compelling and well-established findings have directed the attention of several groups to understand the regional mechanisms of deformation in mechanically ventilated patients. understanding the global strain in the lung has allowed the identification of thresholds of safer vt to prevent vili, currently present in guidelines and consensuses [17] . in injured lungs, there is a wide spectrum of tissue aeration, producing inhomogeneity of ventilation. lung inhomogeneity has been recently proposed as a vili promoter in ards patients, given the fact that lung injury can occur despite the use of recommended vt and pressures, parameters that are considered to be safe in the ventilation of healthy lungs. the concept of stress raisers may explain these findings. the term stress raisers refer to those additional regional factors capable of intensifying the damage. stress raisers produce amplification of the stress applied in certain localized regions of the lung, like the areas of high inhomogeneity of ventilation [19] [20] [21] [22] . the deleterious effects of high regional strain in the lung was confirmed recently in a swine model of injurious mv, where lung zones of increased regional strain had a spatial correlation with areas of tissue inflammation [23] . this study highlights the relevance of a better understanding of the spatio-temporal progression of regional strain, supporting that strain is a relevant and prominent determinant of vili [23] [24] [25] . the heterogeneous distribution of opening pressures throughout the lung results in an overstretch of the aerated lung zones ("baby lung") and also in collapsed (poorly aerated) regions due to repetitive cycles of recruitment-derecruitment. the generation of injurious mechanical forces is inevitable when invasive mv is applied, due to the heterogeneous nature of ards and the inflation/deflation dynamics of the lungs. there is a coupling between the applied mechanical stimuli and the biochemical response of lung cells, a biological process called mechanotransduction [26, 27] . mechanotransduction can be a pathway of lung injury when the mechanical stimuli are excessive, triggering an inflammatory response in the lung. amplification of lung damage, i.e., vili, depends on the level of energy dissipated by the lung parenchyma and its deformation. the lung does not discriminate the origin of these forces that can be generated by mv or by the respiratory muscles. in this way, biomechanical mechanisms that cause p-sili can occur with or without mv. there is strong evidence that spontaneous ventilation during mv has a role in progression of lung injury [28] . although spontaneous breathing has proved beneficial in the treatment of mild ards patients, opposite effects occurred when lung injury was severe. spontaneous breathing amplified the damage in severe lung injury, increasing transpulmonary pressures, atelectasis, cyclic collapse, and histological signs of damage [28] [29] [30] [31] [32] . the paradox of spontaneous breathing and lung damage can be explained by the solid-like biomechanical behavior of injured lungs. some of the mechanisms described for lung injury from spontaneous effort are increased lung stress/strain, increased lung perfusion, and patient ventilator asynchrony. the generation of vigorous diaphragm contractions induces high negative pleural pressures that will be dissipated along the visceral pleura surface in a homogeneous shape (fluid behavior) in case of healthy lungs, but this dissipation is uneven in case of ards lungs and stress is concentrated in the interphase of collapsed and ventilated lung (solid behavior). this increment in local lung stress has been associated with higher lung inflammation in the dependent lung regions in experimental models. in addition, increment of venous return and oscillations in pulmonary blood flow could favor lung edema production, and finally patient-ventilator dyssyncronies as reverse triggering are associated with increments of vt that may induce vili [30, 33, 34] . there has been a particular emphasis on interventions to prevent mv in recent years, such as hfnc and niv, maintaining spontaneous ventilation and avoiding vili [35] [36] [37] [38] [39] . experimental studies and indirect clinical information have given a counter point to this approach, suggesting that spontaneous unregulated ventilatory effort for extended periods of time can also induce progression of the lung damage [13, 14] . in spite of these facts, it may be counterintuitive the current recommendation to avoid or deliberately delay the start of the mv. currently, the knowledge of p-sili in extubated patients is limited. p-sili occurs in healthy lungs without mv, in some conditions, like an intense increase in minute ventilation ( e). stress failure of blood-gas barrier after forced training in racehorses was described by west et al. in 1993 [40] . similar findings have been described in elite athletes after prolonged high intensity exercise (i.e., triathletes, marathon runners, and swimmers), which in fact can led to pulmonary edema, in absence of cardiac alterations. after intense exercise, bronchoscopic samples have found higher concentration of red blood cells, total proteins, albumin, and inflammatory cells (neutrophils), mimicking the findings in other mammals [41] [42] [43] [44] . these alterations can be correlated to the ones described by mascheroni et al. in an experimental ovine study [45] . the authors observed a serious deterioration in pulmonary function after 3.5-13 h of pharmacologically induced hyperventilation in spontaneously breathing animals without lung disease. these alterations were prevented by mv and sedoparalysis. this study confirms that vigorous spontaneous ventilation can affect the lung and controlled mv can prevent or attenuate the damage of the lung in this setting [45] . the alterations in lung function in this experiment were inversely proportional to the exposure time to hyperventilation. as authors point out, they could not discriminate if only the "mechanical stress" was responsible for these observations. off note is that during the observation period, animals were intubated (infraglotic artificial airway) and without positive pressure ventilation. this experimental design may have contributed to the deterioration of lung function by promoting lung atelectasis. for example, hedenstierna et al. described that perioperative atelectasis collapse can easily reach 50% of the total lung tissue after a few minutes even in uneventful anesthesia [46] . atelectasis could contribute to p-sili by two main mechanisms: reduction of frc and subsequent increment in dynamic strain during tidal ventilation and generation of heterogeneous lung tissue [17, 19, 47, 48] . recently, we developed a 4d tomographic study that employs image-based biomechanical analysis [49] to unveil the volumetric distribution of regional deformation of the whole lung in subjects without mv. in healthy sedated rats under (unassisted) spontaneously breathing, we observed volumetric regional strain and strain heterogeneity, quantifying the magnitude of these deformation indices and its progression in time [50] . given the fact that regional strain and heterogeneity are present during a normal respiratory cycle without harming the lung leads to the question: why p-sili does not develop in normal lungs deformed by physiologic vt? the answer probably is related to many factors, as the amount transpulmonary pressure generated, alveolar-capillary barrier indemnity and the magnitude and topographic distribution of dissipated energy on the lungs. a possible explanation might be that the susceptibility to p-sili depends on the size of the frc, prior to injury induced by high global strain. loss of normally aerated lung volume has two main effects: less lung available for tidal deformation and increased force of diaphragmatic contraction. for a same vt, a lung with lower frc is inherently more susceptible to global regional strain. reduced lung volume has important effects on diaphragm position and function. cephalad displacement results in a greater curvature of the diaphragm and an increase in the size of the zone of apposition. further, diaphragmatic fibers are lengthened, augmenting its capability of generate force during the contraction. if respiratory neuromuscular function is intact, then increased drive translates into stronger diaphragm contraction and larger "swings" of negative pressure. this has been demonstrated in laboratory studies, in which spontaneous effort was greater in more severe lung injury. stronger spontaneous effort is linearly related to larger degrees of pendelluft, as well as greater tidal recruitment and regional strain (fig. 1) . in a follow-up experimental study, we compared animals with acute lung injury under controlled mv and spontaneously breathing without mv. lung injury was induced by lung lavage in rats, followed by 3 h of spontaneous breathing or low vt-mv. micro-ct images were acquired at the beginning and at the end of the observation period, and 4d regional strain maps were constructed. we found a marked tomographic progression of the nonaerated-tissue compartment, and a reduction of the normal-tissue compartment, in accordance to de-recruitment phenomenon. additionally, we found a significant progression of regional fig. 2 regional volumetric strain maps in a 3-h murine model of patient self-inflicted lung injury randomized to two groups: group i: subjects with induced lung injury on low tidal volume mechanical ventilation at the beginning of the experiment (t1) and at the end of the experiment (t3) (upper left and right panels). group ii: subjects with induced lung injury on spontaneous breathing (no mechanical ventilation) at the beginning of the experiment (t1) and at the end of the experiment (t3) (lower left and right panels). progression of regional strain and heterogeneity in time is observed in spontaneous breathing, which reaches volumetric strain levels of up to 80%. regional strain distribution remains more uniform and homogeneous in low tidal volume mechanical ventilation volumetric strain and heterogeneity after spontaneous breathing. in contrast, low vt-mv had limited progression of the regional strain and heterogeneity at the end of the study (fig. 2) [51] . lung heterogeneity has been associated with ards severity and mortality [19] . peri atelectatic alveoli, as mead et al. described in a theoretical model of alveolar interdependence, can concentrate tension until 4times in comparison with the global tension applied to the system [52] . some years ago, our group showed that the peri-atelectatic region in a rat-model of injurious mv presented more inflammation and alveolar disruption than the rest of lung [53] . if we project the alveolar interdependence to heterogeneous lung with multiple collapsed regions, we can explain this as a trigger of inflammation during spontaneous ventilation. our group is currently working on topographic correlation of areas of strain and inflammation in the p-sili model. we measured gene expression pathways on lung tissue homogenate and lung histology. preliminary results are supportive of our hypothesis. regions-ofinterest (roi) with high regional strain had increased expression of genes involved in apoptosis, il-2 signaling, g-protein signaling, activation of ligand-activated ion channels, coagulation, and inflammation, among others, compared to rois with low regional strain (taqman™ array rat inflammation 96-well plates, cat. no. 4414081, thermo fisher scientific, usa) (fig. 3) . a similar gene expression was identified in areas of high stretch in mechanically ventilated rats in a high global lung strain model [24] . off note is that in our p-sili model, animals under spontaneous breathing had higher degree of histopathological damage compared to low vt-mv, specifically alveolar wall disruption and hemorrhage, hyperemia, and leucocyte infiltration (fig. 4) . interestingly, although fig. 3 variation of gene expression in high strain and low strain regions of the lung in a murine model of patient self-inflicted lung injury. a representative images of in vivo/ex vivo fit between tomographic maps of regional strain and 3d digitized frozen lungs. red areas represent high strain regions, while the green/blue areas represent low strain regions in spontaneous breathing. low and high strain regions from the same frozen lung were cut, homogenized, and the rna purified. b gene expression variation of inflammation/pathological mechanotransduction between regions of high and low regional strain. the genes that increased their expression in regions of high deformation were tnf superfamily member 13b (tnfsf13b, > 8 times), interleukin-2 receptor subunit beta (il2rb, > 6 times), phosphodiesterase 4a (pde4a,~3 times), 5hydroxytryptamine receptor 3a (htr3a), plasma kallikrein (klkb1), and leukotriene c4 synthase (ltc4s). these genes are involved in apoptosis, il-2 signaling, g-protein signaling, activation of ligand-activated ion channels, coagulation, and inflammation, respectively biomechanical phenomena and gene expression are regional, lung damage was diffuse. a possible explanation for this is that many of the biomarkers mentioned are water soluble and easily diffusible in plasma and respiratory secretions, so they can be secreted locally, but their consequences are more diffuse, and even at distance. rationale of non-invasive support in arf due to sars-cov2: hypothetical fear vs common practice gattinoni et al. recently described two phenotypes in patients with sars-cov2, "non-ards" type 1 (or type l), and ards, type 2 (or type h) [12, 54] . type 1 refers to initial covid-19 pneumonia, characterized by low elastance, low v/q ratio, low lung weight, and low recruitability. on the contrary, type 2 fulfills classic criteria of ards. in a small case series of 16 patients, the authors described that patients switched from type 1 to type 2 after 1 week of non-invasive support. authors proposed that facing high respiratory drive, p-sili is responsible to progression from type 1 to type 2 covid-19 phenotypes. our initial experimental data suggest that one mechanism of the clinical observation of gattinoni et al. may be due to regional lung volumetric deformation and pathological mechanotransduction induced by high strain-spontaneous breathing. as the lung does not discriminate the origin of the force that produce volumetric deformation, whether that can be generated by mechanical ventilation (vili) or the respiratory muscles. under this point of view, this last mechanism can be more precisely describe as "effort-induced lung injury", instead of p-sili. as some authors have pointed out, the type 1 and type 2 phenotypes are an oversimplification of arf due to sars-cov2, as it is not possible to attribute to a single mechanism the complexity of covid-19. thus, respiratory support, non-invasive and invasive, cannot be decided on a single parameter to prevent potential complications and decrease morbidity and mortality. pathophysiology of covid-19 respiratory failure [55] explains why patients with covid-19 usually present with moderate to severe hypoxemia, so it seems appropriate to use standard oxygen therapy, hfnc and niv as initial respiratory support. due to the discordance of hypoxemia and respiratory distress, it is important to have in mind that previous studies that showed that stratified by severity hypoxemia high vt (greater than 9.5 ml/kg [56] or 9 ml/kg [57] ) predicts failure of niv support. niv failure has been associated to mortality [5] , where high global strain may have a role on progression in lung injury. interestingly, a study showed that the use of the helmet as an interface for niv was associated with a better outcome than the traditional interface. whether the possibility to deliver higher peep could be part of the explanation is not known [7] . high peep could reduce the respiratory drive, the negative pressure swings and global/regional strain due to caudal displacement and shortening of the diaphragm muscle. in this way, sartini et al. recently described the effects of niv and prone position cycles in patients with covid-19 respiratory failure [58] . they found a significant decrease fig. 4 representative images of lung histology of a 3-h murine experimental study where subjects were randomized to three groups: group i: subjects with normal (uninjured lungs) on spontaneous breathing (no mechanical ventilation) (a, b). group ii: subjects with induced lung injury on low vt mechanical ventilation (c, d). group iii: subjects with induced lung injury on spontaneous breathing (no mechanical ventilation) (f-j). in the first image set, no edema or perivascular infiltration is appreciated at ×100 (a) and ×200 (b). in the second image set, minimal amount of perivascular fluid is occasionally observed at ×100 (c-e). in the third image set, we observed alveolar wall disruption and hemorrhage at ×400 (f), perivascular edema and hemorrhage at ×200 (g), intense hyperemia in lung parenchyma vascular bed with signs of initial perivascular edema and leucocyte infiltration at ×200 (h), intense hyperemia and perivascular accumulation of leucocytes at ×100 (i), and perivascular accumulation of polymorphonuclear cell leucocytes and lymphoid cells at ×400 (j) in respiratory rate and an improvement of oxygenation parameters. it is impossible to asses isolated respiratory function in covid-19 respiratory failure as well as other causes ards patients. a clear example in the study of carteaux et al. where immunosuppression and severity also where associated to niv failure [56] . as explained before, hypoxemia is infrequently the primary cause of respiratory distress, so it is important to consider other factors as well as non-respiratory organ disfunctions, like acute kidney injury, myocardial, and severe endothelial dysfunction; all of which are common in sars-cov2 [59] [60] [61] [62] . the correct assessment of these factors gives a unique opportunity to non-respiratory treatments for covid-19. hfnc has shown remarkable results as primary respiratory support in de novo arf [63] , improving oxygenation and decreasing escalation of care and intubation rate when compared to standard oxygen therapy [63] [64] [65] . the benefit may result from the decrease of the anatomic dead space, reducing the ventilatory demand and work of breathing (wob) [66] . in covid-19, hfnc has been shown to be safe, well tolerated and it has a synergistic effect when combined with other treatments like prone position [67] [68] [69] [70] [71] . prone position has been extensively studied in patients with ards and invasive mv, showing an improvement of oxygenation due to many mechanisms, like improving frc, ventilation/perfusion heterogeneity, diaphragm motion in dorsal regions, increasing regional ventilation in dependent lung regions, among others [72, 73] . some principles of prone position can be applied to awake extubated patients, but physiology is still not known in depth. it has been demonstrated as a safe intervention, and currently, it is widely used in emergency room, general wards as well as icu settings [58, [68] [69] [70] [71] . the physiological concepts of hfnc, niv, and prone position can also be applied to patients with hypoxemic arf secondary to sars-cov2 infection. comorbidities are highly relevant in the selection of the selected noninvasive support strategy (i.e., morbid obesity, copd, chronic heart failure). awake prone position could attenuate p-sili by reducing distending pressures, and negative swings of intrathoracic pressure, and more importantly, an increase in frc. theoretically, these mechanisms can improve alveolar interdependence phenomena by decreasing global strain and heterogeneity. a pragmatic approach to arf due to sars-cov2 some authors have highlighted the importance of a physiologic approach to sars-cov2 arf [74] [75] [76] [77] [78] . we strongly recommend a conservative approach to respiratory failure due to sars-cov2. hypoxemia alone (as well as all derived parameters, like p/f ratio) should not precipitate intubation, and pao 2 as low as 50 to 60 mmhg can be tolerated when there is no evidence of low end-organ perfusion or signs of dysoxia. all obvious indications of invasive mv, like hemodynamic instability, alteration of consciousness, should be carefully assessed over time. in our experience, in most of these patients, intubation can be prevented using timely non-invasive support, and treating identified or suspected complications early. a special consideration is to prevent fluid overload in these patients, although most of the time initial presentation is some degree of dehydration when acute kidney injury is not present. off note is that ctscans do not change our usual management. when patients develop an increase of wob (respiratory rate greater than 35 breaths per minute, increase of respiratory muscles work, severe dyspnea and shortness of breath), a promptly evaluation of secondary causes is assessed and treated [78] [79] [80] [81] , including end-organ failure, early suspicion of bacterial superinfection, and thromboembolic events. this is in line with the concept of multidimensional dyspnea assessment coined by banzett et al. [79, 81] . we acknowledge that there is no clear threshold to decide invasive mv, even considering hypoxemia and increased wob. a special limitation is that there is no standardized measurement of respiratory distress in covid-19 respiratory failure. given these facts, there are many aspects of p-sili still in debate and our current understanding is very limited on the role of p-sili in progression of lung disease [78] . the tipping point might be the tolerance of the patient to noninvasive measures and the response to treatment, although it is also a subjective decision. mv is a lifesaving intervention in many situations, but it carries a high risk of complications. p-sili during mv can occur in situations where high respiratory drive cannot be controlled. a short course of deep sedation and neuromuscular blocker (nmb), with daily assessment of discontinuation (nmb-holiday) is recommended [82, 83] . weaning in arf-covid-19 also needs a special consideration. we have observed many situations where increase wob due to high e demand, unrelated to the course of covid-19 pneumonia, can prompt weaning failure, prolonging mv duration, or ultimately extubation failure. usual situations include severe fever due to systemic unresolved inflammation, delirium, superinfection, drug withdrawal, and acidosis. clinicians need to prevent them before weaning and extubation (i.e., early initiation of antipsychotics, early discontinuation of benzodiazepines infusions, temperature control, etc.). all of these aspects are used to grasp our gestalt of arf due to sars-cov2. it includes a multisystemic evaluation (not only respiratory system) to decide appropriate respiratory support, invasive or non-invasive, and correction of other factors that increased e demand and wob [79] . after intubation, usual care to prevent complications are instituted [75, 77] , and conditions for success weaning and extubation are assessed daily, to prevent an excessive duration of mv and morbidity and 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contributions pc and fd conceived the idea of the manuscript. pc took the lead in writing the manuscript, in consultation with fd. jr, deh, and pi were the main reviewers of p-sili during mechanical ventilation section, in consultation with pc and fd. deh and pi were responsible of preliminary results of volumetric strain deformation section. pc and be were the primary reviewers of p-sili without positive pressure ventilation, in consultation with fd. cg analyzed and wrote the preliminary results of histology, in consultation with pc and fd. fd, pc, be, and deh contributed to the discussion in accordance with the preliminary results. all authors were involved in manuscript preparation, and they provided critical feedback to the analysis and discussion. pc and fd are the guarantors of and take responsibility for the content of the manuscript. all authors made substantial contributions to the research, provided final approval of the version to be published, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. all authors have read and approved the manuscript. fondo nacional de desarrollo científico y tecnológico grant (fondecyt) # 1160631 to pc, be and deh. ethics approval and consent to participate not applicable consent for publication not applicable the authors have no conflict of interest to disclose. key: cord-325664-9ool5z9s authors: immovilli, paolo; morelli, nicola; antonucci, elio; radaelli, guido; barbera, mario; guidetti, donata title: covid-19 mortality and icu admission: the italian experience date: 2020-05-15 journal: crit care doi: 10.1186/s13054-020-02957-9 sha: doc_id: 325664 cord_uid: 9ool5z9s nan correlation was observed between the cfr and icu admission rate (pearson's r − 0.53, p value 0.014) and r 2 was 0.24, suggesting an association between mortality and the absence of treatment in icu (fig. 1) . the analysis of mortality during an outbreak is no easy feat and a precise evaluation can be obtained only once the outbreak is over. furthermore, the high italian mortality may well be attributable to a large proportion of elderly persons in the italian population, to an ascertainment bias and/or diagnosis bias, leading to an underestimation of the milder cases and mortality overestimation. however, examining the differing outbreak magnitudes in regions with different icu availability evidenced a discrepancy in the percentage of icu-admitted patients. indeed, there was a higher mortality rate in the northern region where fewer patients could be admitted into an icu. these preliminary data evidence the pivotal preventive role played by early lockdown measures to reduce outbreak magnitude and place less pressure on icu beds availability; however, these data should be interpreted with caution because of possible bias: patients could be allowed outside the icu due to various reasons (i.e., age, comorbidities, frailty index), as it occurs in daily clinical practice. covid-19 in china: ten critical issues for intensive care medicine sostieni l'emergenza corona virs the authors thanks elena marchesi, manuela giovini, ignazio semproni, chiara terracciano, domenica zaino, and eugenia rota for their contribution in reading and reviewing the article and barbara wade for her linguistic advice. received: 20 april 2020 accepted: 8 may 2020 paolo immovilli, nicola morelli, elio antonucci, guido radaelli, mario barbera, and donata guidetti are responsible for study design and all authors wrote and reviewed the manuscript. the authors read and approved the final manuscript. there was no funding for this article.availability of data and materials data published online by italian civil protection department (http:// opendatadpc.maps.arcgis.com/apps/opsdashboard/index.html#/b0c68bce2 cce478eaac82fe38d4138b1; seen on march 31, 2020).ethics approval and consent to participate not applicable. not applicable. the authors have nothing to disclose. key: cord-278249-vvhq9vgp authors: blot, mathieu; jacquier, marine; aho glele, ludwig-serge; beltramo, guillaume; nguyen, maxime; bonniaud, philippe; prin, sebastien; andreu, pascal; bouhemad, belaid; bour, jean-baptiste; binquet, christine; piroth, lionel; pais de barros, jean-paul; masson, david; quenot, jean-pierre; charles, pierre-emmanuel title: cxcl10 could drive longer duration of mechanical ventilation during covid-19 ards date: 2020-11-02 journal: crit care doi: 10.1186/s13054-020-03328-0 sha: doc_id: 278249 cord_uid: vvhq9vgp background: covid-19-related ards has unique features when compared with ards from other origins, suggesting a distinctive inflammatory pathogenesis. data regarding the host response within the lung are sparse. the objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ards etiology (i.e., covid-19 vs. non-covid-19). methods: bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-covid-19 ards, and 14 covid-19 ards patients. clinical data, plasma, and epithelial lining fluid (elf) concentrations of 45 inflammatory mediators and cell-free mitochondrial dna were measured and compared. results: covid-19 ards patients required mechanical ventilation (mv) for significantly longer, even after adjustment for potential confounders. there was a trend toward higher concentrations of plasma ccl5, cxcl2, cxcl10, cd40 ligand, il-10, and gm-csf, and elf concentrations of cxcl1, cxcl10, granzyme b, trail, and egf in the covid-19 ards group compared with the non-covid-19 ards group. plasma and elf cxcl10 concentrations were independently associated with the number of ventilator-free days, without correlation between elf cxcl-10 and viral load. mitochondrial dna plasma and elf concentrations were elevated in all ards patients, with no differences between the two groups. elf concentrations of mitochondrial dna were correlated with alveolar cell counts, as well as il-8 and il-1β concentrations. conclusion: cxcl10 could be one key mediator involved in the dysregulated immune response. it should be evaluated as a candidate biomarker that may predict the duration of mv in covid-19 ards patients. targeting the cxcl10-cxcr3 axis could also be considered as a new therapeutic approach. trial registration: clinicaltrials.gov, nct03955887 since december 2019, the world is experiencing an outbreak of coronavirus disease 2019 (covid-19) caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2). clinical, radiological, and biological differences have been found between covid-19-related acute respiratory distress syndrome (ards) and ards from another origin. indeed, the sudden clinical deterioration observed 1 week after symptom onset, together with deep hypoxemia contrasting with "normal" (> 40 ml/cmh 2 o) lung compliance, and the higher incidence of thromboembolic events suggest that sars-cov-2 is driven by a unique pathogenesis resulting in an atypical form of ards [1, 2] . notably, mechanical ventilation appears to be required for twice as long in covid-19 than in non-covid-19 ards patients [3, 4] . it has been established that the virus invades type 2 alveolar cells and ciliated epithelial cells that express ace2 [5] . subsequently, as they die, infected cells release virus particles and intracellular components including molecules likely to act as alarmins (i.e., danger signals), as reflected by rising lactate dehydrogenase (ldh) levels in the plasma [6] . the ensuing recruitment and activation of immune cells lead to lung damage [7] . for now, several studies have established that the hyperinflammatory response (namely the cytokine storm) induced by sars-cov-2 is associated with disease severity and could contribute to the development of ards [8, 9] . in addition, since most patients need to undergo mechanical ventilation in this context, ventilator-induced lung injury (vili) could exacerbate tissue damage as well as local and systemic inflammation, thus acting as a "second hit." our team has previously shown that mitochondrial alarmins (i.e., mitochondrial dna) are released by human epithelial cells submitted to cyclic stretch, and these alarmins are also recovered from bronchoalveolar lavage (bal) fluid obtained from either ventilated rabbits or ards patients. by promoting chemotaxis and activation of polymorphonuclear neutrophils (pmns), mitochondrial alarmins are thought to represent proximal endogenous mediators of vili and ards when they are released by injured alveolar cells [10, 11] . the aim of our study was to compare cytokine response patterns, in both alveolar and systemic compartments, between covid-19-related ards and non-covid-19-related ards (i.e., ards complicating pneumonia from another origin). in addition, we sought to establish the extent to which the immune signature could be associated with clinical evolution according to ards etiology. this is an ancillary study of the ongoing prospective pneu-mochondrie study (clinicaltrials.gov nct03955887) which started in june 2019 in three intensive care units and the department of pneumology at the university hospital of dijon (france). patients were eligible if a bal was considered necessary by the attending physician and if they had (1) pneumonia (≥ 2 acute signs including cough, purulent sputum, dyspnea, chest pain, temperature < 35°c or ≥ 38.5°c, and novel radiological pulmonary infiltrate); (2) ards (according to the berlin definition) [12] ; (3) requiring mechanical ventilation (mv); and (4) bal was performed within 72 h of the start of mv. covid-19 ards patients were eligible if they tested positive for sars-cov-2 by reverse transcriptase polymerase chain reaction (rt-pcr) for at least one respiratory sample. the control population consisted of outpatients without fever during the last 15 days, not under mechanical ventilation, and undergoing a bal for a condition not related to acute infection (evaluation of a pulmonary nodule, chronic interstitial syndrome, or unexplained chronic pulmonary sign). seven control patients and 7 bacterial ards patients were prospectively included between june 11, 2019, and january 20, 2020 (5 weeks before the pandemic covid-19 started in burgundy, france). fourteen covid-19 ards patients were included between march 30 and april 09, 2020. oral consent was obtained from the patients or their legal representatives. approval was obtained from the ethics committee (comité de protection des personnes sud-est iii; 2018-035 b), and an amendment was obtained to include supplementary patients with covid-19-related ards. demographic data, comorbidities, clinical and biological parameters, and severity scores (sequential organ failure assessment (sofa) [13] and the new simplified acute physiology score (saps ii) [14] ) were calculated on the first day of ards. septic shock was defined as persistent hypotension requiring vasopressors and a serum lactate level > 2 mmol/l despite adequate volume resuscitation. clinical outcomes were recorded up to 30 days after the start of ards: 30-day mortality; number of hospital-, icu-, and ventilatorfree days; and hospital-acquired complications (ventilatory-acquired pneumonia (vap), thrombo-embolic disease). the "ventilator-free days" outcome was defined as the number of days alive from day 1 of ards to day 30 during which the patient was breathing without mv. dedicated clinical research assistants collected all data using a standardized electronic case report form. automatic checks were generated for missing or incoherent data. all abnormal data were controlled by a physicianscientist. the concentration of inflammatory cytokines and mitochondrial alarmins (cell-free mitochondrial dna concentrations) was measured within both the systemic and alveolar compartments. bronchoalveolar lavage was performed by fiberoptic bronchoscopy as part of standard care with sterile saline at 37°c. the ten first milliliters of aspirated fluid, reflecting a bronchial sample, was not considered for the study. ten milliliters of bal fluid (balf) was dedicated to the study, transported at 4°c, and used within 2 h of collection. fifty microliters of whole balf was homogenized with 200 μl of thrombo-plus (sarstedt) before cell count by light microscopy. bal was filtered through a 70-μm cell strainer (fisher) and centrifuged at 500×g for 10 min at 4°c to remove mucus and cells. the supernatant was then centrifuged again at 3200×g for 5 min at 4°c to remove the remaining debris and stored at − 80°c until use. in addition, three additional blood tubes (edta) were collected just before the bal procedure (with a maximum delay of 3 h), as part of standard care, and then centrifuged at 2000×g for 10 min at 4°c and stored at − 80°c until use. forty-five analytes were quantified in the plasma and balf using human xl cytokine magnetic 45-plex luminex® assay (r&d systems, usa) according to the manufacturer's instructions: c-c motif chemokine ligand (ccl)2, ccl3, ccl4, ccl5, ccl11, ccl19, ccl20, cd40 ligand, fractalkine, c-x-c motif chemokine ligand (cxcl) 1, cxcl2, cxcl10, epidermal growth factor (egf), fibroblast growth factor (fgf), fms-like tyrosine kinase 3 ligand (flt3l), granulocyte colony-stimulating factor (g-csf), granulocytemacrophage colony-stimulating factor (gm-csf), granzyme b, interferon (ifn)-alpha, ifn-beta, ifn-gamma, interleukin (il)-1α, il-1β, il-1ra, il-2, il-3, il-4, il-5, il-6, il-7, il-8, il-10, il-12, il-13, il-15, il-17a, il-17e, il-33, programmed death-ligand 1 (pdl1), platelet-derived growth factor (pdgf)-aa, pdgf-ab/bb, transforming growth factor (tgf)-α, tumor necrosis factor (tnf)-α, tnf-related apoptosis inducing ligand (trail), and vascular endothelial growth factor (vegf). for mitochondrial dna isolation, collected conditioned media from the plasma and balf were first centrifuged at 3200×g for 5 min to remove cell debris, followed by dna extraction using qiagen dneasy kit (qiagen, valencia, ca, usa). quantitative pcr was performed on a steponeplus™ real-time pcr (applied biosystem), using sybr green reagent (powerup®, thermo) with one-tenth and one-fiftieth dilutions of the final product of plasma and balf respectively, using mitochondrialspecific pcr primers for cytochrome c oxidase subunit iii (coxiii) and nadh dehydrogenase subunit i [15] , in reference to a standard curve of human mitochondrial dna to quantify the amount of mitochondrial dna, amplified as previously reported [10, 11, 15] . rna extraction was performed on a nuclisens® easy-mag® platform (biomerieux, marcy-l'étoile, france), from 200 μl of cell-free balf, and according to the manufacturer's instructions. two target genes were amplified and tested simultaneously, namely the rnadependent rna polymerase (rdrp) ip2 and ip4 regions [16] . amplification was performed using quantstudio 5 rtpcr systems (thermo fisher scientific, waltham, ma, usa). quantification of the number of rna copies was done according to a scale ranging from 10 3 to 10 6 copies/ml. all positive balf samples were quantified and expressed as the number of rna copies/μl. to correct for dilution of balf, the elf concentration of all analytes or sars-cov-2 was calculated by multiplying the balf concentration with a dilution factor and using urea, according to the formula [analyte] elf = [analyte] balf × [urea] plasma /[urea] balf , as described by rennard et al. [17] . determination of the urea concentration in balf and plasma was performed using the liquid chromatography tandem mass spectrometry (lc-msms) method, adapted from han et al. [18] with modifications. plasma (10 μl) or balf (20 μl) were extracted with 1 ml of cold ethanol containing 1000 ng or 50 ng of 13c and 15n2 urea used as internal standard, respectively. high-performance liquid chromatography (hplc) was performed on an agilent 1260 lc system coupled to a 6460 qqq mass spectrometer. the analysis was conducted in a positive selected reaction monitoring mode. calibration curves using authentic urea standards (santa cruz, dallas, usa) dissolved in water were prepared. linear regression was used for calculations. collected data were described according to the covid-19 status of the ards (i.e., non-covid-19 or covid-19) and for the control group. continuous variables were expressed as median and inter-quartile ranges (iqr) and categorical variables as number and percentages. the univariate analysis consisted of comparisons between variables, according to the covid-19 status, performed using the chi-square test (fisher's exact test if conditions were not met) for percentages and wilcoxon mann-whitney test for medians and iqrs. subsequently, the association between covid-19 s non-covid-19 ards and the number of ventilator-free days was assessed using two multivariate median regression models including some other clinically relevant explicative variables: (i) age, septic shock (yes/no) and pao 2 /fio 2 (model 1) and (ii) age and baseline sofa score (model 2). then, cytokines were presented by boxplots to visualize potential associations between cytokines and covid-19 status (those for which differences were observed according to the covid-19 status or according to physiopathological considerations). finally, multivariate median regression models were built to test the association with the most pertinent clinical outcome associated with covid-19 status in univariate analysis comparison, including the five most relevant covariates (i.e., covid-19 status and the cytokines that differed the most between covid-19 and non-covid-19 ards patient, either clinically or with a p value below 0.3) and treatments that differ between both groups. in order to avoid overfitting, the choice of variables was not only made on the p value but also considering statistical (i.e., collinearity) and physio-pathological considerations. model variability explicative power was quantified using the r 2 coefficient. then, mitochondrial dna levels were compared between controls, non-covid-19, and covid-19 ards patients using a kruskal-wallis analysis of variance test. to account for multiple comparisons, the p value was adjusted for a false discovery rate (fdr) using the benjamini and hochberg method. correlations were sought using the spearman test between the concentration of cytokines, mitochondrial dna, and outcome, and also elf concentrations of sars-cov-2, and depicted with a heatmap representation and scatter plot. all tests were two-tailed. a p value lower than 0.05 was considered statistically significant. all analyses were performed using the stata (13.1, stata corporation, college station, tx, usa) or prism software (graphpad prism®, version 8.0, san diego, ca, usa). twenty-eight patients were enrolled in this study (7 in the control group, 7 in the non-covid-19 ards group between june 2019 and january 2020, and 14 in the covid-19 ards group between march and april 2020). the control patients were outpatients suffered from sarcoidosis (n = 2), pulmonary langerhans histiocytosis (n = 1), pulmonary carcinoma (n = 1), scleromyositis (n = 1), focal bronchiectasis (n = 1), or unknown cause (n = 1), and none had any evidence of current infection or acute disease. bacterial pneumonia was proven in five patients from the non-covid-19 ards group (pseudomonas aeruginosa (n = 1), legionella pneumophila (n = 3), mycoplasma pneumonia (n = 1)), while co-infection occurred in only one covid-19 ards patient (staphylococcus aureus). while demographic and comorbidity data were not statistically different, baseline severity according to the sofa score in particular was found to be lower in covid-19 ards patients (p = 0.045), with a trend toward less frequent septic shock (p = 0.120) and a marginally lower baseline arterial lactate levels (p = 0.079) at the onset of ards (table 1) . according to the berlin criteria, ards severity was marginally significantly different between non-covid-19 and covid-19 patients, with a median baseline pao 2 : fio 2 of as low as 68.5 (iqr = 60.9-90.7) and 88.4 (iqr = 79.2-116.6) mmhg, respectively (p = 0.067). moreover, we found no difference in terms of ventilator settings or lung mechanics. procalcitonin tended to be only slightly higher in covid-19 ards patients than in the other ards patients (0.3 [0.2-0.5] vs. 21.6 [3.8-38.7 ] μg/l, respectively; p = 0.167) ( table 1) . the 30-day mortality rate reached 14% in the non-covid-19 group and 21% in the covid-19 group (table 1) . however, the number of ventilator-free days was significantly lower in covid-19 patients, compared to non-covid-19 patients (8 [0-15] vs. 18 [17] [18] [19] [20] [21] ; p = 0.034), along with a higher rate of ventilator-acquired pneumonia (10 (71%) vs. 0 (0%); p = 0.004). covid-19 etiology remained associated with a fewer ventilator-free days within the 30 days following admission, even after adjustment on age and baseline severity (i.e., septic shock and pao 2 :fio 2 (model 1; p = 0.046) or baseline sofa score (model 2; p = 0.076)) (supplementary tables 1 and 2). plasma cytokine levels are shown in fig. 1 and additional table 3 . covid-19 ards patients had significantly higher plasma concentrations of ccl5 (p = 0.025) and non-significantly higher plasma concentrations of cxcl2 (p = 0.094), cxcl10 (p = 0.287), cd40 ligand (p = 0.125), il-10 (p = 0.232), and gm-csf (p = 0.332) compared with non-covid-19 ards patients. at the same time, we observed lower concentrations of plasma il-2 (p = 0.047), trail (p = 0.059), and g-csf (p = 0.067). plasma cxcl10 concentration was independently associated with a greater number of ventilator-free days, after adjustment for the covid-19 etiology, submission to non-invasive ventilation (niv) prior to intubation, exposure to multiple antibiotics, cxcl2, ccl5, and cd40 ligand plasma concentrations (p = 0.049) ( table 2) . interestingly, cxcl10 levels were highly correlated with those of gm-csf (r = 0.991; p < 0.0001) and il-10 (r = 0.958; p < 0.0001). epithelial lining fluid cytokine levels are shown in fig. 2 and additional table 4 . a trend toward higher elf concentrations of cxcl1 (p = 0.287), cxcl10 (p = 0.287), granzyme b (p = 0.110), trail (p = 0.094), and egf table 3) . we also addressed the magnitude and impact of mitochondrial dna released into both the systemic and alveolar compartments during non-covid-19 and covid-19 ards. plasma and elf concentrations of mitochondrial dna were significantly higher in ards patients, regardless of covid-19 involvement (fig. 3a-d) . figure 1) . the same results were observed when only covid-19 ards patients were considered (additional figure 2) . however, neither plasma nor elf mitochondrial dna concentrations were correlated with the number of ventilator-free days. finally, sars-cov-2 concentrations were measured, and correlations with cytokine levels were sought in the alveolar compartment. first, the sars-cov-2 genome was detected in 13 covid-19 ards patients with a median of 20,449 (iqr = 893-2,092,104) copies per microliter of elf. there was a strong negative correlation with elf il-6 (r = − 0.719; p = 0.005) and ccl20 (r = − 0.723; p = 0.005), while no correlation was observed with elf cxcl10 (r = − 0.165, p = 0.573) (fig. 4a, b ). our findings suggest that covid-19 ards is associated with prolonged mechanical ventilation in comparison with non-covid-19 ards patients, regardless of the baseline characteristics. this comprehensive evaluation of systemic and pulmonary immune response showed that the higher cxcl10 concentrations in both the systemic and alveolar compartments of patients with covid-19 ards were associated with a longer duration of mechanical ventilation. interestingly, alveolar concentrations of sars-cov-2 were not correlated with alveolar cxcl10 concentration. finally, in both covid-19 and non-covid-19 patients, higher mitochondrial dna concentrations in the plasma and elf compartment were highly correlated with alveolar inflammation, as assessed by balf cell count and elf il-8 and il-1β concentrations. this result highlights the key role of mitochondrial alarmins in ards and vili. ards is the leading cause of death during covid-19. given the increasing number of cases, and especially the protracted duration of ards, attention was rapidly focused on the number of required icu beds, ventilators, and intensivists [19] . however, covid-19-associated ards, despite meeting the berlin definition, is now considered "atypical" with peculiar features such as the discrepancy between the relatively well-preserved lung mechanics and the depth of hypoxemia [20] . our findings support these observations since we show that patients with covid-19 ards received prolonged mechanical ventilation when compared to non-covid-19 ards patients, regardless of baseline severity. in the most severe forms of sars-cov-2, common features including systemic cytokine storm (including macrophage activation syndrome), organizing diffuse alveolar damage (acute fibrinous and organizing pneumonia (afop)) with excessive immune cells infiltration into the lung (in particular t cell infiltration), and thrombosis have been reported, but these features have also been observed in patients with sars-cov-1 infection and middle east respiratory syndrome (mers) [9, [21] [22] [23] . we assume that this atypical dysregulated immune response may cause the lung immunopathology that leads to the protracted and inflammatory nature of covid-19 ards. since there is no available effective direct anti-viral treatment so far, mitigating the "cytokine storm" through immune modulation is a promising therapeutic avenue. however, it is worth noting that most of the currently tested immunomodulatory agents (especially anti-il-6, anti-il-1β, and anti-tnfα) have been put forward despite gaps in our understanding of the immune response behind covid-19 ards, especially within the pulmonary compartment. however, assessing the alveolar compartment is challenging in severe ards patients. to the best of our knowledge, there is currently no published study comparing cytokine concentrations in bronchoalveolar lavage fluid obtained from either covid-19 or non-covid-19 ards patients, and basically, data regarding inflammation within the alveolar space of the former patients are sparse [24] . we report herein new insights into this issue. we show that plasma cxcl2, cxcl10, ccl5, cd40 ligand, il-10, and gm-csf concentrations and elf cxcl1, cxcl10, granzyme b, trail, and egf concentrations were found in greater concentrations in covid-19 than in non-covid-19 ards patients. interestingly, almost all of these mediators are chemokines or cytokines involved in either recruitment or activation of t lymphocytes (ccl5, cxcl10) and/or monocytes/macrophages (gm-csf). others are associated with anti-inflammation (il-10 and trail) or endothelial dysfunction (cd40 ligand, egf). among them, we found that cxcl10 was the most likely to account for the protracted nature of covid-19 ards in both the systemic and the alveolar compartments. cxcl10 (or inf-γ-induced protein (ip-10)) is secreted upon inf-γ stimulation by various cell types (endothelial cells, fibroblasts, monocytes/macrophages, and t lymphocytes) and promotes chemoattraction for activated t lymphocytes, natural killer cells, and monocytes through cxcr3 [25] . interestingly, plasma concentrations of cxcl10 have been previously reported at high levels in sars-cov-1 [26] , respiratory syncytial [27] , and influenza infections [28] , and significantly associated with a higher risk of death in ards associated with a/h1n1 influenza infection [29] . yang et al. recently reported that among 44 inflammatory mediators measured in covid-19 patients, the plasma concentration of cxcl10 was highly associated with disease severity, especially the murray score, and could independently (see figure on previous page.) fig. 1 boxplot graph depicting plasma concentration of cytokines. plasma cytokines were measured in covid-19 ards (n = 14), non-covid-19 ards (n = 7), and control patients (n = 7). covid-19 ards patients had significantly higher plasma concentrations of ccl5 and non-significantly higher plasma concentrations of cxcl2 (p = 0.09), cxcl10 (p = 0.29), cd40 ligand (p = 0.14), il-10 (p = 0.23), and gm-csf (p = 0.33) compared with non-covid-19 ards patients. we observed lower concentrations of plasma il-2 (p = 0.04), trail (p = 0.055), and g-csf (p = 0.06). the mann-whitney u test was used for comparison between non-covid-19 and covid-19 ards patients (pneumochondrie study, 2019-2020) predict covid-19 disease progression [9] . interestingly, ichikawa et al. showed that the cxcl10-cxcr3 signaling pathway was critical in viral and non-viral ards pathogenesis. moreover, they showed that lung injury could be prevented, and therefore, survival improved, when the cxcl10-cxcr3 axis was blocked [30] . since our results emphasize the involvement of the cxcl10-cxcr3 signaling axis in the pathogenesis of the most severe forms of covid-19 infection, this axis represents a potential therapeutic target. corticosteroids that showed beneficial effects in the most severe forms of covid-19 [31] may act upstream from cxcl10 through inhibition of the th1 pathway. however, specifically blocking cxcl10 (e.g., eldelumab/mdx-1100) or cxcr3 may be a promising therapeutic approach. interestingly, lev et al. reported that upon the administration of corticosteroid, a significant decrease of cxcl10 levels was observed in covid-19 patients [32] . in addition, if validated in larger cohorts, plasma cxcl10 measurement could be helpful in predicting the risk of prolonged mv. since plasma cxcl-10 and gm-csf were strongly correlated (r = 0.991, p < 0.0001), the latter was also highly associated with a longer duration of mechanical ventilation. the most severe forms of covid-19 were associated with macrophage activation syndrome, characterized by a fulminant hypercytokinemia with multiorgan failure [23] . gm-csf has recently emerged as a potential therapeutic target, since it plays a pivotal role in initiation (monocyte activation and macrophage transformation) and perpetuation of the immune response and could represent the link between t cell-driven acute pulmonary inflammation and self-amplifying cytokine loop leading to monocyte/macrophage activation [33, 34] . interestingly, an anti-gm-csf therapy (lenzilumab) has been previously evaluated in severe covid-19 and associated with improved clinical outcomes, oxygen requirement, and cytokine release [35] . still, a cautious approach is required since any immune modulation is likely to alter the body's antimicrobial defenses. this point is particularly relevant, since deep dysfunctions of the myeloid and lymphoid responses have also been described in covid-19 patients, with a decrease of hla-dr expression on monocytes [23] and t cell exhaustion [36] . interestingly, no correlation was found between the alveolar viral load of sars-cov-2 and elf cxcl10, suggesting that activation of the cxcl10-cxcr3 axis may play a role in the dysregulated immune response independently from viral clearance. thus, its blockage might not compromise the host's ability to bring the virus under control. in contrast, we observed a strong negative correlation between elf concentrations of sars-cov-2 and il-6, suggesting that il-6 production within the alveolar compartment is associated with effective viral clearance. in addition, dampening inflammation in a context of high immune suppression level is not always a hazardous route. in the setting of chimeric antigen receptor t (car-t) cell therapy, gm-csf inhibition reduces cytokine release syndrome and neuro-inflammation but enhances antitumoral cart-t cell function [37] . moreover, the il-6 blocker partially rescues immune dysregulation caused by sars-cov-2 [23] . nevertheless, as advocated for sepsis [38] , immune profiling (including cxcl10 measurement) may serve for the selection of patients that could be eligible for immunotherapy. finally, it is worth noting that higher viral alveolar loads were associated with more severe ards in terms of blood oxygenation and remote organ failure [39] , highlighting the need for drugs likely to prevent covid-19 replication in addition to therapies targeting host response. in addition to our findings regarding the cxcl10-cxcr3 axis, we observed that the released amount of mediators involved in chemotaxis and/or activation of pmns (i.e., il-8, il-1β, il-6, and tnf-α) was similar when ards was caused by sars-cov-2. moreover, alveolar cell counts and elf concentrations of il-8 and il-1β were highly correlated with the release of mitochondrial dna, whose levels were significantly increased in both the systemic and pulmonary compartments of ards patients, regardless of etiology. it is worth noting that cell-free mitochondrial dna release can elicit neutrophil-mediated lung injury through the promotion of il-8 and il-1β secretion by activation of the tlr-9 (toll-like receptor 9) and the nlrp-3 (nod-like receptor pyrin domain 3) inflammasome pathways, respectively [15, 40] . this finding suggests that systemic and pulmonary immune response could be triggered in part by the release of endogenous mediators originating from injured alveolar cells. this reaction may be subsequent to a twohit lung injury (i.e., infection of alveolar epithelial cells and ventilator-induced lung injury), as suggested by previous clinical and experimental findings from our group [10, 11] . surprisingly, we observed a trend toward lower elf concentrations of il-6 in covid-19 patients compared with non-covid-19 ards patients (p = 0.11), thus challenging the interest of anti-il-6 therapies in severe covid-19 pneumonia. these results are in line with retrospective observations by sinha et al., showing that plasma il-6 concentrations were lower in the severe form of covid-19 as compared to those reported in ards from another origin and arguing that the term "cytokine storm" may be misleading in covid-19 ards [41] . finally, it is worth noting that early bacterial coinfection was unlikely in covid-19 ards patients from our cohort, in accordance with previously published data [42, 43] . one could argue that previous exposure to antibiotics has led to false-negative results. more interestingly, it ascertains the safety of introducing new therapies (i.e., including those targeting cxcl-10) likely to dampen the host inflammatory response at this stage of the viral disease. this statement has to be mitigated by the fact that vap complicated ards in 71% of the covid-19 patients, as compared to 0% in patients with ards from another origin. although the longer duration of mv could account at least in part for such an obvious difference, one cannot exclude that vap occurrence reflected exhaustion of the lung immune defense following the strong activation of the cxcl10-cxcr3 axis. moreover, the impact of blocking this critical pathway remains uncertain regarding the risk of subsequent bacterial infection. our study has some limitations. first, the origin of non-covid-19 ards was mainly gram-negative bacteria, which is not representative of all ards of pulmonary origin. as a result of the difficulty in obtaining balf, the small sample size prevented us from performing a mortality analysis and resulted in a lack of power for some comparisons. as a result, our findings should be taken cautiously, and new studies are required in order to ascertain our hypothesis. however, pulmonary compartment assessment remains challenging, and there is currently no published data comparing balf in covid-19 and non-covid-19 ards patients. moreover, the criteria of inclusion of our control group remain questionable, and non-infected icu patients under mv would have been preferred but not possible given ethical concerns related to the fiberoptic procedure, which could not be considered as part of standard care. one can also argue that in the context of such an emerging disease, some treatments likely to influence the release of cytokines could have been given to the covid-19 patients prior to the study inclusion. however, such treatments (i.e., hydrocortisone and hydroxychloroquine) were administrated prior to blood and balf collection in a small number of patients. moreover, the time elapsed between treatment administration and sampling was quite short, making unlikely any impact on cytokine concentrations (additional table 5 ). finally, the specific impact of mechanical ventilation on pulmonary immune response cannot be evaluated since patients with less severe disease who did not require mv were not included. this study provides new insights into the peculiar pathogenesis of covid-19 ards. first, cxcl10 may represent the dysregulated immune response that drives the duration of mv in covid-19 ards patients. cxcl10 appears to be a potential biomarker for the duration of mv, and the cxcl10-cxcr3 signaling axis may be a potential therapeutic target in covid-19 ards. this target seems all the more interesting since no correlation was found between alveolar concentrations of cxcl10 and sars-cov-2 clearance. apart from those particular features, covid-19 and non-covid-19 ards share the wellknown involvement of both il-8 and il-1β within the airway, potentially driven by the release of endogenous mediators originating from injured alveolar cells (e.g., mitochondrial alarmins). supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03328-0. additional file 1: table 1 . model 1: factors associated with the number of ventilator-free days in the 21 patients with ards (multivariate median logistic regression; pseudo r 2 = 0.237; n=21, pneumochondrie study, 2019-2020). table 2 . model 2: factors associated with the number of ventilator-free days in the 21 patients with ards (multivariate median logistic regression; pseudo r 2 = 0.223; n=21, pneumochondrie study, 2019-2020). table 3 . plasma concentrations of cytokines. table 4 . epithelial lining fluid concentrations of cytokines. figure 1 . heatmap of the spearman correlation (r) between epithelial lining fluid (elf) concentrations of mitochondrial dna (nadh i and cytochrome c), elf concentration of cytokines, and outcomes for the 21 ards patients. spearman correlations: p<0.05 *; p<0.01 ** between each cytokine and the elf concentration of nadh i mitochondrial dna. figure 2 . heatmap of the spearman correlation (r) between the epithelial lining fluid (elf) concentrations of mitochondrial dna (nadh i and cytochrome c), the elf concentration of spearman correlations: p<0.05 *; p<0.01 ** between each cytokine and the elf concentration of nadh i mitochondrial dna abbreviations ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage balf: bronchoalveolar lavage fluid; ccl: c-c motif chemokine ligand; covid-19: coronavirus disease 2019; cxcl: c-x-c motif chemokine ligand cxcr3: cxc chemokine receptor 3; dna: deoxyribonucleic acid ecmo: extracorporeal membrane oxygenation; elf: epithelial lining fluid egf: epidermal growth factor; fgf: fibroblast growth factor; flt3l: fms-like tyrosine kinase 3 ligand; g-csf: granulocyte colony-stimulating factor; gm-csf: granulocyte-macrophage colony-stimulating factor; icu: intensive care medicine iqr: interquartile range; mv: mechanical ventilation; nadh i: nicotinamide adenine dinucleotide i; nlrp3: nod-like receptor pyrin domain 3 fio 2 : arterial pressure of oxygen/oxygen inspiratory fraction; pd-l1: programmed death-ligand 1; pdgf: platelet-derived growth factor rdrp: rna-dependent rna polymerase; rt-pcr: reverse transcriptase polymerase chain reaction; saps ii: simplified acute physiology score ii sars-cov-2: severe acute respiratory syndrome coronavirus 2 sofa: sequential organ failure assessment; tgf: transforming growth factor tnf: tumor necrosis factor; trail: tnf-related apoptosis-inducing ligand; vap: ventilator-acquired pneumonia high risk of thrombosis in patients with severe sars-cov-2 infection: a multicenter prospective cohort study management of covid-19 respiratory distress epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries epidemiology, clinical course, and outcomes of critically ill adults with covid-19 in new york city: a prospective cohort study sars-cov-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes clinical characteristics of 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hypercytokinemia factors identified in h7n9-infected patients can predict fatal outcomes angiogenic and inflammatory markers in acute respiratory distress syndrome and renal injury associated to a/h1n1 virus infection cxcl10-cxcr3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin dexamethasone in hospitalized patients with covid-19 -preliminary report real-time ip-10 measurements as a new tool for inflammation regulation within a clinical decision support protocol for managing severe covid-19 patients. medrxiv gm-csf-based treatments in covid-19: reconciling opposing therapeutic approaches therapeutic blockade of granulocyte macrophage colony-stimulating factor in covid-19-associated hyperinflammation: challenges and opportunities first clinical use of lenzilumab to neutralize gm-csf in patients with severe covid-19 pneumonia. medrxiv severe immunosuppression and not a cytokine storm characterize covid-19 infections gm-csf inhibition reduces cytokine release syndrome and neuroinflammation but enhances car-t cell function in xenografts the immunopathology of sepsis and potential therapeutic targets pneumochondrie study group. alveolar sars-cov-2 viral load is tightly correlated with severity in covid-19 ards oxidized mitochondrial dna activates the nlrp3 inflammasome during apoptosis is a "cytokine storm" relevant to covid-19? bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid-19 antimicrobial prescribing bacterial and fungal coinfection among hospitalized patients with covid-19: a retrospective cohort study in a uk secondary-care setting publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors acknowledge all the members of the pneumochondrie study group (françois aptel, auguste dargent, marjolaine georges, marie labruyère, laurent lagrost, audrey large, serge monier, jean-baptiste roudaut, charles thomas). we thank hélène choubley from the lipidomic analytical platform of the university of burgundy and serge monier and anabelle sequeira from the cytometry core facility which are supported by the following institutions: conseil régional de bourgogne franche-comté and feder. we thank alexandra lamotte-felin, lydie rossie, and aurélie degot from the cic-ec (cic-ec1432) and solenne villot and mathilde audry from the intensive care medicine research team. we thank suzanne rankin for the editing assistance, maud carpentier from the drci (direction de la recherche clinique et de l'innovation), shaliha bechoua (centre de ressources biologiques), and cécile pitoiset and magali darnio for the technical assistance (virology). we thank the patients. all data are available on demand.ethics approval and consent to participate approval was obtained from the ethics committee (comité de protection des personnes sud-est iii; 2018-035 b), and an amendment was obtained to include supplementary patients with covid-19. oral consent was obtained from the patient or their legal representatives. all authors consented for the publication. we declare no competing interests. received: 4 august 2020 accepted: 5 october 2020 key: cord-314737-2fun90ze authors: cardoso, filipe s.; papoila, ana l.; machado, rita sá; fidalgo, pedro title: age, sex, and comorbidities predict icu admission or mortality in cases with sars-cov2 infection: a population-based cohort study date: 2020-07-28 journal: crit care doi: 10.1186/s13054-020-03173-1 sha: doc_id: 314737 cord_uid: 2fun90ze nan previous studies have identified risk factors for severe acute respiratory syndrome coronavirus 2 (sars-cov2) severe outcomes preferentially among hospitalized patients; therefore, they may have understated the denominator of such estimations [1, 2] . we aimed to determine pre-hospital risk factors and estimate individual probabilities of sars-cov2 severe outcomes among a nationwide cohort of cases of sars-cov2 infection, including those with and without hospitalization. this was a retrospective analysis from a nationwide prospective registry, including confirmed (nasal/pharynx swab real-time polymerase chain reaction) cases of sars-cov2 infection notified to the directorate-general of health from march 02 until april 21, 2020, in portugal. primary endpoint was a composite of icu admission or all-cause mortality until april 21. multivariable analysis was performed with logistic regression. internal validation was performed with bootstrapping. models' performance was studied with calibration plots, c-statistic, and brier score [3, 4] . significance level was α = 0.05. informed consent was waived due to the use of anonymized data and the current state of public health emergency. overall, 18,647 cases were included in our analyses, following exclusion of 1623 (8.0%) cases without hospital admission status and 23 (0.1%) cases without outcome status. among all cases, median (iqr) age was 50 (36-66) years ( there were 687 (3.7%) cases admitted to the icu or deceased (table 1) . cases with icu admission or nonsurvivors had higher median age (80 vs. 49 years; p < 0.001) and were more frequently men (54.7% vs. 40.8%; p < 0.001) than those that were not admitted to the icu and survived. cases with icu admission or non-survivors had more frequently any comorbidity than those that were not admitted to the icu and survived (56.6% vs. 14.5%; p < 0.001). all types of comorbidities were more frequently reported in cases with icu admission or non-survivors than those that were not admitted to the icu and survived. in multivariable analysis with logistic regression, higher age (aor 1.065), male sex (aor 1.896), or higher number of comorbidities (aor 2.953 if one vs. aor 3.568 if 2 vs. aor 6.002 if ≥ 3; p < 0.001 for all comparisons) were associated with higher risk of icu admission or all-cause mortality ( table 2) . the model's calibration plot showed a very good predictive performance up to estimated probabilities of among cases with sars-cov2 infection at an early phase of the epidemic in portugal, pre-hospital characteristics like age, sex, and the number of comorbidities were useful to predict icu admission or all-cause mortality [5] . these findings may inform health policies designed to protect specific subgroups of the population and project allocation of health resources, especially while measures of containment are being eased in many countries. comorbidity and its impact on 1590 patients with covid-19 in china: a nationwide analysis prevalence of comorbidities and its effects in cases infected with sars-cov-2: a systematic review and meta-analysis regression modelling strategies: with applications to linear models, logistic regression, and survival analysis bias reduction of maximum likelihood estimates estimating excess 1-year mortality associated with the covid-19 pandemic according to underlying conditions and age: a population-based cohort study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to acknowledge the portuguese directorate-general of health and all staff of the portuguese national health system. dr. cardoso is the guarantor of the paper, taking responsibility for the integrity of the content of the manuscript as a whole, from inception to published article. dr. cardoso conceived and designed the study, performed statistical and data analyses, drafted the manuscript, revised the manuscript, and provided final approval. prof papoila provided significant contribution to data analyses and interpretation, revised the manuscript, and provided final approval. dr. machado provided significant contribution to data acquisition, contributed to the data analysis and interpretation, revised the manuscript, and provided final approval. dr. fidalgo contributed to the conception and design of the study and data analysis and interpretation, contributed to drafting and revision of the manuscript, and provided final approval. the manuscript has been reviewed and approved by all authors. the authors received no funding at all pertaining to this study. the datasets generated and/or analyzed during the current study are not publicly available due to confidentiality but are available from the corresponding author on reasonable request. this study was approved by the ethics committee at curry cabral hospital, central lisbon university hospital center, lisbon, portugal. informed consent was waived due to the use of anonymized data and the current public health state of emergency. not applicable. the authors declare that they have no competing interests.author details 1 intensive care unit, curry cabral hospital, central lisbon university hospital center, nova medical school, nova university, lisbon, portugal. key: cord-287333-h89tmi0w authors: sanfilippo, filippo; bignami, elena; lorini, ferdinando luca; astuto, marinella title: the importance of a “socially responsible” approach during covid-19: the invisible heroes of science in italy date: 2020-05-26 journal: crit care doi: 10.1186/s13054-020-02998-0 sha: doc_id: 287333 cord_uid: h89tmi0w nan the importance of a "socially responsible" approach during covid-19: the invisible heroes of science in italy filippo sanfilippo 1* , elena bignami 2 , ferdinando luca lorini 3 and marinella astuto 1 we would like to emphasize the importance of "socially responsible" approaches from physicians and societies during the coronavirus disease-2019 pandemic. in italy, a valuable example has been provided by the intensive care (icu) community. it is important that other disciplines follow such "socially responsible" behavior, as irresponsible communication has generated potentially dangerous consequences. we summarize the "socially responsible" approach of our icu community in three key points. cornerstone has been the avoidance of "public notoriety" at all costs, even when journalists are eager to obtain "shocking" news and notoriety is easily gained. "shocking" news increase audience, sales, and sharing, but diffusion of unsupported information irresponsibly generates public disorientation with loss of guidance. ironically, icu physicians commented we desperately need football games back, so that millions of people become again football managers rather than covid-19 experts! the second key point is the identification of few strategic scientists delivering information. only crisis-unit coordinator for lombardy icus and a couple of highly respected scientists who have (or held) apical positions at national and/or international level (siaarti and esicm) were in charge to talk. one of them was recognized as "healthcare hero" [1] . few other experienced physicians (icu director in "red areas" of north italy) fighting covid-19 on the frontline rarely appeared on tv programs for short communications. the third key point is the scientific interaction between icu physicians. they preferred to interact scientifically via webinars with the idea of sharing knowledge gained on the battlefield, generating protocols and, hopefully, improving outcomes of covid-19. such webinars were responsibly promoted by both siaarti and esicm. in summary, italian icu physicians avoided "compulsory public notoriety," behaving as "invisible heroes of science." unfortunately, the same has not happened in other disciplines with compulsory appearance on tv, social media, and newspapers by physicians with low h-index, predatory publication attitude, and no experience in coronavirus delivering highly misleading and scientifically unsupported information. among other "self-proclaimed experts," we had previous "nobel-prize candidates" stating the coronavirus will disappear in summer or others reporting 100% survival on a couple of patients treated with a drug, generating false beliefs in the population. such approach is "socially irresponsible" and should be stopped. more than ever, laypeople should be maturely informed. a "socially responsible" approach to public information should be implemented to all fields involved in covid-19, and the one delivered by the italian icu "invisible heroes" should be a leading worldwide example for other disciplines and countries. health care heroes of the covid-19 pandemic +health+care+heroes+of+the+covid-19+pandemic.+jama+2020. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to wholeheartedly thank all the healthcare personnel that worked extremely hard under the pressure of this pandemic, always putting patients at the top of their priorities, even before their own health and in some instances the safety of their own families. unfortunately, we lost a lot of these heroes and they will be sincerely missed. key: cord-303577-2gxo5mft authors: flaczyk, adam; rosovsky, rachel p.; reed, clay t.; bankhead-kendall, brittany k.; bittner, edward a.; chang, marvin g. title: comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with covid 19: implications for clinical practice and future investigations date: 2020-09-16 journal: crit care doi: 10.1186/s13054-020-03273-y sha: doc_id: 303577 cord_uid: 2gxo5mft critically ill patients with covid-19 are at increased risk for thrombotic complications which has led to an intense debate surrounding their anticoagulation management. in the absence of data from randomized controlled clinical trials, a number of consensus guidelines and recommendations have been published to facilitate clinical decision-making on this issue. however, substantive differences exist between these guidelines which can be difficult for clinicians. this review briefly summarizes the major societal guidelines and compares their similarities and differences. a common theme in all of the recommendations is to take an individualized approach to patient management and a call for prospective randomized clinical trials to address important anticoagulation issues in this population. covid-19-associated coagulopathy [1] is well established in covid-19 patients and is marked by a state of profound inflammation with endothelial dysfunction, abnormal flow dynamics, platelet activation, and hypercoagulability resulting in higher rates of thrombotic complications such as deep venous thrombosis (dvt), pulmonary embolism (pe), and microvasculature thrombosis [2] [3] [4] [5] . given the evidence that covid-19 patients are at increased risk for thrombotic complications, a number of consensus guidelines and recommendations are now available to facilitate clinical decision-making. however, these guidelines are limited by their lack of data from randomized controlled clinical trials. this review provides an overview of major societal guidelines and recommendations that focus on prevention, monitoring, and treatment of covid-19-associated coagulopathy (cac). in addition, the similarities and differences between the guidelines are highlighted, and their implications for practice are explored. lastly, proposed topics for future consideration and study are offered. we review seven major societal recommendations and guidelines addressing the management of coagulopathy in covid-19 patients: the centers for disease control and prevention (cdc) [6] , international society on thrombosis and haemostasis interim guidance (isth-ig) [7] , american society of hematology (ash) [8, 9] , american college of chest physicians (accp) [10] , scientific and standardization committee of isth (scc-isth) [11] , anticoagulation forum (acf) [12] , and american college of cardiology (acc) [13] . these recommendations and guidelines were specifically selected for review because of their focus on anticoagulation in critically ill patients. moreover, each sponsoring organization has prior expertise in developing evidence-based guidelines and providing health-related recommendations in the arena of venous thromboembolism (vte). the aims of the major societal recommendations and guidelines vary. the isth interim guidance is unique in that it provides guidance on the risk stratification for covid-19 patients on admission and the management of coagulopathy based on laboratory parameters. alternatively, acf, ash, cdc, accp, acc, and scc-isth offer guidance on in-hospital and postdischarge vte prevention, treatment, and monitoring. tables 1, 2, 3, 4, 5, 6, and 7 highlights six major societal recommendations and guidelines on the management of cac focusing on several critical care issues: (1) laboratory testing for risk stratification and triage, (2) use of biomarkers to guide anticoagulation, (3) proposals for alterations of standard prophylactic vte anticoagulation regimens for the prevention of thrombotic complications, (4) examination of available medications preferred for anticoagulation, (5) considerations for initiation of therapeutic anticoagulation, (6) indications for thrombolytic therapy, (7) decision-making regarding withholding anticoagulation treatment, (8) use of mechanical thromboprophylaxis, (9) monitoring of anticoagulation, (10) duration of therapeutic anticoagulation, (11) necessity of anticoagulation at discharge, and (12) treatment of active bleeding. we specifically focus on the recommendations and guidelines for critical care patients if mentioned in the major societal guidelines and recommendations; otherwise, we include the highest acuity patient population (i.e., hospitalized patients). a comparison of the similarities and differences between the guidelines and recommendations on each of the critical issues is provided. both isth-ig and ash are the only societies that recommend monitoring d-dimer, ptt, platelet count, and fibrinogen levels for risk stratification of critical care treatment and consideration of experimental covid-19 therapies based on changes in these parameters. isth-ig also recommends obtaining d-dimer, ptt, platelet count, and fibrinogen for all patients who present with covid-19 infection to help guide which patients may require admission. specifically, they provide an algorithm and the table 1 major societal recommendations regarding laboratory testing for risk stratification and triage laboratory testing for risk stratification and triage centers for disease control and prevention (cdc) guidelines [6] mentions lack of prospective data demonstrating laboratory testing in risk stratification of patients who are asymptomatic or with mild infection. mentions that there is insufficient data to recommend for or against using laboratory values to guide management. international society for thrombosis and haemostasis's interim guidance (isth-ig) [7] recommends obtaining d-dimer, ptt, platelet count, and fibrinogen levels for all patients who present with covid-19 as the measurements may be helpful for risk stratification (d-dimer markedly raised three-to fourfold, prothrombin time prolonged, platelet count < 100 × 10 9 , and fibrinogen < 2.0 g/l) of patients who may need close monitoring and admission to hospital. monitoring of parameters after admission may be helpful as more aggressive critical care treatment is warranted and experimental therapies should be considered if parameters worsen. anticoagulation forum (acf) [12] not mentioned american society of hematology (ash) [8, 9] recommends monitoring d-dimer, ptt, platelet count, and fibrinogen. mentions that worsening of these parameters may predict more aggressive critical care and experimental therapies might be considered. american college of chest physicians (accp) [10] not mentioned scientific and standardization committee of isth (scc-isth) [11] states further study is required. acknowledges that use of very elevated d-dimer (> 6 times upper limit of normal) is a consistent predictor of thrombotic events and poor overall prognosis in this population. american college of cardiology (acc) [13] similar to other acutely ill medical patients without covid-19. regular monitoring of platelet count, pt, ddimer, and fibrinogen is important to diagnose worsening coagulopathy. mentions that the treatment of underlying conditions of dic and bacterial superinfections is important. abbreviations: covid-19 coronavirus disease 2019, dic disseminated intravascular coagulation, pt prothrombin time, ptt partial thromboplastin time following thresholds for admission to the hospital: d-dimer markedly raised three-to fourfold, prothrombin time prolonged, platelet count < 100 × 10 9 , and fibrinogen < 2.0 g/l. alternatively, the cdc states that there is a lack of prospective data demonstrating laboratory measures of coagulopathy for risk stratification in patients who are asymptomatic or with mild infection, and insufficient data to recommend for or against using such laboratory values to guide management. the scc-isth mentions that the risk stratification algorithm for hospitalized patients requires further study while acknowledging the use of very elevated d-dimer (> 6 times upper limit of normal (uln)) appears to be a consistent predictor of thrombotic events and poor overall prognosis in this patient population. acc recommends that risk stratification of covid-19 patients should be similar to other acutely ill medical patients without covid-19 while stating that regular monitoring of platelet count, pt, d-dimer, and fibrinogen is important to diagnosing worsening coagulopathy and treatment of underlying conditions of dic and bacterial superinfections is important. none of the societies recommend daily monitoring of biomarkers as a means to guide intensity of anticoagulation management. the acf states that biomarker thresholds such as d-dimer for guiding anticoagulation management should not be done outside the setting of a clinical trial. similarly, the scc-isth remarks that d-dimer levels should not be used to solely to guide anticoagulation regimens. only ash and acc address the issue of anticoagulation in patients with lupus anticoagulant inhibitors. ash recommends that those patients be treated with prophylactic anticoagulation regimens similar to other hospitalized patients, and acc mentions that further investigation is required to determine the role of antiphospholipid antibodies in pathophysiology of cac. ash also mentions that thromboelastography (teg) and rotational thromboelastometry (rotem) are currently under investigation for cac and disseminated intravascular coagulopathy (dic) and should not be used routinely to guide management. the acc mentions that d-dimer > 2 times uln may suggest that patient is at high risk for vte and to consider extended prophylaxis (up to 45 days) in patients with low risk of bleeding. alterations from standard venous thromboembolism anticoagulation regimens to prevent thrombotic complications none of the major societies recommend therapeutic anticoagulation for prevention of thrombotic complications. only the acf recommends increasing the intensity of anticoagulation in critically ill patients (enoxaparin 40 mg twice daily or heparin 7500 unit/dose three times daily) while they recommend standard dose anticoagulant prophylaxis for all other hospitalized noncritically ill patients. the scc-isth mentions that intermediate lmwh dosing can be considered in high risk critically ill patients (50% of respondents) and may be considered in non-critically ill hospitalized patients (30% of respondents). the scc-isth also specifically mentions that the anticoagulation regimens may be modified based on extremes of body weight (50% increase in dose if obese), severe thrombocytopenia, or worsening renal function. the acc mentions that while there is insufficient data to consider routine intermediate or therapeutic dosing, a minority of their panel considers an intermediate intensity (31.6%; i.e., enoxaparin 1 mg/ kg/day, enoxaparin 40 mg bid, ufh with target ptt 50-70) or therapeutic anticoagulation (5.2%) reasonable. the cdc recommends that any changes in anticoagulation regimens that are different than the current standard of care for patients without covid-19 should only be administered in the setting of a clinical trial. many of the societies recommend using once daily prophylactic anticoagulants to reduce healthcare worker exposure. the isth-ig, ash, and accp recommend using lmwh in critically ill patients. ash particularly mentions that lmwh is preferred over ufh to reduce table 2 major societal recommendations regarding using biomarkers to guide anticoagulation biomarkers to guide anticoagulation cdc insufficient data to recommend for or against using hematologic and coagulation parameters to guide management decisions. acf biomarker thresholds such as d-dimer for guiding anticoagulation management should not be done outside the setting of a clinical trial. no particular change to regimen recommended for patients with lupus like inhibitors. teg and rotem should not be used routinely to guide management. d-dimer levels should not be used solely to guide anticoagulation regimens. further investigation is required to determine the role of antiphospholipid antibodies in pathophysiology of covid-19associated thrombosis. d-dimer > 2 times the upper limit may suggest that patient is at high risk for vte and consideration of extended prophylaxis (up to 45 days) in patients at low risk of bleeding. abbreviations: covid-19 coronavirus disease 2019, rotem rotational thromboelastometry, teg thromboelastography, vte venous thromboembolism exposure unless the risk of bleeding outweighs the risk of thrombosis. the cdc, acf, and scc-isth recommend lmwh or ufh with the rationale provided by the cdc being due to their short half-lives, versatility in administration (iv or subcutaneously), and less drugdrug interactions compared to oral anticoagulants. the scc does particularly mention that there are several advantages of lmwh over ufh including once vs twice or more injections and less heparin-induced thrombocytopenia. similarly, the acc mentions that enoxaparin 40 mg daily or similar lmwh regimen (i.e., dalteparin 5000 u daily) can be administered with consideration of subcutaneous heparin (5000 u twice to three times per day) in patients with renal dysfunction (i.e., creatinine clearance < 30 ml/min). they mention that once daily regimens of lmwh may be advantageous over ufh to reduce missed doses associated with worse outcomes, reduce healthcare worker exposure, and conserve personal protective equipment. none of the societies recommend routine use of direct oral anticoagulants because of potential drug-drug interactions, renal and hepatic function abnormalities that have implications on pharmacodynamics, longer half-lives, cost implications, and/or lack of reversal agents in some hospitals (specifically mentioned in cdc, scc-isth, anticoagulation forum, and accp guidelines). the acf and accp generally prefer lmwh over ufh to decreases staff exposure and laboratory monitoring. the accp also prefers fondaparinux over ufh and mentions that ufh may be preferred in patients at high bleeding risk, with renal failure or needing imminent table 3 cdc and societal recommendations regarding thrombotic prophylaxis and treatment in covid-19 vte prophylaxis regimen and preferred medications therapeutic anticoagulation regimens and preferred medications cdc lmwh or ufh (standard dosing). insufficient data to recommend for or against the increase of anticoagulation intensity outside of a clinical trial. standard regimens for non-covid-19 patients. isth-ig lmwh (standard dosing) not mentioned suggests an increased intensity of venous thromboprophylaxis be considered for critically ill patients # (i.e., lmwh 40 mg sc twice daily, lmwh 0.5 mg/kg subcutaneous twice daily, heparin 7500 sc three times daily, or low-intensity heparin infusion) that they state is based largely on expert opinion. lmwh over ufh whenever possible to avoid additional laboratory monitoring, exposure, and personal protective equipment. in patients with aki or creatinine clearance < 15-30 ml/min, ufh is recommended over lmwh. ash lmwh over ufh (standard dosing) to reduce exposure unless risk of bleeding outweighs risk of thrombosis. lmwh or ufh over direct oral anticoagulants due to reduced drugdrug interactions and shorter half-life. medication regimen likely to change depending on comorbidities (i.e., renal or hepatic dysfunction, gastrointestinal function, thrombocytopenia). parenteral anticoagulation (i.e., ufh) may be preferred in many ill patients given it may be withheld temporarily and has no known drug-drug interactions with covid-19 therapies. lmwh may be preferred in patients who are unlikely to need procedures as there are concerns with ufh regarding the time to achieve therapeutic ptt and increased exposure to healthcare workers. doacs have advantages including lack of monitoring that is ideal for outpatient management but may have risks in settings of organ dysfunction related to clinical deterioration and lack of timely reversal at some centers. abbreviations: aki acute kidney injury, bid twice daily, doac direct oral anticoagulant, i.e. for example, kg kilograms, lmwh low molecular weight heparin, mg milligram, min minute, ml milliliter, ptt partial prothrombin time, u units, sc subcutaneous, ufh unfractionated heparin, vte venous thromboembolism *platelet count not defined # for non-critically ill hospitalized patients, standard dose thromboprophylaxis regimens are recommended procedures. similarly, the acf recommends ufh over lmwh in patients with aki or creatinine clearance < 15-30 ml/min. ash mentions that lmwh or ufh is preferred over oral anticoagulants due to potential drug-drug interactions and their shorter half-lives. the scc-isth and isth-ig do not mention preferred medication regimens for therapeutic anticoagulation. the cdc mentions that standard regimens for patients without covid-19 patients should be used. the acc mentions that the medication regimen is likely to change depending on comorbidities (i.e., renal or hepatic dysfunction, gastrointestinal function, thrombocytopenia). they give no particular preference to an agent but do mention that (1) parenteral anticoagulation (i.e., ufh) may be preferred in many ill patients given it may be withheld temporarily and has no known drug-drug interactions with covid-19 therapies, (2) lmwh may be preferred in patients who are unlikely to need procedures as there are concerns with ufh regarding the time to achieve therapeutic ptt and increased exposure to healthcare workers, and (3) direct oral anticoagulants (doac) have advantages including lack of monitoring that are ideal for outpatient management but have risks in settings of organ dysfunction related to clinical deterioration and lack of timely reversal at some centers. most of the major societal guidelines and recommendations (isth-ig, acf, cdc, and ash) advise holding anticoagulation in patients who are actively bleeding or severely thrombocytopenic. isth-ig recommends holding lmwh prophylactic anticoagulation for patients table 4 cdc and societal recommendations regarding thrombotic prophylaxis and treatment in covid-19 when to hold anticoagulation when to use mechanical thromboprophylaxis cdc active hemorrhage or severe thrombocytopenia* not mentioned hold when signs of active bleeding or platelet count < 25 × 10 9 /l. abnormal pt or ptt is not a contraindication to thromboprophylaxis. not mentioned acf active bleeding or profound thrombocytopenia* recommends intermittent pneumatic compression in patients with contraindication to pharmacological thromboprophylaxis. mentions that it is reasonable to consider both mechanical and pharmacological thromboprophylaxis in critically ill patients if no contraindication exists for each modality. thromboprophylaxis is recommended even with abnormal coagulation tests in the absence of active bleeding and held only if platelet count < 25 × 10 9 /l or fibrinogen < 0.5 g/l. abnormal pt or ptt is not a contraindication to thromboprophylaxis. therapeutic anticoagulation may need to be held if platelet count < 30-50 × 10 9 /l or fibrinogen < 1.0 g/l. recommends mechanical thromboprophylaxis (i.e., pneumatic compression devices) when pharmacological thromboprophylaxis is contraindicated. suggest the use of mechanical thromboprophylaxis in critically ill patients who have a contraindication to pharmacological thromboprophylaxis. suggest against the additional use of mechanical thromboprophylaxis in critically ill patients receiving pharmacological prophylaxis while mentioning that its addition is likely not to cause harm. no specific recommendations. reports that 50% of respondents report holding if platelet count < 25 × 10 9 /l. mechanical thromboprophylaxis (intermittent pneumatic compression devices preferred) should be used when pharmacological therapy contraindicated. multimodal thromboprophylaxis with mechanical methods (i.e., intermittent pneumonic compression devices) should be considered (60% of respondents). in patients with moderate or severe covid-19 on chronic therapeutic anticoagulation who develop suspected or confirmed dic without overt bleeding, it is reasonable to consider the indication of anticoagulation and risk of bleeding for adjusting dose or discontinuation of anticoagulation. the majority of authors recommended reducing the intensity of anticoagulation unless there was an exceedingly high risk of thrombosis. mechanical thromboprophylaxis (intermittent pneumatic compression) should be considered in immobilized patients if pharmacological prophylaxis is contraindicated. majority of panel members (55%) considered the use of both pharmacological thromboprophylaxis and intermittent pneumatic compression reasonable while acknowledging a lack of high-quality evidence. abbreviations: covid-19 coronavirus disease 2019, i.e. for example, g gram, l liter, pt prothrombin time, ptt partial thromboplastin time *platelet count not defined with platelet count less than 25 × 10 9 /l. ash mentions that therapeutic anticoagulation should be held if platelet count < 30-50 × 10 9 /l or fibrinogen < 1.0 g/l, and prophylactic anticoagulation should be held only if platelet count < 25 × 10 9 /l or fibrinogen < 0.5 g/l. the scc-isth does not recommend a particular platelet level to hold anticoagulation but does report that 50% of their respondents report holding for a platelet count < 25 × 10 9 /l. while the cdc and acf recommend holding prophylactic anticoagulation in patients who are severely thrombocytopenic, they also do not recommend a particular platelet count threshold. the accp does not make any specific recommendations regarding the holding of anticoagulation. the acc mentions that in patients with moderate or severe covid-19 on chronic therapeutic anticoagulation who develop suspected or confirmed dic abbreviations: covid-19 coronavirus disease 2019, iu international unit, lmwh low molecular weight heparin, ml milliliter, ptt partial prothrombin time, u units with overt bleeding, it is reasonable to consider the indication of anticoagulation and risk of bleeding for adjusting dose or discontinuation of anticoagulation. the majority of their authors recommend reducing the intensity of anticoagulation unless there is an exceedingly high risk of thrombosis. of note, the isth-ig, acf, and ash mention that abnormal pt or ptt is not a contraindication to thromboprophylaxis. the acf, ash, accp, acc, and scc-isth recommend or suggest mechanical thromboprophylaxis when pharmacological thromboprophylaxis is contraindicated. the acf, ash, acc, and scc-isth particularly mention pneumatic compression devices as examples of mechanical thromboprophylaxis. the acf mentions that it is reasonable to consider both mechanical and pharmacological thromboprophylaxis in critically ill patients if no contraindication exists for each modality. the scc-isth mentions that multimodal thromboprophylaxis with mechanical methods (i.e., intermittent pneumonic compression devices) should be considered (60% of respondents). similarly, the majority of acc panel members (55%) considered the use of both pharmacological thromboprophylaxis and intermittent pneumatic compression reasonable while acknowledging a lack of high-quality evidence. the accp suggests against the additional use of mechanical thromboprophylaxis in critically ill patients receiving pharmacological prophylaxis while mentioning that its addition is likely not to cause harm. the cdc and isth-ig do not mention any not mentioned either lmwh or fda-approved post-discharge prophylactic anticoagulation regimen (rivaroxaban and betrixaban) should be considered in patients with high vte risk criteria. duration is 14 days at least and up to 30 days. of note, they report that none of the respondents recommended aspirin for post-discharge thromboprophylaxis. not mentioned reasonable to consider extended prophylaxis with lmwh or doacs for up to 45 days in patients at high risk for vte (i.e., d-dimer > 2 times the upper limit, reduced mobility, active cancer) and low risk of bleeding. transfuse platelets to maintain platelets > 50 × 10 9 /l in dic and active bleeding or if platelets < 20 × 10 9 /l in patients at high risk of bleeding or requiring invasive procedures. ffp (15 to 25 ml/kg) in patients with active bleeding with either prolonged pt or ptt ratios (> 1.5 times normal) or decreased fibrinogen (< 1.5 g/l). fibrinogen concentrate or cryoprecipitate in patients with persisting severe hypofibrinogenemia (< 1.5 g/l). prothrombin complex concentrate if ffp is not possible. tranexamic acid should not be used routinely in patients with covid-19-associated dic given the existing data. the cdc, accp, and acf do not recommend therapeutic anticoagulation except in cases where there is a thromboembolic event or a high suspicion for a thromboembolic event when imaging is not possible. ash recommends therapeutic anticoagulation only if there is a documented clinical indication (e.g., vte, atrial fibrillation, or mechanical valve). acc mentions that therapeutic anticoagulation is the key to vte treatment but does not make a distinction between confirmed or suspected vte. they do mention that hemodynamically stable patients with intermediate-low to intermediate-high risk pe should be managed initially with anticoagulation and close monitoring rather than fibrinolytics. while the scc-isth recommends that therapeutic anticoagulation should not be considered for primary prevention until randomized trials are available, they do mention that therapeutic anticoagulation (i.e., changing from standard or intermediate intensity to therapeutic intensity) can be considered in patients without confirmed vte but who have deteriorating pulmonary or ards. ash also states that it is reasonable to consider increasing the intensity of the patient's anticoagulation regimen (i.e., from standard to intermediate intensity, from intermediate to therapeutic intensity) or change anticoagulants in patients who have recurrent thrombosis of catheters and extracorporeal circuits (i.e., ecmo, crrt) on prophylactic anticoagulation regimens. similarly, the accp recommends increasing the dose of lmwh by 25-30% in patients with recurrent vte despite being on therapeutic lmwh anticoagulation. the cdc specifically mentions that patients who have thrombosis of catheters or extracorporeal filters should be treated accordingly to standard institutional protocols for patients without covid-19. the acf recommends against the use of thrombolytics outside of a clinical trial unless there is a clinical indication for which it is already approved such as st elevation myocardial infarction, acute ischemic stroke, or massive pe with hemodynamic instability. the cdc also mentions that there is insufficient data to recommend for or against thrombolytic therapy outside the context of a clinical trial. however, the cdc specifically mentions that in pregnant patients in particular, thrombolytic therapy should only be used for acute pe with lifethreatening hemodynamic instability due to risk for maternal hemorrhage. the isth-ig, ash, and scc-isth do not mention any recommendations or suggestions regarding the use of thrombolytic treatment. the accp suggests the use of thrombolytic therapy in patients with massive pe (i.e., hypotension with systolic blood pressure < 90 mmhg or when there are signs of obstructive shock) and specifically recommends peripheral thrombolysis using a peripheral vein over catheterdirected thrombolysis. in addition, accp suggests that in patients in whom therapeutic anticoagulation fails and who continue to have evidence of cardiopulmonary compromise, thrombolytic therapy may be beneficial. similarly, the acc mentions that systemic fibrinolysis is indicated in patients with significant hemodynamically unstable high risk pe and catheter-based therapies be reserved for situations that are not amenable to systemic fibrinolysis. furthermore, hemodynamically stable patients with intermediate-low or intermediate-high risk pe should receive anticoagulation and fibrinolysis or catheter-directed therapies should be considered in cases of further deterioration. they also report that a multidisciplinary pe response team (pert) may be helpful for intermediate and high risk patients with vte and that catheter-directed therapies should be limited to most critical situations given minimal data demonstrating a mortality benefit. the acf recommends at least a 3-month course of anticoagulation for patients who are started on anticoagulation for a presumed provoked thrombus from the inflammatory state of cac but did not have imaging available for confirmation. the acf also recommends that standard anticoagulation guidelines be used to determine length of anticoagulation beyond the initial 3month period. the acf mentions that an exception to the minimum 3-month course is in patients with recent bleeding or high risk of bleeding. in addition, the acf comments that if confirmatory imaging cannot be obtained within a couple days of presumed diagnosis, it is possible that delayed imaging may show an absence of thrombus when one was present initially. therefore, they recommend continuing empiric treatment for the minimum 3-month course. similarly, the accp and scc-isth recommend a minimum of 3 months of anticoagulation in those patients with confirmed pe or proximal dvt. the isth-ig, ash, acc, and cdc do not mention any recommendations or suggestions regarding the duration of therapeutic anticoagulation. none of the guidelines recommend or mentions routine monitoring for lmwh anticoagulation, with the exception of isth-ig which advises monitoring in patients with severe renal impairment receiving lmwh prophylactic anticoagulation. the acf does not recommend dosing lmwh based on anti-xa levels, and accp mentions that lmwh can be administered without laboratory monitoring in the majority of patients. the cdc, acc, and ash do not have particular monitoring recommendations other than the current standard of care for other hospitalized patients. the acf is the only society to recommend monitoring anti-xa levels in patients with prolonged baseline ptt levels receiving therapeutic anticoagulation with ufh. while both ash and accp do not make any specific recommendations regarding patients with prolonged ptt levels receiving therapeutic anticoagulation with ufh, ash does mention that monitoring anti-xa levels for patients receiving ufh may be necessary given artefactual increases in ptt and accp recommends monitoring anti-xa levels in all patients receiving ufh given a potential for heparin resistance. the isth-ig, cdc, accp, acc, and scc-isth do not mention any recommendations or suggestions regarding monitoring of patients with prolonged ptt levels receiving therapeutic anticoagulation. none of the societal guidelines and recommendations make specific monitoring recommendations for patients receiving therapeutic anticoagulation with the exception of the acf and accp which both recommend monitoring anti-xa levels to monitor ufh due to baseline abnormalities in ptt. acf does mention that it is reasonable to monitor anti-xa or ptt in patients without prolonged ptt at baseline receiving ufh for therapeutic anticoagulation. ash particularly mentions that anti-xa monitoring of ufh may be necessary given artefactual increases in ptt secondary to lupus-like inhibitors. the scc-isth does not make any specific recommendations regarding the use of anti-xa levels to monitor ufh but does mention that expert clinical guidance statements and clinical pathways from large academic healthcare systems target an anti-factor xa level of 0.3-0.7 iu/ml for ufh. the cdc and acf recommend against the routine use of prophylactic anticoagulation for patients discharged from the hospital. however, the cdc and acf as well as ash and scc-isth mention that fda-approved post-discharge prophylactic anticoagulation (pdpa) regimens (rivaroxaban and betrixaban) may be considered in patients with high risk for vte and low risk for bleeding. similarly, the accp mentions that pdpa can be considered in patients who are at low risk of bleeding if emerging data suggests that the risk of vte outweighs the risk of bleeding. the acf and scc-isth both mention that enoxaparin in addition to betrixaban or rivaroxaban can be considered if pdpa is thought to be reasonable. the duration of anticoagulation recommended by acf is based on the timing used in clinical trials which is 31-39 days for rivaroxaban, 35-42 days for betrixaban, and 6-14 days for enoxaparin. the scc-isth recommends a duration of a minimum of 14 days and up to 30 days. acc mentions that it is reasonable to consider extended prophylaxis with lmwh or doacs for up to 45 days in patients at high risk for vte (i.e., ddimer > 2 times uln, reduced mobility, active cancer) and low risk of bleeding. as an alternative, ash mentions that aspirin can also be considered based on studies for vte prophylaxis in low risk patients after orthopedic surgery. aspirin is not mentioned in any of the other guidelines and recommendations with the exception of scc-isth which reports that none of their respondents recommended aspirin for post-discharge thromboprophylaxis. in the setting of bleeding, the isth-ig recommends transfusion to keep platelet count > 50 × 10 9 /l, fibrinogen > 1.5 g/l, and pt ratio < 1.5. acc recommends platelet transfusion to maintain platelet count > 50 × 10 9 /l in dic and active bleeding (> 20 × 10 9 /l in patients at high risk of bleeding or requiring invasive procedures), fresh frozen plasma (ffp) (15 to 25 ml/kg) in patients with active bleeding with either prolonged pt or ptt ratios (> 1.5 times normal) or decreased fibrinogen (< 1.5 g/l), and fibrinogen concentrate or cryoprecipitate in patients with persisting severe hypofibrinogenemia (< 1.5 g/l). similarly, ash recommends transfusion if platelets < 50 × 10 9 /l, inr < 1.8, and fibrinogen < 1.5 g/l. ash also recommends that in the setting of severe coagulopathy and bleeding, 4f-pcc be considered instead of plasma so as to prevent significant volume overload. acc mentions that prothrombin complex concentrate is recommended if ffp is not possible and tranexamic acid should not be used routinely in patients with covid-19-associated dic given the existing data. moreover, ash mentions that transfusions to simply to correct laboratory abnormalities in the absence of bleeding may worsen disseminated thrombosis and deplete blood product resources without any evidence of improving clinical outcomes. similarly, acc mentions that correction of coagulopathy in unselected patients without significant bleeding is not recommended. these societal guidelines are based on consensus of expert opinion with limited evidence available in the form of robust clinical trials. consequently, it is not surprising there are clinical issues that are either not addressed by the guidelines or have varying opinions. for instance, practitioners who deem a critically ill covid-19 patient at high risk for thrombotic complication (e.g., trauma, cancer, antiphospholipid antibody) may decide to use a higher intensity prophylactic anticoagulation regimen consistent with the acf guidelines rather than routine anticoagulation prophylactic regimen recommended by other societies. the major societal guidelines and recommendations share significant similarities, but also have some discrepancies. we recommend that providers manage their patients in the framework of these major societal guidelines, and where discrepancies do exist, decisions be made based on the practitioner's experience and their understanding of a patient's medical history, clinical course, and perceived risk. based on this review and comparison of the societal guidelines, there are a number of unaddressed issues that warrant further investigation and incorporation into updated guidelines. further studies of covid-19 pathophysiology are required to elucidate the mechanisms of coagulation disruption in order to identify potential pharmacologic targets and new biomarkers for risk stratification. large randomized control trials are needed to investigate the optimal prophylactic anticoagulation regimen, the utility of intermediate and therapeutic anticoagulation, and the use of fibrinolytic therapy in covid-19 patients. there are several clinical trials currently in the clinicaltrials.gov database focused on optimizing prophylactic anticoagulation regimens (8 total) (table 8) , therapeutic anticoagulation (5 total) (table 9) , and fibrinolytic therapy (2 total) (table 10) in covid-19 patients [14] , and we eagerly await those results. further guidance from prospective studies is required to guide the clinical significance of biomarkers (e.g., ddimer, antiphospholipid, and lupus anticoagulant antibodies) in risk stratification and treatment of cac. there are significant similarities and differences surrounding the major societal recommendations and guidelines regarding risk stratification and management of covid-19-associated coagulopathy in regard to use of laboratory makers, prevention, treatment, and monitoring of vte, and post-discharge thromboprophylaxis. in addition, there are a number of unanswered questions that warrant further investigation. it is incumbent on the clinicians to remain updated on emerging literature in this area in order to optimize the care of critically ill patients with covid-19. covid-19 and its implications for thrombosis and anticoagulation acute pulmonary embolism and covid-19 pneumonia: a random association? pulmonary embolism in a young pregnant woman with covid-19 coagulopathy and antiphospholipid antibodies in patients with covid-19 covid and coagulation: bleeding and thrombotic manifestations of sars-cov2 infection covid-19) treatment guidelines isth interim guidance on recognition and management of coagulopathy in covid-19 covid-19 and vte/anticoagulation: frequently asked questions covid-19 and coagulopathy: frequently asked questions prevention, diagnosis and treatment of venous thromboembolism in patients with covid-19: chest guideline and expert panel report scientific and standardization committee communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with covid-19 thromboembolism and anticoagulant therapy during the covid-19 pandemic: interim clinical guidance from the anticoagulation forum covid-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: jacc state-of-the-art review clinical trials none. authors' contributions af, rpr, ctr, bkb, eab, and mgc wrote and reviewed the manuscript. the authors read and approved the final manuscript. availability of data and materials not applicable.ethics approval and consent to participate not applicable. competing interests rr is on the board of directors for the pulmonary embolism response team (pert) consortium and has no other competing interests as it relates to this manuscript. all other authors declare to have no competing interests. key: cord-278838-qraq5aho authors: mirouse, adrien; vignon, philippe; piron, prescillia; robert, rené; papazian, laurent; géri, guillaume; blanc, pascal; guitton, christophe; guérin, claude; bigé, naïke; rabbat, antoine; lefebvre, aurélie; razazi, keyvan; fartoukh, muriel; mariotte, eric; bouadma, lila; ricard, jean-damien; seguin, amélie; souweine, bertrand; moreau, anne-sophie; faguer, stanislas; mari, arnaud; mayaux, julien; schneider, francis; stoclin, annabelle; perez, pierre; maizel, julien; lafon, charles; ganster, frédérique; argaud, laurent; girault, christophe; barbier, françois; lecuyer, lucien; lambert, jérôme; canet, emmanuel title: severe varicella-zoster virus pneumonia: a multicenter cohort study date: 2017-06-07 journal: crit care doi: 10.1186/s13054-017-1731-0 sha: doc_id: 278838 cord_uid: qraq5aho background: pneumonia is a dreaded complication of varicella-zoster virus (vzv) infection in adults; however, the data are limited. our objective was to investigate the clinical features, management, and outcomes of critically ill patients with vzv-related community-acquired pneumonia (vzv-cap). methods: this was an observational study of patients with vzv-cap admitted to 29 intensive care units (icus) from january 1996 to january 2015. results: one hundred and two patients with vzv-cap were included. patients were young (age 39 years (interquartile range 32–51)) and 53 (52%) were immunocompromised. time since respiratory symptom onset was 2 (1–3) days. there was a seasonal distribution of the disease, with more cases during spring and winter time. all but four patients presented with typical skin rash on icu admission. half the patients received mechanical ventilation within 1 (1–2) day following icu admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (pao(2)/fio(2)) = 150 (80–284), 80% with acute respiratory distress syndrome (ards)). sequential organ failure assessment (sofa) score on day 1 (odds ratio (or) 1.90 (1.33–2.70); p < 0.001), oxygen flow at icu admission (or 1.25 (1.08–1.45); p = 0.004), and early bacterial co-infection (or 14.94 (2.00–111.8); p = 0.009) were independently associated with the need for mechanical ventilation. duration of mechanical ventilation was 14 (7–21) days. icu and hospital mortality rates were 17% and 24%, respectively. all patients were treated with aciclovir and 10 received adjunctive therapy with steroids. compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, icu length of stay, and a similar hospital mortality, but experienced more icu-acquired infections. conclusions: severe vzv-cap is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. steroid therapy did not influence mortality, but increased the risk of superinfection. electronic supplementary material: the online version of this article (doi:10.1186/s13054-017-1731-0) contains supplementary material, which is available to authorized users. pneumonia is associated with significant morbidity and mortality worldwide [1] . the importance of viruses as pathogens responsible for community-acquired pneumonia (cap) has been emphasized by several epidemic outbreaks over the last decade: severe acute respiratory syndrome (sars), avian influenza a (h5n1) virus, and the 2009 pandemic influenza a (h1n1) [2] [3] [4] [5] . it is estimated that about 200 million cases of viral cap occur annually, accounting for 17 to 39% of cap [6] [7] [8] [9] [10] . in the intensive care unit (icu) setting, viruses have been reported to account for up to one-third of patients with severe cap, with a similar mortality to that observed with bacterial pneumonia [11] . the availability of new molecular techniques (such as polymerase chain reaction (pcr)) has greatly increased our ability to detect a wide range of viruses in respiratory secretions [12] [13] [14] [15] . nevertheless, although convincing data are available for agents such as influenza virus or respiratory syncytial virus and their role in severe pneumonia, the role of other recently discovered viruses (bocavirus, coronavirus nl63) remains debated and requires further research [16] [17] [18] [19] . varicella-zoster virus (vzv) is one of eight herpes viruses known to cause human infection and is distributed worldwide. varicella or chickenpox is defined as the vzv primo-infection. in adults, vzv infection is associated with a greater number of complications, of which pneumonia is the most common and serious. since its initial description in 1942, vzv-related communityacquired pneumonia (vzv-cap) has become increasingly recognized as a serious and potentially lethal complication of what was once considered a relatively benign and self-limited viral infection [20] . a study with systematic chest x-ray showed an incidence of 16.3% of vzv-cap in adult patients [21] . autopsy findings have demonstrated the role of vzv in fatal cases of pneumonia. microscopic findings included pulmonary edema, extensive alveolar hemorrhage, and mononuclear cell infiltration with histological evidence of intranuclear inclusion bodies [22, 23] . data on critically ill adult patients with vzv-cap are limited to case reports and small case series. the purpose of this study was to describe the clinical, biological, and radiological features and the outcome of severe forms of vzv-cap (i.e., requiring icu admission) in a large cohort and to report its implication for icu management. this retrospective study was conducted in 29 french adult icus (see additional file 1: table s1 ). this study has been approved by the french intensive care society ethics committee (n°15-12) and an authorization to use patient data from the french data protection agency (n°1868870). according to french law, a waiver of informed consent was obtained. all adult patients (≥18 years old) admitted for vzv-cap in the participating icus between 1 january 1996 and 1 january 2015 were included. patients were identified from the icu databases using codes j171 and b012 from the international classification of diseases system (icd-10) system. all the medical records of patients were reviewed by two investigators (am and ec). the data reported in tables 1, 2, and 3 were abstracted from medical charts. chickenpox features at icu admission were collected including skin rash, pulmonary involvement, neurological impairment, or abdominal symptoms. patients were defined as immunosuppressed if they met one of the following criteria: hematopoietic stem cell or solid organ transplantation, hematological malignancy, solid tumor progressing or in remission less than 5 years, steroid treatment for more than 3 months, and other immunosuppressive drugs. physiological variables, laboratory data, and radiographic findings (chest x-ray and computed tomography (ct) when available) on icu admission were also reported. thrombocytopenia was defined as platelet count <150 g/l and hepatitis as alanine aminotransferase and/or aspartate aminotransferase ≥3 n. disease severity was assessed using the sequential organ failure assessment (sofa) on day 1 after icu admission [24] . patients were classified as having acute respiratory failure (arf) if they met the following criteria: severe dyspnea at rest; a respiratory rate greater than 30 breaths/min or clinical signs of respiratory distress; and oxygen saturation less than 92% or arterial oxygen partial pressure (pao 2 ) less than 60 mmhg on room air. hypoxemia severity was assessed using the pao 2 /fraction of inspired oxygen (fio 2 ) ratio [25] . the decision to perform fiberoptic bronchoscopy and bronchoalveolar lavage (fo-bal) and the use of life-sustaining treatments (i.e., noninvasive or invasive mechanical ventilation, renal replacement therapy, and vasopressors) was left at the discretion of the attending physicians. acute respiratory distress syndrome (ards) was defined according to the berlin definition [26] . therapeutic regimens were reported including antiviral therapy (molecule, dose, and length of treatment) and the use of steroids. high-dose steroids was defined as >30 mg per day of prednisone [27] . patients receiving steroids were matched in a 1:6 ratio to a control group of patients within this cohort who did not receive steroids. the four matching criteria were: age, year of icu admission, sofa score on day 1, and ards criteria according to the berlin definition. icu-acquired infections were recorded. the diagnosis of infection was confirmed if patients met both the following criteria: microbiological identification of a pathogen and administration of related antibiotic treatment. icu and hospital length of stays, and vital status at icu and hospital discharge were obtained in all patients. patient characteristics at baseline and during icu stay were described using medians and interquartile ranges for quantitative variables and counts and percentages for qualitative variables. characteristics of patients requiring mechanical ventilation during their icu stay were compared to those of patients without mechanical ventilation using either wilcoxon rank sum test or fisher's exact test. to assess variables independently associated with the requirement for mechanical ventilation, baseline characteristics significantly associated with the requirement for mechanical ventilation were included in a multivariable logistic regression model. due to the small sample size, a forward stepwise p value-based variable selection was performed, and, when several highly correlated variables were associated with the requirement for mechanical ventilation, only one was included in the multivariable analysis based on clinical relevance. missing covariates were handled using multivariate imputation by chained equations. baseline and icu management characteristics were also compared between deceased patients and those discharged alive. cumulative incidence of death in the icu and death in hospital were estimated considering discharge alive from icu/hospital as competing events. to assess the prognostic effect of steroid therapy in the context of an observational cohort, a matched comparison of patients receiving and not receiving steroids was performed. patients receiving steroids were matched in a 1:6 ratio to a control group of patients within this cohort who did not receive steroids. the four matching criteria were: age, year of icu admission, sofa score on day 1, and ards criteria according to the berlin definition. during the study period, we identified 102 adult patients admitted to the icu for the management of vzv-cap. there was a seasonal distribution over the study period, with the highest incidence observed during winter and spring (additional file 2: figure s1 ). the median age was 39 (32-51) years and 53 (52%) patients were immunocompromised. six (6%) cases of vzv pneumonia occurred in pregnant women (table 1) . a typical chickenpox skin rash was reported in all but four (96%) patients and occurred 3 (2-5) days before the onset of respiratory symptoms. the median time from onset of respiratory symptoms to icu admission was 2 (1-3) days. on admission, patients were severely hypoxemic with a pao 2 /fio 2 ratio of 150 (80-284) mmhg and 6 (3-15) l/min oxygen flow. respiratory symptoms included a cough in 45 (44%) patients, chest pain in 10 (10%) patients, and hemoptysis in 9 (9%) patients. arf was noted in 69 (68%) patients (table 2 ). in addition to skin and respiratory symptoms, 13 (13%) patients had encephalitis. laboratory findings indicated thrombocytopenia in 81 (79%) patients and hepatitis in 34 (33%) patients. blood pcr to amplify vzv dna was always positive when performed (n = 15, 14.7%). the median sofa score on day 1 was 4 (3-7). a chest ct was performed in 31 (30%) patients and was never normal. common abnormalities were diffuse bilateral centrolobular nodules with tree-in-bud appearance (n = 14, 50%) and diffuse ground glass opacities (n = 11, 39%) ( fig. 1) . alveolar consolidations were also reported (n = 14, 50%). fiberoptic bronchoscopy was performed in 35 (35%) patients and demonstrated vesicular lesions or ulcerations on bronchial mucosa in 13 (36%) cases. pcr for vzv in the bronchoalveolar lavage was tested in 24 patients and yielded a positive result in 96% of cases. noninvasive mechanical ventilation was implemented in 29 (28%) patients, failing in 19 (66%) who were subsequently intubated. invasive mechanical ventilation was used in 52 (51%) patients overall, of whom 42 (80.8%) fulfilled the ards criteria according to the berlin definition (table 3) . patients were intubated 1 (1-2) day after icu admission. three factors were independently associated with the need for invasive mechanical ventilation: sofa score on day 1 (odds ratio (or) 1.90 (1.33-2.70); p < 0.001), oxygen flow at icu admission (or 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (or 14.94 (2.00-111.8); p = 0.009) ( table 4 and fig. 2 ). vasopressors were required in 36 (35%) patients and renal replacement therapy in 24 (24%). among the 102 patients, 40 (39%) patients had documented bacterial co-infection with 20 (50%) early infections (documented within 72 h after icu admission) and 20 (50%) late infections. the primary sources of co-infections were the lungs (n = 24, 60%), bloodstream (n = 8, 20%), and skin (n = 4, 10%), with staphylococcus aureus being the most often recovered pathogen (n = 12, 30%). the median icu and hospital length of stay were 8 (4-16.75) days and 14 (9-33) days, respectively. duration of mechanical ventilation was 14 (7-21) days. all patients were treated with aciclovir 10 mg/kg/8 h during 11 (9.2-14) days. one (1%) patient received a treatment with a varicella-zoster immune globulin preparation. high-dose adjunctive steroid therapy, in addition to antiviral therapy, was reported in 10 patients. patients treated with high-dose steroids were no different compared to steroid-free patients regarding demographics, respiratory parameters on icu admission, and icu management ( table 5 ). compared to steroid-free patients, steroid treatment was associated with a longer duration of mechanical ventilation, and prolonged icu and hospital stays. icu mortality was similar in the two groups (20% vs. 20%; p = 1.00). icu-acquired bacterial infections were more frequently reported in steroid-treated patients (80% vs. 43%; p = 0.04) ( table 5) . overall icu and hospital mortality were 17% and 24%, respectively, without significant variation over the study period (additional file 3: table s3 ). the main causes of death were: multi-organ failure in 10 patients (42%), refractory ards in 5 patients (21%), and septic shock in fig. 1 imaging characteristics from lung ct. a 46-year-old woman was admitted to the icu for acute respiratory failure. she underwent kidney transplantation 12 years ago. she reported fever and a typical chickenpox skin rash 5 days before admission. the onset of respiratory symptoms started 2 days before icu admission and invasive mechanical ventilation was implemented at day 1. she developed a severe ards requiring prone positioning, neuromuscular blockers, and 14 days of invasive mechanical ventilation. lung ct scan demonstrated diffuse bilateral nodules, patchy ground glass opacities, and interlobular septal thickening. a fiber bronchoscopy with bronchoalveolar lavage documented a staphylococcus aureus co-infection. she received intravenous aciclovir 10 mg/kg/8 h during 15 days associated with 10 days of oxacilline and was discharge alive from the icu 17 days after admission 4 patients (17%). one (4%) patient died from fulminant hepatic failure attributed to vzv infection and 1 (4%) patient died from brain edema. the cause of death was missing for 3 patients. by univariate analysis, factors associated with hospital mortality were: age (60 (49-72.5) vs. 36 (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) ; p < 0.0001), underlying immunosuppression (92% vs. 40%; p < 0.0001), sofa score on day 1 (7 (5-10.75) vs. 4 (2-5.25) ; p = 0.0002), disseminated intravascular coagulation (42% vs. 4%; p = 0.0001), and empiric antibiotic treatment on icu admission (91% vs. 53%; p < 0.0001) (additional file 4: table s2 , additional file 5: figure s2 , and additional file 6: figure s3 ). we identified 102 patients with severe forms of vzv-cap who were admitted to 29 french icus. underlying immunosuppression accounted for half of the patients we evaluated, mainly related to impaired cellular immune response (lymphoproliferative disorders, immunosuppressive drugs for solid-organ transplant recipients, and/or steroid exposure). nevertheless, we identified severe illness from vzv-cap among 11 (11%) young and healthy patients. more than half of the patients required invasive mechanical ventilation, of which 80% met ards criteria. risk factors for intubation were related to the severity of the respiratory failure, the presence of an early bacterial co-infection, and the onset of other organ failures. in addition to antiviral therapy, high doses of steroids were used in 10 (10%) patients without benefit either on improvement of respiratory parameters or on mortality, and were associated with an increased number of superinfections. there was a 5 (3-7)-day period of illness prior icu admission, which is similar to influenza virus infection and other causes of viral pneumonia [5, 28, 29] . all patients but four presented with a typical chickenpox skin rash, suggesting that vzv-cap is mostly a dreaded complication of primary vzv infection rather than recurrent vzv infection. the four patients without rash were all immunocompromised (solid cancer or hematological malignancy). atypical cases of recurrent vzv infection with pulmonary involvement have been reported, almost exclusively in immunocompromised patients, and cannot be excluded in our study [30] [31] [32] [33] . in addition, exogenous clinical reinfection by vzv has also been demonstrated and is thought to occur more likely in immunocompromised patients [30] . the illness course was characterized by a short period of acute and severe respiratory deterioration, requiring invasive mechanical ventilation in half of the cases, shortly after icu admission. we identified that risk factors for intubation were related to the presence of a bacterial coinfection, the severity of the respiratory failure, and the onset of other organ failures. neither comorbidities nor underlying immunosuppression were independent predictors of invasive mechanical ventilation. these results are in agreement with previous studies suggesting that the underlying medical context was no longer significantly associated with the risk for intubation after adjustment for the severity of the acute disease [34] [35] [36] . the factors we identified are easy to assess at the bedside and may contribute to recognizing hospital admission patients who may benefit from early icu admission. results are presented for the imputed data candidate predictors were: age, any comorbidity, underlying immunosuppression, sofa score at day 1, oxygen flow at icu admission, alveolar consolidation on chest x-ray, antibiotics at icu admission, and early bacterial co-infection ci confidence interval, icu intensive care unit, or odds ratio, sofa sequential organ failure assessment in our study, the overall mortality was 24% and reached 43% in patients who received invasive mechanical ventilation. viruses have been increasingly recognized as pathogens responsible for both severe community-acquired and healthcare-associated pneumonia [11, 29] . choi et al. recently demonstrated in a prospective study that, in the icu setting, the mortality rate of patients with viral pneumonia was similar to that of patients with bacterial pneumonia [11] . nevertheless, most of our knowledge on severe forms of viral pneumonia is related to the influenza virus. we report that patients with vzv-cap who required intubation experienced a long period of invasive mechanical ventilation (14 (7-21) days) and a high rate of bacterial coinfections (69%). these findings might be explained by the extent of skin and mucosal vesicular lesions. indeed, previous clinical and autopsy studies have demonstrated that these lesions are responsible for necrotic and hemorrhagic foci distributed both in the upper airways and in the lower respiratory tract that may promote bacterial co-infection [37, 38] . in our study, 36% of the patients who underwent fiberoptic bronchoscopy had vesicular lesions on bronchial mucosa. in addition to antiviral therapy, the use of steroids has been reported by observational studies in the treatment of vzv pneumonia [39] [40] [41] . the role of steroids in the management of pneumonia remains controversial. on the one hand, steroids might have the potential to decrease intrapulmonary inflammation and thus to reduce some ards-related pulmonary lesions. but, on the other hand, steroids might increase immunosuppression, favor persistent viral replication, and promote superinfection. based on the results of two randomized controlled trials, the benefit-to-risk ratio argues for its use patients who received steroids were matched in a 1:6 ratio to a control group of patients who did not receive steroids. matched controls were screened from the current cohort with the following four matching criteria: age, year of icu admission, sofa score at day 1, and ards criteria according to the berlin definition ards acute respiratory distress syndrome, icu intensive care unit, pao 2 :fio 2 ratio of arterial oxygen partial pressure to fractional inspired oxygen, sofa sequential organ failure assessment in severe pneumocystis jirovecii pneumonia in the acquired immunodeficiency syndrome [42, 43] . a recent meta-analysis reported that it may decrease the risk of ards as adjunctive therapy in community-acquired pneumonia [44] . on the other hand, no benefit has been demonstrated with the use of steroids in influenza pneumonia [45] . in 1998, mer and richards [39] reported on 15 adult patients treated for vzv-cap, six of whom received steroids in addition to antiviral therapy and supportive care. these six patients experienced clinical improvement, a significantly shorter icu and hospital length of stay, and no mortality when compared to those who did not receive steroids. however, the study design precluded any robust conclusion. another study from saudi arabia reported improvement in oxygenation parameters in 10 adult patients treated for vzv-cap with steroids as adjunctive therapy [40] . this was not our experience in the present study. ten patients received steroids 4.5 (1-15) days after icu admission. we compared these 10 patients to 60 matched controls who did not receive steroids. there was no difference between the steroid group and the nonsteroid group in icu and hospital mortality. however, patients treated with steroids had a longer duration of invasive mechanical ventilation, more bacterial superinfection, and an increased icu and hospital length of stay than control patients not treated with steroids. thus, our data did not report any benefit associated with the use of steroids as adjunctive therapy in severe vzv-cap. our study has several limitations. first, given the retrospective design over a long period of time, supportive care practices may have changed throughout the study period and influenced the results. however, we report the largest study on the severe forms of vzv-cap and we believe that it adds valuable data to the current knowledge. second, we had no biological identification of vzv for all patients included our study. nevertheless, clinical signs and symptoms of chickenpox are obvious in most cases and laboratory diagnosis is restricted to unusual cases. thus, we can reasonably assume that the patients included in the present study had vzv-cap. third, due to the limited number of death we were unable to identify independent predictors of hospital mortality. however, we report predictors of invasive mechanical ventilation that conceivably may be related to mortality. fourth, for the diagnosis of vzv-cap we used a database encoded by physicians at patient icu discharge and we cannot exclude that some patients with vzv-cap had been missed. in conclusion, severe vzv-cap in adults is an acute respiratory disease that requires invasive mechanical ventilation in more than half of the cases. although underlying medical conditions or immunosuppression are common, healthy young individuals 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in children corticosteroids in life-threatening varicella pneumonia effect of corticosteroids on adult varicella pneumonia: cohort study and literature review combining corticosteroids and acyclovir in the management of varicella pneumonia: a prospective study corticosteroids as adjunctive therapy for severe pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. a double-blind, placebo-controlled trial a controlled trial of early adjunctive treatment with corticosteroids for pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. california collaborative treatment group efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis the influence of corticosteroid treatment on the outcome of influenza a(h1n1pdm09)-related critical illness none. none. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.authors' contributions am, jl, ppi, and ec made substantial contributions to the conception of the work, the acquisition, analysis, and interpretation of data for the work. they drafted the work and revised it critically for important intellectual content. they gave final approval of the version to be published. they agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. pv, rr, lp, gg, pb, cgui, cgué, nb, ar, al, kr, mf, jdr, ase, bs, asm, sf, am, jmay, fs, ast, ppe, jmai, ds, fg, la, gb, fb, and gc made substantial contributions to the acquisition of data for the work. they revised the work critically for important intellectual content. they gave final approval of the version to be published. they agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. additional file 1: table s1 . participating centers (n = 29) with the number of cases of vzv pneumonia during the study period . the authors declare that they have no competing interests. ethics approval and consent to participate this study has been approved by the french intensive care society ethics committee (n°15-12) and an authorization to use patient data from the french data protection agency (n°1868870). according to french law, a waiver of informed consent was obtained. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. submit your next manuscript to biomed central and we will help you at every step: key: cord-307592-hyeshh63 authors: kong, yaxian; han, junyan; wu, xueying; zeng, hui; liu, jingyuan; zhang, henghui title: vegf-d: a novel biomarker for detection of covid-19 progression date: 2020-06-23 journal: crit care doi: 10.1186/s13054-020-03079-y sha: doc_id: 307592 cord_uid: hyeshh63 nan variable importance of the feature rankings. a receiver operating characteristic (roc) curve was generated to evaluate the diagnostic accuracy of a protein. a total of 24 covid-19 patients were enrolled in this study, including 14 (58.3%) severe patients and 10 (41.7%) critical patients (table 1 ). compared to the severe group, critical cases were of significantly older ages and showed higher white blood cell counts and neutrophil counts. levels of vegf-d, tnf-α, scf, lif, il-2, il-4, il-6, il-8, il-10, il-15, il-17a, il-18, il-1β, and ifn-γ were significantly higher in the critical group than in the severe group (table 1) . additionally, lymphocyte count, crp, ldh, and coagulation indicators (d-dimer, platelet count, pt, and aptt), which were reported to associate with clinical outcome [4, 5] , were also included in the random forests model. strikingly, vegf-d was identified as the most important indicator related to the severity of covid-19 (ranked as 1, fig. 1a ). as expected, d-dimer, age, il-6, and lymphocyte count associated with clinical outcomes of covid-19 patients reported previously were also highly ranked. vegf-d had a higher area under the curve (auc) (0.836 (95% ci 0.648-1); fig. 1b ) than ddimer (0.755 (95% ci 0.527-0.982); fig. 1c ). consistently, vegf-d levels were positively correlated with sequential organ failure assessment (sofa) scores (fig. 1d ). as shown in fig. 1e , critical patients had higher levels of vegf-d than the severe cases during the whole course of hospitalization. to our knowledge, this is the first report of vegf-d as a potential biomarker for detecting the progression of covid-19. despite limited evidence in covid-19, previous studies demonstrated an important role of vegf in the pathogenesis of acute lung injury (ali) and acute respiratory distress syndrome (ards) by its properties to increase vascular permeability. furthermore, vegf is regarded as an indirect procoagulant for altering the wbc white blood cells, crp c-reactive protein, ldh lactate dehydrogenase, pt prothrombin time, aptt activated partial thromboplastin time, alt alanine aminotransferase, vegf vascular endothelial growth factor; tnf-α tumor necrosis factor-alpha, scf stem cell factor; lif leukemia inhibitory factor, il interleukin, ifn interferon hemostatic features of endothelial cells [6] . we hypothesized that elevated vegf-d level might potentially relate to the storm of blood clots occurring in covid-19 patients. notably, it is of great interest to investigate the therapeutic effects of vegf inhibitor in covid-19 patients. this study has limitations, including the small sample size, a single-center experience, and a variable time interval of each patient from admission to symptoms onset. studies based on a larger cohort in additional sites are needed to verify our findings. clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in cytokine release syndrome in severe covid-19 coronavirus blood-clot mystery intensifies prediction models for diagnosis and prognosis of covid-19 infection: systematic review and critical appraisal d-dimer levels on admission to predict in-hospital mortality in patients with covid-19 platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all patients included in this study. we appreciate the works from dr. authors' contributions yk and h. zhang designed the study and wrote the manuscript. jl conducted the study and recruited the patients. yk and jh collected the samples, performed the experiments, and analyzed the data. xw analyzed the data and performed the statistical analysis. h. zeng participated in the critical review of the manuscript. all authors read and approved the final manuscript. all data generated or analyzed during this study are included in this published article. this study was approved by the committee of ethics at beijing ditan hospital, capital medical university, beijing, china, and each patient gave written informed consent. not applicable. the authors declare that they have no competing interests. key: cord-314310-g1zmggf4 authors: honore, patrick m.; barreto gutierrez, leonel; kugener, luc; redant, sebastien; attou, rachid; gallerani, andrea; de bels, david title: tpe seems to be a treatment that may improve outcomes by effectively removing fibrin degradation products and restoring coagulation status: fact or fiction? date: 2020-10-06 journal: crit care doi: 10.1186/s13054-020-03309-3 sha: doc_id: 314310 cord_uid: g1zmggf4 nan tpe seems to be a treatment that may improve outcomes by effectively removing fibrin degradation products and restoring coagulation status: fact or fiction? patrick m. honore * , leonel barreto gutierrez, luc kugener, sebastien redant, rachid attou, andrea gallerani and david de bels gucyetmez et al., noting that elevated d-dimer levels have been found as a predictor for mortality in patients with covid-19 pneumonia, concluded that therapeutic plasma exchange (tpe) seems to be a treatment that may improve outcomes by effectively removing fibrin degradation products (fdps) and restoring coagulation status [1] . we are not sure that the authors have demonstrated the point that they intended to make. they propose the use of tpe to remove fdps, with the rationale that while unfractionated heparin (ufh) and low molecular weight heparin (lmwh) decrease production of fdps, they cannot contribute to the metabolization of existing fdps [1] . after propensity score matching, the mortality rate, in the patients with d-dimer level ≥ 2 mg/l, was 8.3% in patients who received tpe (tpe +) versus 58.3% in those who did not (tpe −), with no thromboembolic events detected in either sub-group [1] . while there was a reduction in the d-dimer levels in the tpe + group and not in the tpe − group, this cannot automatically be assumed to be the underlying cause of the decreased mortality rate. the cause of death is important information that has been omitted from this paper. furthermore, "treating the numbers" does not necessarily equate to an improvement in the status of the patient. it is also important to note that tpe has the potential to cause harm by diluting or attenuating the patient's adaptive response to infection via depletion of immunoglobulins and complement components 3 and 4 [2] . in the case of patients with covid-19, tpe will remove the protective antibodies formed by the patient, which is not desirable. indeed, tpe may not restore immune homeostasis but may rather aggravate immunoparalysis [3] . finally, given the variety of additional treatments (e.g., antiviral drugs, cytokine filters, steroids) that the patients in the study received, how can one be certain of which treatment(s) ultimately influenced mortality? a randomized controlled trial is needed to truly assess the therapeutic efficacy of tpe in patients with covid-19 and coagulation activation. all patients should receive standard supportive intensive care without any of the recently proposed treatments for covid-19, with the exception of dexamethasone. the treatment group would receive three daily sessions of tpe. the prognostic model at admission, the daily severity measure, and outcome measures including detection of thromboembolic events and mortality would be clearly defined by the investigators as in any good quality intensive care trial. dear editor, we would like to thank honore et al. for their considerable comments. firstly, we should emphasize three important points about our study: (1) we investigated the effect of therapeutic plasma exchange (tpe) on overall mortality, not mortality predictors, (2) we emphasized that "major thromboembolic events" were not detected, not only thromboembolic events, and (3) we did not mention the cause of deaths because all of them were multi-organ failure (mof) caused by covid-19 [1] . even if "major thromboembolic events" are not detected, patients will be under risk in terms of micro-embolisms as long as their ddimer levels are high and this could be a reason for mof. in the study, 95% and 80% of deaths were in gii and giib respectively although all therapies except tpe were similar. additionally, in propensity score matching (psm), 14 covariates including "the usage of steroid, interleukin blocker and cytokine filter" were matched [1] . therefore, we think that the result of psm is acceptable evidence for the effect of tpe on mortality in patients with high d-dimer level although the number of patients are limited. on the other hand, references which are used by honore et al. actually support our results [2, 3] . namely, rimmer e et al. mentioned the benefits of tpe before its harmful effects in the introduction section. moreover, despite the possible rare adverse effects of tpe, they concluded that the mortality was decreased by tpe in adult patients with sepsis [2] . in another reference that 54 patients were included, 41 of them were administered steroid plus immunosuppressive agents. nevertheless, authors emphasized that "88.9% of procedures were carried out without complications" and they opined that "lower leucocyte counts could have affected increased susceptibility to infections; however, it is difficult to attribute them exclusively to tpe procedures" [3] . additionally, fresh frozen plasma (ffp) was administered at 1/4 ratio with albumin during tpe in both studies [2, 3] . dilution is more expected in this technique. yet, we only used ffp by calculating estimated plasma volume while performing tpe. lastly, it should not be forgotten that dexamethasone, which was mentioned as a proposed treatment by honore et al., is also an immunosuppressive agent [4] . the main treatments of covid-19 pneumonia are antiviral and anticoagulation therapies. however, we still strongly believe that "tpe should be featured as a part of the treatment especially in covid-19 pneumonia patients with a high risk of thrombosis". abbreviations tpe: therapeutic plasma exchange; fdps: fibrin degradation products; ufh: unfractionated heparin; lmwh: low molecular weight heparin; tpe +: patients who received tpe; tpe −: patients who did not receive tpe covid-19 study group. therapeutic plasma exchange in patients with covid-19 pneumonia in intensive care unit: a retrospective study the efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis complications in patients treated with plasmapheresis in the intensive care unit dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions pmh, sr, and ddb designed the paper. all authors participated in drafting and reviewing. all authors read and approved the final version of the manuscript. none.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare to have no competing interests.received: 27 august 2020 accepted: 22 september 2020 key: cord-288284-fghu8ouc authors: hawryluck, laura; lapinsky, stephen e; stewart, thomas e title: clinical review: sars – lessons in disaster management date: 2005-01-13 journal: crit care doi: 10.1186/cc3041 sha: doc_id: 288284 cord_uid: fghu8ouc disaster management plans have traditionally been required to manage major traumatic events that create a large number of victims. infectious diseases, whether they be natural (e.g. sars [severe acute respiratory syndrome] and influenza) or the result of bioterrorism, have the potential to create a large influx of critically ill into our already strained hospital systems. with proper planning, hospitals, health care workers and our health care systems can be better prepared to deal with such an eventuality. this review explores the toronto critical care experience of coping in the sars outbreak disaster. our health care system and, in particular, our critical care system were unprepared for this event, and as a result the impact that sars had was worse than it could have been. nonetheless, we were able to organize a response rapidly during the outbreak. by describing our successes and failures, we hope to help others to learn and avoid the problems we encountered as they develop their own disaster management plans in anticipation of similar future situations. the commission recognizes the skill and dedication of so many individuals in the ontario public health system and those volunteers from ontario and elsewhere who worked beyond the call of duty … they faced enormous workloads and pressures in their tireless fight, in a rapidly changing environment, against a deadly mysterious disease. the strength of ontario's response lay in the work of the people who stepped up and fought sars. what went right in a system where so much went wrong, is their dedication … [1] disaster management plans have traditionally been required to manage major traumatic events that create a large number of victims. infectious diseases, whether they be natural or the result of bioterrorism, have the potential to create a large influx of critically ill patients, and disaster management planning should take such eventualities into account. this need was demonstrated in february 2003, when a new illness -sars (severe acute respiratory syndrome) -spread from the people's republic of china to 28 countries, resulting in 8096 probable cases with 774 deaths [2] . this review explores the toronto critical care experience of coping in a disaster outbreak situation. by sharing our experiences and our coping strategies, we hope that others will learn from our successes and avoid the problems we encountered, many of which were a direct result of lack of preparedness. we hope that this review will encourage others to make plans to cope with similar outbreaks in the future, should they occur. the diagnosis of sars relies on a high index of clinical suspicion because there is no early, reliable and readily available diagnostic test for the responsible virus (sars-cov) [3] [4] [5] [6] . likewise, it is expected that other emerging infectious agents will pose diagnostic challenges. because of this, as infected individuals present to medical institutions where staff are unprepared, the risk for spread is considerable. an outbreak situation may arise quickly and without much warning, taxing the resources of any health care system and the ability of its personnel to cope. the most fundamental guidance we offer is that you need to have a plan in advance. since 11 september 2001, the usa and other countries have run exercises to prepare for attacks, including bioterrorism [7] [8] [9] [10] [11] [12] . we believe that, based on the way in which sars crippled our health care system (in particular critical care delivery) and dealt significant blows to our economy, a great deal could be gained from simulating similar events and planning a system wide response to emerging pathogens. the development of a disaster management plan in the event of emerging diseases poses very unique challenges, and we offer some insights into these below. core to any disaster management plan are leaders with clear responsibilities to coordinate efforts and develop policies to contain the disease; to coordinate resource allocation and manpower; to advise and share information regarding infection control and treatment; to share data and research endeavours; to maintain staff morale; and to provide information to various levels of government, health care institutions, front-line workers and the public [1, 13] . the model we propose (fig. 1 ) is one of a central critical care crisis team, composed of leaders of different subteams of multidisciplinary professionals responsible for domains of crucial importance: clinical management, infection control, education, communication, team morale, manpower and system thinking, data collection, research and, finally, lobbying to ensure resources are available to meet critical care needs. appointed leaders should have the capacity to gather quickly a team of professionals to help address issues within their domains. team membership is not a competition or a measure of professional worth. rather, consideration must be given to who can best fulfill the roles. the role of the central critical care crisis team is to coordinate the efforts of the various leaders, to avoid duplication of efforts and, through regular sharing of information, problems and support, to work together to devise creative solutions and anticipate future needs. concerted efforts to address cross-institutional problems can be addressed in these forums. any jurisdiction dealing with an outbreak of a new infectious disease must ensure that it has the means to communicate clearly and quickly, as well as receive information, on the following: updated diagnostic criteria; suspected and established epidemiological links; numbers of infected patients as well as those quarantined and at risk; prognosis and treatment issues; current knowledge regarding the most effective means of infection control; and infection control issues specific to different settings [1, 13] . any disaster plan must anticipate needs for infection control equipment [11, 14] . the sars outbreak and the ongoing risk for other emerging infections emphasize the importance of having some basic stock [14] , and creating a list of potential suppliers who could rapidly increase their supply is advisable. requirements may be enormous; one toronto hospital used 18,000 n95 masks and 14,000 pairs of gloves daily during the sars outbreak [15] . the importance of infection control measures, and of the development of clear protocols and training cannot be overemphasized [14] . in toronto one of the greatest challenges that arose was handling the uncertainty of exactly what level of precautions were needed to ensure staff safety. this was an issue that had to be addressed immediately because getting appropriate staff to work required that they felt as protected as possible. anecdotally, we found in some centres that distrust occasionally emerged between front-line health care workers and leadership. this may have been due to several issues, including the following: there was no clear system-wide communication strategy, and as a result rumours and speculation frequently went unchecked; infection control and other recommendations changed frequently, leading many individuals to question the validity of previous directives; and confusion over whether the responsible virus could be airborne and variable use of airborne versus droplet protection. of note, subsequent evidence suggests that airborne transmission may in fact be possible [16] . in retrospect, we believe a city-wide, consistent and regular communication strategy (which occurred in some institutions) that acknowledged the fact that leadership was making decisions in the face of uncertainty would have minimized the distrust. unlike traditional notions of disaster (e.g. bombings), disaster situations from infectious disease outbreaks do not have a clear beginning or end. disaster planning for these circumstances is unique in that it challenges us to develop practical means to conduct ongoing, widespread surveillance and screening [1, 11, 13] , particularly in light of unclear prodromes and illness presentations and in the absence of diagnostic testing. there is a need to develop a team to track and follow potential epidemiological linkages quickly and to engage in surveillance for de novo cases. this team will infectious disease outbreak disaster plan. potentially have to collaborate across wide geographical regions, engage in open discussion of uncertainty, and develop a surveillance and quarantine strategy that is practical, as comprehensive as possible and does not needlessly isolate individuals and restrict their freedoms. in the face of uncertain diagnostic criteria, it is important to acknowledge that some individuals will be isolated needlessly and some infected asymptomatic individuals will be missed, leading to new cases with the potential to perpetuate the outbreak. it is important that the surveillance team does not seek to assign blame under these circumstances; instead, an analysis of each 'failed' surveillance or error should be undertaken to improve overall knowledge of disease transmission and presentation, and to prevent other infected individuals from falling through the cracks. from the critical care point of view, it is important that there is a feedback loop from these surveillance teams to the critical care leadership, so that that subsequent reliable communication and preparation can be assured. front-line workers any information regarding the transmission of disease to staff, an analysis of how such spread may have occurred and advice regarding future preventative measures should be made available to everyone. in the present era of global travel, it is increasingly unlikely that one centre or one country will be dealing with new emerging diseases in isolation. disaster planners are challenged to develop a global perspective, including accurate communication of events as they unfold in distant jurisdictions. as a result, links to colleagues locally, nationally and internationally are vital in a disaster situation. websites providing the most up-to-date information regarding the outbreak, modes of transmission, clinical presentation and required infection control measures can ensure speedy communication to large numbers of people. in addition, such websites can be used to teach how to don protective gear, discuss and outline treatment strategies, teach how to respond to unique crisis situations (e.g. cardiac arrests while maintaining infection control measures), and serve as a way to train treatment teams at different hospital sites. indeed, internet-based technology proved invaluable during the sars outbreak in toronto by allowing our experiences and our newly, on occasion painfully, gained knowledge to be shared with other affected centres and countries. colleagues in unaffected countries were warned and prepared (for example, see sars resources [17] ). the establishment of such systems for communicating and sharing information, resources, data and research endeavours is one of the clear successes in the management of sars. efforts to establish such links should be made in all future outbreak situations [18] . those affected by sars were scared. we were unable to provide them with much information; they were isolated and prognosis was very uncertain. affected patients must be kept as informed as possible. family members who had had any contact with the patient were placed in strict quarantine, and as a result they were not allowed to visit, even if a loved one was dying. any disaster management plan must anticipate the isolation and need for informational, psychological and emotional support for those immediately affected, including loved ones. the toronto experience suggests that there is a need to develop more effective means to convey information on quarantine and infection control and to provide support [19] . in toronto, the sars outbreak received unprecedented media attention. daily headlines generated widespread fear and panic. efforts to decrease sensationalism, to portray an honest picture, and to elicit the help and understanding of the public were lessons that can be learned for any disaster management plan [20, 21] . assigning one team of professionals, as outlined in fig. 1 , to inform and update the media would ensure that consistent information is provided, and would avoid the confusion, fear, anxiety and even chaos that can potentially arise (frequently resulting from inaccurate information) if left unchecked. educating teams on how to treat infected individuals, mount surveillance for others, observe infection control measures, respond to emergency situations, collect data and conduct research, and support each other is vital. the education team would be responsible for the creation of educational packages that could be disseminated across many institutions. in addition, mobile educational teams can be deployed to individual institutions to meet specific needs. by developing and ensuring consistent standards of infection control across institutions, these teams not only will help to decrease the transmission of disease and avoid prolongation of the outbreak, but also will serve to support staff morale by helping them to develop means to overcome any environmental barriers to infection control, sharing experiences and emphasizing the fact that everyone faces similar challenges and is working together. when the outbreak is controlled, educational efforts are not over. the team responsible for education must also be prepared to analyze its performance and devise ways to improve. in addition, ongoing training exercises, potentially using simulators and mock outbreak/disaster exercises, must be instituted to ensure that knowledge gained is not lost and that front-line workers are prepared for the next time, because this next time may arise with little or no warning. finally, the sars outbreak also helped us to identify another educational need by our intensive care unit (icu) fellowship trainees -the need to provide them with practical hands-on experience in leadership. during the sars outbreak health care providers felt isolated [22, 23] . many front-line workers curtailed interactions with their families and friends for fear of transmitting the disease [22] . others were treated as pariahs. front-line workers were required to manage a level of critical illness that they might not usually have managed [23, 24] . infection control measures were burdensome and difficult to bear. despair and depression became common [23, 24] . regular communication via teleconferences and e-mails became the new means to provide support. these provided a forum to dispel rumours, clarify media reports, synthesize the barrage of government directives, and support those feeling isolated as we sought to work in extremely difficult and demanding conditions, such as seeing our colleagues placed in quarantine after exposure, some of them falling ill, becoming critically ill and even succumbing to sars. staff morale was addressed in some institutions by encouraging and commending health care workers, and congratulating them, whether for their efforts to treat patients, collect data, communicate with other centres and share information, improve infection control measures or teach others, or for simply surviving the day and/or night. some hospitals instituted regular group support meetings and debriefing with the help of psychiatric or emergency response crisis teams. the most effective way to provide support is not currently known. particular attention to devising ways to decrease isolation and the emotional and psychological burdens should be an integral part of any disaster management plan. during an outbreak, providing support does not necessarily require a complicated plan. providing meals or refreshments to staff working in cumbersome, hot and heavy protective gear, and providing safe areas to relax in are simple, easy and well appreciated means to convey support. the presence of leaders who are prepared to risk their own health alongside front-line staff, who listen to staff concerns and address them to the best of their ability, and who discuss and/or reiterate management plans is another straightforward means to provide much needed support and a boost to staff morale. it is important that leadership demonstrate willingness to participate in the front-line environment. finally, consideration of the need for management of post-traumatic stress disorder, in consultation with psychiatric colleagues, is prudent, and such investment is likely to prevent some of the long-term disability we have seen. any future similar situations will also pose challenges to professionalism. as seen with sars [22] and the emergence of hiv [25] [26] [27] , most health care providers never anticipated being in a situation that put their personal safety, health and potentially their lives and those of their families on the line. questions arose regarding whether there is a duty to care and how much personal risk should be expected [22] . some refused to care for sars patients, and some refused to even enter wards containing sars patients [22] . others demanded 'danger pay' and compensation for illness and quarantine. understandably, some worried about the extent of their disability and life insurance coverage. these views raised further challenges, fracturing the front-line teams who found themselves asking what, if anything, made their colleagues' lives more 'valuable' than their own. issues of duty to care and of balancing personal risk and professional obligations remain for a large part unanswered. further research and debate is required. disaster planning must, however, consider whether such issues are likely to arise and include potential strategies to deal with them. consideration should be given to developing means to decrease the anxiety regarding transmission of illness to family members; these could include child care and arranging the provision of alternate living quarters for staff, among others. during the sars outbreak, the supply of critical care beds became a significant concern because of the need to manage a surge of unanticipated critically ill patients. this was a big problem because our occupancy rates were already unacceptably high. this supply issue will become a crucial concern in any future outbreak or disaster situation. in addition to our problem with bed availability, the human resources component further exacerbated the problem; the staff numbers were reduced by fear of contracting the disease, quarantine and illness. when sars transmission occurred in icus, entire units were quarantined for 12-14 days. of tertiary care university medical/surgical icu beds and community icu beds in toronto, 38% and 33%, respectively, were closed at some point [28] . maintaining provision of icu services to non-sars patients became an important consideration as the outbreak progressed. in anticipation of future outbreaks, plans to organize critical care resources to meet the needs of all critically ill patients should be developed. for example, critical care beds can be rapidly augmented by other areas of the hospital that are adequately equipped (e.g. recovery rooms, operating rooms, emergency rooms, etc.). institutions do need to develop their own individual plans based on their available resources, and must share the models/strategies that they institute so that others can learn and potentially adapt these plans to their own centres. however, one of the most important roles played by the central critical care crisis team is to help create more icu resources, rapidly. the scope of future outbreaks or disasters will always be uncertain, but, potentially, critical care providers will need to be able to care for many, many more patients very quickly. because most icus currently function at very high occupancy rates, absorbing such additional numbers is unimaginable. meeting these needs clearly requires us to move from institution-based to system-based thinking. in addition, critical care providers must be prepared to make tough decisions regarding triage and standards of care. critical care providers should pre-develop engineering plans to isolate wards, rather than those that were developed by necessity on-the-fly in toronto. the creation of such a system-based disaster management plan is not an easy task. sharing information and learning from collective experience requires unprecedented collaboration and open communication between all levels of government, health care organizations and front-line workers. there is no room for political barriers, institution-based thinking (as opposed to system-wide thinking), bickering over responsibilities, or consideration of personal professional gain [1, 13] . system-wide thinking may challenge even the most seasoned of critical care providers because the scope of current barriers, the number of people involved and the effort needed to get them to collaborate on such a broad scale is not something that they will necessarily have experienced or tried to tackle in the past. these systems versus institutional issues are common in any health care system; in toronto they worsened the impact of sars, and in the early days of the outbreak they diminished much needed communication and collaboration [1, 13] . we also observed that in many hospitals there was duplication of some efforts, wasting precious resources [1, 13] at a time when, after many years of cutbacks and strain, we did not have resources to waste. events such as sars challenge all of us to review the organizational structure of our health care systems and correct potential problems that may arise in similar situations [1, 13] . consideration should be given to designating specific hospitals as main centres for screening suspected cases and treating those affected; identifying hospitals to meet general and those to meet more specialized care needs of other critically ill patients; devising means to increase critical care resources within the affected region; and identifying institutions to decant certain patients to (e.g. alternate level of care patients) and to provide for specific ongoing needs of the population (e.g. cardiac services). although the designation of outbreak hospitals does place a greater toll on front-line workers in these institutions, those health care providers caring for greater numbers of sars patients in toronto actually experienced less anxiety in the form of post-traumatic stress disorder symptomatology [29] . such measures may also result in faster disease containment (by decreasing breaches in infection control) and better patient care as the teams become more familiar with the disease. unlike the toronto experience, in which sars hospitals were designated late in the outbreak, sars hospitals in other countries experienced little to no transmission to staff [30] . in toronto, entire icus were quarantined as a result of transmission of sars to staff [28] . subsequently, provision of critical care to both sars patients and all other critically ill patients was jeopardized. although designation of outbreak hospitals seems a simple solution, it is not as easy as it appears. for example, finding staff willing to work in such a setting is a challenge. in addition, such a plan does not preclude other hospitals from knowing how to deal with the illness because, for the most part, the diagnosis is not clear for several days and originating hospitals will need to be prepared to manage patients until that point. furthermore, designated hospitals will need access to other medical services as affected individuals develop other complications. finally, the act of transporting such contagious individuals is not without considerable risk, and hence transportation requires careful planning. we recommend that regions develop and, importantly, test plans for working as a system during a disaster like this. intensivists played a vital role during the sars outbreak. the icu saw the greatest mortality and had to deal with high-risk situations that increased the risk for contracting the disease [14, 28, 30] . infection control and issues specific to icu care and resource allocation meant that having a voice was vital. such lobbying for icu resources must be started now. the sars outbreak has taught us that we can no longer accept, without comment or objection, the present need to cope and function, day in and day out, in a situation of inadequate critical care resources and manpower. the importance of having all levels of government understand what critical care is, what our needs are, and the help we require to serve our patients now and in the future is perhaps the most valuable lesson of all that we offer to our readers -one that we learned the hard way from surviving the sars outbreak. sars emphasized the need for disaster management plans to include new emerging infectious diseases. as our knowledge of sars-cov grows, our strategies for diagnosis, treatment and containment will improve. new infectious diseases and/or possibly bioterrorism will take the place of sars-cov and will similarly challenge us. training our staff and our future icu trainees for such eventualities, through the use of simulators and mock disaster codes, has become necessary to build on our successes and learn from our past to avoid the problems we encountered during sars. the sars commission interim report: sars and public health in ontario world health organization: severe acute respiratory syndrome (sars): summary of probable sars cases with onset of illness from 1 surveillance and response: consensus document on the epidemiology of the severe acute respiratory syndrome clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study clinical features and short-term outcomes of 144 patients with sars in the greater toronto area a major outbreak of severe acute respiratory syndrome in hong kong medical examiners, coroners and biologic terrorism: a guidebook for surveillance and case management measures of effectiveness in large scale bioterrorism events lack of hospital preparedness for chemical terrorism in a major bioterrorism and critical care the model state emergency health powers act: planning for and response to bioterrorism and naturally occurring infectious diseases biological and chemical terrorism: recognition and management learning from sars -renewal in public health in canada icu management of severe acute respiratory syndrome the impact of sars on healthcare supply trains. logistics q evidence of airborne transmission of the severe acute respiratory syndrome virus mount sinai hospital critical care unit: sars resources sars: looking back over the first 100 days the other side of quarantine: experiences from the sars outbreaks in toronto role of mass media during the severe acute respiratory syndrome epidemic severe acute respiratory syndrome and its impact on professionalism: qualitative stusdy of physicians' behaviour during an emerging healthcare crisis communication in the toronto critical care community: important lessons learned during sars challenging beliefs and ethical concepts: the collateral damage of sars medical students and aids: knowledge, attitudes and implications for education loewy eh: duties, fears and physicians critically ill patients with severe acute respiratory syndrome posttraumatic stress disorder (ptsd) among healthcare workers (hcw) at a hospital treating patients with sars acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome the author(s) declare that they have no competing interests. key: cord-338990-vrtzyo2o authors: nelson, sarah e. title: covid-19 and ethics in the icu date: 2020-08-25 journal: crit care doi: 10.1186/s13054-020-03250-5 sha: doc_id: 338990 cord_uid: vrtzyo2o nan the covid-19 pandemic has brought into focus many medical ethics questions; several have burdened intensive care unit physicians in particular (fig. 1) . the aim of this article is to provide a frank yet thoughtful discussion of the many facets of these ethical dilemmas. we intensivists potentially put ourselves at risk each time we report to work. this is scary and unsettling. hundreds of years ago, physicians had no professional or ethical obligation to take care of sick patients during disease outbreaks, some purposely fleeing from plagueridden areas [1] . however, times have changed. most medical students now recite the hippocratic oath, which states that: "i will apply, for the benefit of the sick, all measures [that] are required," though nowhere does it state that physicians must work in settings that could put their own health at risk [2] . following the events of september 11, 2001 , the american medical association (ama) reaffirmed their stance that "it is a responsibility of health professionals to continue caring for patients even if doing so presents some danger to them" [1] . this includes an "obligation to provide urgent medical care during disasters … even in the face of greater than usual risks to physicians' own safety, health, or life." given the large scope of the pandemic and the deadliness of sars-cov-2, these statements may not adequately address this ethical quandary. for instance, it is not entirely clear how much of a hazard is actually acceptable. and risk to healthcare workers is real: > 3300 were infected in china as of early march 2020 as were 20% of healthcare workers in italy [3] ; hundreds of these workers around the world have died since the pandemic began [4] . healthcare providers may feel they did not sign up for their jobs knowing that they may need to sacrifice themselves for others [5] . in addition, hospitals have periodically suffered from shortages of personal protective equipment (ppe). is it ethical to ask intensivists and other healthcare providers to counter this contagious threat with inadequate battle gear? one of the most upsetting issues of the pandemic is the limited number of critical care resources, including ventilators and intensive care unit beds, available to covid-19 patients and other critically ill patients. in countries such as italy, healthcare providers have had to make difficult decisions about who is provided a ventilator and who is not and thus forced to dictate life and death [6] , and other countries have prepared to face similar difficult decisions. in what almost seems a foreshadowing, distribution of limited resources was explored recently by a johns hopkins intensivist and her team. participants in the study felt that, in times of crisis, shortand long-term outcomes should be primarily considered (versus a lottery system or first come, first served) in deciding who should be prioritized to receive scarce resources [7] . the same research group then generated a framework based on the 2 major ethical considerations they had identified: short-term survival, with the support of all available resources, and long-term survival, with consideration of comorbidities [8] . specific to the covid-19 pandemic, 4 ethical guiding principles to consider when resources are limited have been noted: (1) maximizing benefits of scarce resources, (2) treating all people equally, (3) preferentially selecting those with instrumental value, and (4) prioritizing patients who are worst off [9] . based on these principles, 6 recommendations have been made for the current outbreak: maximizing benefits including using scarce resources responsibly and saving more lives/years of life, prioritizing covid-19 resources (i.e., ppe, vaccines) to healthcare workers, invoking equality using random allocation or lottery to distribute resources to those with similar prognoses, thoughtful consideration of resource allocation (e.g., prioritizing older patients, among the most affected by sars-cov-2, to receive a vaccine), prioritizing those who have participated in covid-19-related research, and providing equal resources to those with covid-19 and those with other medical conditions [9] . in response to the pandemic, the johns hopkins hospital convened a scare resource taskforce to reach a consensus about available resources in maryland and triggers for initiating a framework requiring allocation of scarce resources. other us states have formally approved a scare resource allocation protocol, and individual medical centers have been forced to put together such polices or released recommendations regarding issues to consider when designing them [10, 11] . one of the most severely afflicted epicenters in the world, new york state has instituted legal immunity for physicians forced to make these difficult triage decisions. given the increasing number of covid-19 cases, the potential need to triage critical care resources has deeply affected physicians [12] . further, visitor restrictions in hospitals have led to emotionally painful experiences. visitors can augment patient histories and provide sources of comfort to patients. unfortunately, by increasing the number of people in a hospital at one time, hospital visitors can potentially hamper social distancing and contribute to increased spread of sars-cov-2. as a result, many hospitals have closed their doors to visitors except under special circumstances. in one of the more heartbreaking aspects of this crisis, many patients have therefore died alone and without loved ones at their bedside [13] . inpatients admitted for other reasons have also been affected and unable to communicate with their families in person [14] . another ethical dilemma exists at home. what level of interaction after a day at work is safe between healthcare providers caring for covid-19 patients and their families? while essential workers wish to sustain their personal relationships, their interactions with other people after working in the hospital could possibly increase spread of sars-cov-2 and cause additional suffering. many physicians have struggled with this quandary [15] . in a similar vein, large family gatherings including weddings and funerals have been impacted and thus forced to downsize, which has also created great distress. several ethical dilemmas associated with the covid-19 pandemic affect intensive care physicians. no one yet knows the full extent of the psychological injury that these issues have caused, but unfortunately it will likely be significant. doctors obliged to provide pandemic care the hippocratic oath today covid-19: protecting health-care workers memoriam: healthcare workers who have died of covid-19 physicians are disposable and are taken for granted facing covid-19 in italy -ethics, logistics, and therapeutics on the epidemic's front line scarce resource allocation during disasters: a mixed-method community engagement study too many patients … a framework to guide statewide allocation of scarce mechanical ventilation during disasters fair allocation of scarce medical resources in the time of covid-19 the toughest triage -allocating ventilators in a pandemic considerations for ventilator triage during the covid-19 pandemic the psychological trauma that awaits our doctors and nurses not dying alone -modern compassionate care in the covid-19 pandemic i'm on the front lines. i have no plan for this part of the cure or am i part of the disease? keeping coronavirus out when a doctor comes home publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations author's contributions s.e.n. designed the topic of the paper, collected the data, wrote the first and final drafts of the manuscript, and critically revised the paper. the author read and approved the final manuscript. key: cord-304327-mtkgr542 authors: jouffroy, romain; jost, daniel; prunet, bertrand title: prehospital pulse oximetry: a red flag for early detection of silent hypoxemia in covid-19 patients date: 2020-06-08 journal: crit care doi: 10.1186/s13054-020-03036-9 sha: doc_id: 304327 cord_uid: mtkgr542 nan the covid-19 pandemic, which has been expanding since the first cases in asia in late 2019, may result in acute respiratory failure (arf) with severe hypoxemia [1] [2] [3] . in prehospital settings, the paucity of clinical respiratory signs has made assessing the severity of some covid-19 patients challenging. indeed, even though hypoxic arf generally leads to an increase in respiratory rate (rr) [4] , in some covid-19 patients, a persistent normal rr was inconsistent with the severity of hypoxia. based on retrospective data, we aimed to describe the discrepancy between prehospital initial rr (rri) and initial spo2 (spo2i; i.e., before oxygen supplementation, fio2 = 21%) in covid-19 patients suffering from arf. we retrospectively examined consecutive covid-19 patients suffering from arf who were treated by the paris fire brigade's basic life-support (bls) teams in the prehospital setting. data were provided from primary home care providers. based on a previous study [5] , we used the spo2i/rri ratio as an estimator of the discrepancy insofar as a low numerator is associated with hypoxia, whereas a high denominator is typically associated with respiratory failure. after having measured the spo2i/rri values in covid-19 patients, we compared them to those of non-covid-19 patients (i.e., patients with other causes of arf treated by the bls teams over the previous 3 years in the same period). continuous data were described as median (interquartile range) and were compared by applying the kruskal-wallis test. the french society of anaesthesia and intensive care approved the trial protocol on april 7, 2020 (irb 00010254-2020-055). the study examined 1201 patients who experienced covid-19 between march 13 and 29, 2020. the median spo2i/rri value was significantly higher than that of patients treated in the previous 3 years (5 [4, 5] fig. 1 ). in summary, this retrospective study based on prehospital first responder data highlighted a relatively higher discrepancy between spo2i and rri in covid-19 arf patients, in comparison with previous non-covid-19 arf patients. without a systematic spo2i measurement, a normal breathing rate could mask profound hypoxia and make severity assessment in covid-19 patients all the more difficult in an out-of-hospital setting. despite differences in worldwide prehospital emergency medical services, pulse oximetry is an accessible tool that prehospital healthcare providers can easily use. in conclusion, prehospital pulse oximetry might be used as a red flag for early detection of "silent hypoxemia" in covid-19 patients. the prehospital spo2i/rri ratio needs further investigation because it might help to identify non-clinically obvious arfs. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. fig. 1 scatter plot representing the initial spo2 (spo2i) and initial respiration rate (rri) values for each patient, for covid-19 (march 2020) and non-covid-19 patients from the previous 3 years. the horizontal and vertical lines indicate the threshold values of spo2 95% and respiration rate, 20 breaths per minute, respectively. we used the kruskal-wallis test to compare the median spo2i/rri value, between the period "13 th to march 29, 2020," and the three previous years (p value < 0.001). rri, initial respiratory rate; spo2i, initial pulse oximetry value; n, number of patients included estimates of the severity of coronavirus disease 2019: a model-based analysis case-fatality rate and characteristics of patients dying in relation to covid-19 in italy clinical characteristics of coronavirus disease 2019 in china the regulation of normal lung function predicting success of high-flow nasal cannula in pneumonia patients with hypoxemic respiratory failure: the utility of the rox index the authors declare that they have no competing interests.received: 20 may 2020 accepted: 27 may 2020 key: cord-293167-3bd3adip authors: nepal, gaurav; rehrig, jessica holly; shrestha, gentle sunder; shing, yow ka; yadav, jayant kumar; ojha, rajeev; pokhrel, gaurab; tu, zhi lan; huang, dong ya title: neurological manifestations of covid-19: a systematic review date: 2020-07-13 journal: crit care doi: 10.1186/s13054-020-03121-z sha: doc_id: 293167 cord_uid: 3bd3adip introduction: severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is responsible for the global spread of coronavirus disease (covid-19). our understanding of the impact this virus has on the nervous system is limited. our review aims to inform and improve decision-making among the physicians treating covid-19 by presenting a systematic analysis of the neurological manifestations experienced within these patients. methods: any study, released prior to may 20, 2020, that reported neurological manifestations in patients infected by sars-cov-2 was systematically reviewed using the prisma (preferred reporting items for systemic review and meta-analysis) statement. results: our systematic review included data from 37 articles: twelve retrospective studies, two prospective studies, and the rest case reports/series. the most commonly reported neurological manifestations of covid-19 were myalgia, headache, altered sensorium, hyposmia, and hypogeusia. uncommonly, covid-19 can also present with central nervous system manifestations such as ischemic stroke, intracerebral hemorrhage, encephalo-myelitis, and acute myelitis, peripheral nervous manifestations such as guillain-barré syndrome and bell’s palsy, and skeletal muscle manifestations such as rhabdomyolysis. conclusion: while covid-19 typically presents as a self-limiting respiratory disease, it has been reported in up to 20% of patients to progress to severe illness with multi-organ involvement. the neurological manifestations of covid-19 are not uncommon, but our study found most resolve with treatment of the underlying infection. although the timeliness of this review engages current challenges posed by the covid-19 pandemic, readers must not ignore the limitations and biases intrinsic to an early investigation. coronavirus disease is caused by the novel virus, severe acute respiratory syndrome coronavirus 2 (sars-cov-2) [1] . since its recent discovery in wuhan, china, coronavirus disease has spread across the world, leaving physicians challenged by its variable clinical manifestations. most patients infected by sars-cov-2 have presented with a mild clinical course: beginning with fever and dry cough, progressing to a form of mild or moderate respiratory disease, and resolving without specific treatment [2] . serious complications of the infection, however, remain a central concern. acute respiratory distress syndrome, acute heart injury or failure, acute kidney injury, sepsis, disseminated intravascular coagulation, and lifethreatening metabolic derangements have all been reported in covid-19 patients, particularly among those with underlying comorbidities or advanced age [1, 3] . as knowledge of sars-cov-2 and its clinical appearance continue to grow, the literature has shown a significant number of infected patients exhibit neurological symptoms [4, 5] . in this systematic review, we evaluate various neurological manifestations reported in covid-19 patients and hypothesize their underlying pathophysiology. we deem the timeliness of this systematic review relevant, given the state of the covid-19 pandemic, but encourage readers to consider the implications of early review and analysis in the clinical setting. our systematic review utilized the prisma (preferred reporting items for systemic review and meta-analysis) statement in conjunction with the prisma checklist and flow diagram for manuscript format development [6] . the following databases were reviewed for published studies prior to may 20, 2020: pubmed, google scholar, and china national knowledge infrastructure (ckni). we also searched pre-print servers including research square, medrxiv, ssrn, and chinaxiv. boolean logic was used for conducting database search and boolean search operators "and" and "or" were used to link search terms. the following search strategy was adopted: covid-19 or sars-cov-2 or 2019-ncov or ncov or novel corona and neurological or neurologic or brain or cns or nervous and manifestation or symptoms or presentation. titles, abstracts, and full text were screened to ensure they met eligibility criteria. two authors (gn and jhr) screened, retrieved, and excluded reports. additional investigators were consulted if uncertainty arose during the review process. we included any study, published in any language, which reported neurological manifestations in patients infected by sars-cov-2. this included case reports and pre-print publications. we excluded all review articles, hypotheses papers, and papers reporting neurological symptoms in mers-cov and sars-cov patients. data was manually extracted from eligible studies by the research investigators. the following variables were included: first author, type of design, site of study, year of publication, published journal or pre-print server, sample size, and reported neurological manifestations. our outcome was to elucidate the neurological manifestations of covid-19 reported in the medical literature. the results were divided into three categories: central nervous system manifestations (e.g., headache, encephalopathy, and stroke), peripheral nervous system impairment (e.g., dysfunction of taste, dysfunction of smell, neuropathy), and skeletal muscle manifestations (e.g., myalgia). in total, our literature search yielded 106 articles. after excluding duplicates and those not meeting inclusion criteria, 37 papers were included in our systematic review. figure 1 displays the results of our literature search and selection. the characteristics of each study are summarized in table 1 . there were twelve retrospective studies [1, 2, 5, 7, 18-23, 35, 40] , two prospective studies [36, 37] , and the rest were case reports/series. one article was a multicenter study [36] , 18 were from mainland china, six from the usa [11, 15, 30, 34, 35, 39] , five from iran [14, 17, 33, 37, 38] , four from italy [8, 23, 29, 32] , and one each from japan [24] , switzerland [31] , and spain [10] . out of all included studies, one was published in a premier news agency of china [12] , eight were unpublished scientific articles deposited in pre-print servers [7, 13, 16, 26, [28] [29] [30] [31] , and the remaining 28 were journal publications. eight retrospective studies reported covid-19 patients presenting with headache. we found that an overall average of 19.88% of patients experienced headache (fig. 2) . mao et al. reported that some of covid-19 patients with neurologic manifestation initially presented with fever and headache only. however, several days later, they developed cough, throat pain, lymphopenia, and a ground-glass appearance on their respective chest computed tomography (ct) images. real-time reverse-transcription pcr (rt-pcr) analysis of nasopharyngeal swabs confirmed covid-19 infection in these patients [5] . a retrospective study from china reviewed 274 cases of covid-19, of which 24 (8.8%) developed hypoxic encephalopathy which progressed to death in 23 (95.8%) and recovery in 1 (4.2%) [18] . a separate study from china reported encephalopathy in 8 (2.6%) out of 304 cases, out of which one was obtunded, one was delirious, and six were comatose [40] . among the deceased cases in both studies, there were high rates of acute respiratory distress syndrome (ards), respiratory failure, heart failure, and sepsis. three other case reports of covid-19 encephalopathy have been documented, one each from the usa [15] , iran [17] , and italy [29] , with an age group spanning 30-75. all three cases presented with symptoms of fever and cough for a duration of approximately 5 days before the onset of confusion and asthenia. ct and magnetic resonance imaging (mri) of the brain were unremarkable. electroencephalogram (eeg) was employed in the usa and italy case which revealed diffuse slowing consistent with encephalopathy [15, 29] . chloroquine, lopinavir, and ritonavir were administered in the first two cases. at the time of the report, the first patient was critically ill and the second had complete resolution of her symptoms [15, 17] . the third patient showed dramatic response to high-dose steroids and with slightly more than a week of therapy, he was back at baseline mentation with a normal neurological examination [29] . a retrospective observational study from wuhan, china, reported that six (2.8%) patients, out of the 214 reviewed covid-19 cases, developed ischemic stroke. of these six patients, two arrived at the emergency department owing to sudden onset of hemiplegia without any fever or upper respiratory tract symptoms. five of the six patients were severe cases of covid-19. d-dimer levels were high in patients with severe disease, compared to non-severe, as well as in those with cns manifestations, compared to those without [5] . a retrospective observational study from a different center in wuhan, china, found eleven (5.0%) patients, out of 221 reviewed covid-19 cases, developed acute ischemic stroke. those who had covid-19 infection with new onset of ischemic stroke were more likely to have a severe sars-cov-2 presentation, an advanced age (71.6 ± 15.7 years versus 52.1 ± 15.3 years), and preexisting cardiovascular risk factors including hypertension, diabetes, and previous cerebrovascular disease. an increased inflammatory response and hypercoagulable state, typified by raised crp and d-dimer levels, was also more common among these patients [7] . three other cases of ischemic stroke were reported in china among covid-19 patients aged 40-80. each of them initially presented with a dry cough. at least 1 week later, they developed limb weakness, dysarthria, and tongue deviation. a ct scan of the brain revealed basal ganglia infarction in one case; normal findings were reported in the other two cases. laboratory studies showed elevated d-dimer, decreased fibrinogen level, prolonged prothrombin time (pt), and activated partial thromboplastin time (aptt). additionally, serum cytokine levels including il-6, il-8, and il-10, were markedly elevated. all three patients recovered with good functional outcomes after stroke treatment and supportive therapy [13, 26] . oxley et al. reported five cases of large-vessel stroke in patients younger than 50 years of age from the usa. only three cases were symptomatic for covid-19. the mean nihss score was 17 at admission. ct brain, ct angiography, and/or mri revealed severe large-vessel stroke in all patients. all but one underwent mechanical thrombectomy. among these patients, d-dimer, ferritin, pt, and aptt were raised while the fibrinogen level was reduced. one was discharged home, two were transferred to a rehabilitation facility, and two were in the icu/stroke unit at the time of the report [39] . a retrospective observational study from wuhan, china, reported one (0.45%) patient, out of 221 reviewed covid-19 cases, who developed intracerebral hemorrhage. he was a 62-year-old male cigarette smoker who presented to the hospital with a severe case of covid-19. about a week later, he developed an intracranial hemorrhage and died. of note, his blood pressure averaged 150/80 mmhg during treatment [7] . there are two case reports from iran, one of a 79year-old male with no medical history of hypertension or anticoagulation therapy [14] and another of a 54year-old lady with a history of hypertension [38] . both presented with an acute loss of consciousness preceded by fever and dry cough. initial glasgow coma scale (gcs) for them was seven and ten, respectively. coagulation studies were normal for both. the ct brain revealed massive intracerebral hemorrhage in the right hemisphere accompanied by intraventricular and subarachnoid hemorrhage for the former, and bilateral subacute basal ganglia hemorrhage in the latter, and a lung ct scan showed bilateral ground-glass opacities in both cases. the respective authors suspected the intracranial hemorrhage was secondary to infection with sars-cov-2 in both cases. six cases of encephalitis have been described to date; two from china [12, 27] , two from switzerland [31] , one from japan [24] , and one from america [11] . their ages range from early 20s to late 60s. all of them had preceding symptoms of fever and cough followed by a rapidly deteriorating level of consciousness. meningeal irritability in the form of nuchal rigidity, kernig's, and brudzinski's was reported in two out of the six cases [24, 27] . where lumbar puncture (lp) was performed, it showed lymphocytic pleocytosis typical of a viral meningo-encephalitis [12, 24, 31] . sars-cov-2 was detected in the cerebrospinal fluid (csf) in only one chinese patient [12] and japanese patient [24] . for one of the switzerland patients who presented with psychosis and focal status epilepticus, an eeg was done which showed abundant bursts of anterior low-medium voltage irregular spike and waves superimposed on an irregularly slowed theta background. this was managed with intravenous (iv) clobazam and valproate, and she had a marked improvement 96 h after admission with the resolution of her symptoms [31] . ct brain was normal in all but the case of the american whose scan demonstrated symmetric hypoattenuation within the bilateral medial thalami. she had a follow-up mri brain which revealed hemorrhagic, rimenhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. in her case, a presumptive diagnosis of covid-19-associated acute necrotizing hemorrhagic encephalopathy was made, and she was thereafter started on intravenous immunoglobulin (ivig) [11] . the mri of the patient from japan revealed right lateral ventriculitis and encephalitis mainly involving the mesial temporal lobe and hippocampus [24] . mri brain performed for the switzerland patients were normal [31] . at the time of writing, the chinese and switzerland patients recovered completely with supportive therapy [12, 24, 27] , and the outcome of the patients from america and japan is not known. one case of acute disseminated encephalomyelitis (adem) has been reported in new jersey, america [30] . the case was a female in her early 40s who presented with a 2-day history of dysphagia, dysarthria, and encephalopathy preceded by headache and myalgia. covid-19 nasal swab rt-pcr was positive. a lumbar puncture (lp) showed a csf with normal cell counts, protein, and glucose. ct brain showed multifocal patchy areas of white matter hypoattenuation and mri brain showed extensive patchy areas involving bilateral frontoparietal white matter, anterior temporal lobes, basal ganglia, external capsules, and thalami. she was treated with hydroxychloroquine, ceftriaxone, and a 5-day course of ivig. improvement was noted at the 5-day mark of therapy. one covid-19 case from wuhan, china, came with the presentation of acute myelitis. a 66-year-old male, with a 5-day history of fever, was admitted to the hospital after outpatient oral moxifloxacin hydrochloride and oseltamivir failed to improve his symptoms. ct scan of the chest found patchy changes in both lungs, and nasopharyngeal swab tested positive for sars-cov-2. after a night of high fever, he developed bilateral weakness of his lower limbs, with urinary and bowel incontinence, rapidly progressing to flaccid lower extremity paralysis and paresthesia and numbness below t10. planters were down going bilaterally. a clinical diagnosis of post-infectious acute myelitis was made. he received treatment with ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, ivig, and mecobalamin. his bilateral lower extremity paralysis ultimately improved, and he was discharged to a rehabilitation facility [16] . five studies assessed the prevalence of smell disorder. an overall average of 59.45% of patients experienced olfactory disturbance (fig. 2) . additionally, four studies assessed the prevalence of taste disorder. an overall average of 56.48% of patients experienced taste disorder (fig. 2) . a multicenter prospective study by lechien et al., reported time course of the aforementioned disorders. the olfactory dysfunction appeared before, in unison, and after the appearance of general symptoms in 11.8, 22.8, and 65.4% of the cases, respectively. this olfactory abnormality persisted after the resolution of other symptoms in 63.0% of cases [36] . in an iranian study by moein et al., majority of patients with olfactory dysfunction reported that the onset of the olfactory dysfunction occurred at the same time or immediately after the onset of their other covid-19 symptoms [37] . in china, a 65-year-old woman was admitted to the hospital for a left facial droop preceded by a 2-day history of pain in the mastoid region. there was no preceding fever, cough, or respiratory symptoms. physical examination showed a left lower motor neuron facial nerve paralysis. mri brain showed no abnormality. however, a throat swab rt-pcr turned positive for sars-cov-2 virus and the ct chest revealed ground-glass shadows in the right lower lung. the left facial paralysis was relieved after antiviral treatment with umifenovir and ribavirin [28] . toscano et al. reported 5 cases of guillain-barré syndrome (gbs) in covid-19 patients. the interval between the onset of viral illness and the first symptoms of gbs was between 5 and 10 days. the first symptoms of gbs were lower limb weakness and paresthesia in four patients and facial diplegia followed by ataxia and paresthesia in one patient. generalized, flaccid quadriparesis or tetraplegia evolved over a period of 36 h to 4 days in four patients; three received mechanical ventilation. csf analysis showed raised protein levels in two patients and raised lymphocytes in all five patients. csf rt-pcr for covid-19 was negative in all patients. neurological examination and nerve conduction studies were consistent with a demyelinating neuropathy in two patients, while the others were diagnosed as axonal variants of gbs. all five patients were treated with ivig; two received a second course of ivig and one required plasma exchange. four weeks after treatment, two patients remained in the icu and were receiving mechanical ventilation, two were undergoing physical therapy, and one was discharged without any residual symptoms [8] . four other case reports of gbs, one in america [34] , iran [33] , italy [32] , and china [9] , respectively, were reported. age ranged from mid-50s to 70s. all but the chinese patient presented with flu-like symptoms preceding weakness and/or numbness of the lower limbs with a progressive ascending paralysis; the chinese patient presented with neurological symptoms first and respiratory symptoms only on day 8 of admission [9] . in all cases, neurological examination and nerve conduction studies were consistent with a demyelinating neuropathy [9, [32] [33] [34] . where lp was done, an albuminocytologic dissociation was revealed [9, 32] . ivig was administered in the above 4 case reports with variable response. two gbs variants have been described in a case series from spain. specifically, one case of miller fisher syndrome and one case of polyneuritis cranialis associated with covid-19 was described. the former case was a 50-year-old man who presented with anosmia, ageusia, right internuclear ophthalmoparesis, right fascicular oculomotor palsy, ataxia, areflexia, albuminocytologic dissociation, and positive testing for gd1b-igg antibodies. five days prior, he had developed a cough, malaise, headache, low back pain, and a fever. the latter case was a 39-year-old man who presented with ageusia, bilateral abducens palsy, areflexia, and albuminocytologic dissociation. three days prior, he had developed diarrhea, a low-grade fever, and a poor general condition. the oropharyngeal swab for covid-19 by rt-pcr was positive in both patients and negative in the cerebrospinal fluid. the first patient was treated with ivig and the second with acetaminophen. two weeks later, both patients made a complete neurological recovery, except for residual anosmia and ageusia in the first case [10] . an overall average of 25.1% of patients reported experiencing myalgia in seven retrospective studies (fig. 2) . the character and course of myalgia was not detailed in any of those studies. mao et al. reported that out of 214 covid-19 patients, skeletal muscle injury occurred in 23 (10.7%). compared with the patients without muscle injury, patients with muscle injury had significantly higher levels of creatine kinase (median 400 u/l [range 203.0 to 12, 216.0] versus median 58.5 u/l [range 8.8-212]; p < 0.001). in addition, patients with muscle injury had higher c-reactive protein (crp) levels and d-dimer levels-manifestations of increased inflammatory response and associated coagulopathy. furthermore, patients with muscle injury showed more signs of multiorgan damage, including more serious liver and kidney abnormalities, than patients without muscle injury [5] . a case report by jin et al. described a 60-year-old man in wuhan who presented with a 6-day history of fever and cough and a ct chest which showed bilateral ground-glass opacities. rt-pcr analysis of the patient's throat swab specimen indicated sars-cov-2 infection. he was treated supportively and with antivirals and antibiotics. on day 9 of admission, the patient complained of pain and weakness in his lower limbs, and tenderness was noted on examination. urgent laboratory reports indicated raised myoglobin (> 12,000.0 μg/l), creatine kinase (11,842 u/l), lactate dehydrogenase (2347 u/l), alanine aminotransferase (111 u/l), and aspartate aminotransferase (213 u/l). the patient's kidney function and electrolytes were normal. urinalysis revealed a lightyellow color of the urine, with positive occult blood and positive urine protein. these results indicated the onset of rhabdomyolysis. in addition to ongoing supportive therapy, the patient was treated with hydration, alkalization, plasma transfusion, and gamma globulin. the patient improved subsequently [25] . coronavirus contains four structural proteins, including the spike protein (s), envelope protein (e), membrane protein (m), and the nucleocapsid protein (n). among them, the s protein plays the most important role in virus attachment, fusion, and entry. sars-cov-2, like sars-cov, recognizes the angiotensin-converting enzyme 2 (ace2) as a host cell entry receptor [41] . high expression of the ace2 receptor is seen in type ii alveolar cells of the lung, intestine, esophagus, cardiomyocytes, proximal tubular cells, and urothelial cells [42] . glial cells and neurons have been reported to express ace2 receptors, making the brain a potential target of covid-19 infection [43] . how the virus enters the central nervous system is still a subject of debate. one plausible route of entry is through the olfactory nerve. retrograde transfer into the axon, whether through synapses, endocytosis, or exocytosis, could explain viral migration into the brain [44, 45] . experimental studies using transgenic mice suggest that sars-cov and mers-cov may enter the central nervous system intranasally through the olfactory nerve. once in the brain, they have the potential to spread to the thalamus and brain stem, two regions highly involved in coronaviridae infections [46] [47] [48] . a study evaluating specific receptors in the nasal mucosa, however, suggest sars-cov-2 may reach the brain through mechanisms independent of axonal transport via olfactory sensory nerves [49] . another theory suggests if sars-cov-2 gained access to the general circulation, it could potentially invade the cerebral circulation and continue viral spread [43] . slow movement in the cerebral microvasculature may promote interaction of the sars-cov-2 s protein and capillary endothelium ace2 receptor. once bound, the virus would have the potential to infect, damage, and bud from the capillary endothelium, thereby facilitating viral entry into the cerebrum [43, 50] . sars-cov-2 could also cause damage to the central nervous system indirectly. viruses do not have to enter the brain to cause damage; they can activate an immune response that triggers subsequent damage within neuronal tissue. sars-cov-2 has been reported to cause a massive release of cytokines, a syndrome known as "cytokine storm"-downstream effects of this immune response include endothelial damage, disseminated intravascular coagulation, and disrupted cerebral autoregulation [51, 52] . common symptoms elucidated from our systematic review include myalgia, headache, altered sensorium, hyposmia, and hypogeusia. acute viral respiratory tract infections have already been shown to cause the aforementioned neurological symptoms [53] . peri-and postinfectious hyposmia and hypogeusia is hypothesized to be secondary to olfactory nerve and/or apparatus damage from direct insult of viral infection [54] . according to the multicenter prospective european study by lechien et al., it appears that a large number of covid-19 patients experience olfactory and gustatory symptoms. in their study, olfactory and gustatory dysfunction occurred in 85.6 and 88.8% of patients, respectively, with a majority of patients (65.4%) experiencing abnormalities in olfaction after the appearance of their general symptoms [36] . we found that in covid-19 patients, altered sensorium and encephalopathy were not uncommon. the basic pathological change seen in this disease is cerebral edema, with key clinical features being headache, confusion, delirium, loss of consciousness, seizure, and coma. covid-19 patients with encephalopathy were, by large, older male patients with cardiovascular comorbidities and severe infection with systematic inflammation and multi-organ dysfunction. early identification of covid-19 patients with altered sensorium is critical, as underlying potential reversible causes, including impending respiratory failure, require timely intervention [55] . the pathophysiology behind the cerebral dysfunction is hypothesized to be in part inflammatory-mediated [56] . this is supported by the fact that the encephalopathic italian patient had a dramatic response to high-dose steroids [29] . ischemic stroke is another clinical entity which can present in patients with covid-19 infection. this presentation may arise secondary to a cytokine storm syndrome [51] , which can cause endothelial damage, disseminated intravascular coagulation, and disrupted cerebral auto-regulation [52] . through the ace2 receptor of the vascular endothelium, the virus's extensive invasion of the vascular endothelium obviously may cause extensive endotheliitis, increasing the risk of thrombosis leading to ischemic stroke. critically ill patients with severe sars-cov-2 infection often show elevated levels of d-dimer, a fibrin-degraded product which serves as a marker of dysfunctional activation of the coagulation system, such as in acute ischemic stroke [1, 5, 57] . however, it is observed that the stroke prevalence in covid-19 patients and non-covid-19 patients are similar. two retrospective studies in wuhan, china, reported prevalence rates of between 2.8-5.0% of acute ischemic stroke [5, 7] which is consistent with the stroke prevalence in northeast china prior to the outbreak [58, 59] . although the biochemistry suggests an association of covid-19 with disorders of the coagulation system, further studies are warranted to establish a relationship. for the three cases of covid-19-associated intracerebral hemorrhage, a few potential explanations exist. it is known that the expression and the ability of ace2 receptor to lower blood pressure is reduced in patients with hypertension. in sars-cov-2 infection, the presence of s protein could further reduce the expression and function of ace2 proteins. this could potentially lead to uncontrolled hypertension, arterial wall rupture, and cerebral hemorrhage in infected patients [56] . moreover, if the virus disseminates within the cerebral microvasculature, subsequent damage of capillary endothelial cells could result in a tear of the vasculature sufficient enough to cause parenchymal hemorrhage [43] . additionally, covid-19 patients have been reported to have thrombocytopenia and coagulopathy, both of which are contributory factors for secondary brain parenchymal hemorrhage [5, 60] . it is still unknown how covid-19 causes encephalomyelitis. it is thought that once viral particles gain entry into the milieu of the neuronal tissue, their interaction with the ace2 receptors in neurons could initiate a cycle of viral budding accompanied by neuronal damage. this can occur without substantial inflammation [43] . in other cases, it may cause an acute inflammatory demyelination resulting in adem, which was described in one covid-19 case [30] , and previously in mers-cov [61] . covid-19 is also thought to cause acute hemorrhagic encephalitis through the mechanism of a cytokine storm [11] . acute hemorrhagic leukoencephalitis is a rare demyelinating disorder that is usually fatal; icu care, use of high-dose corticosteroid therapy, immunoglobulins, plasma exchange, and dehydrating agents have led to survival in only some patients [62] . this has been seen in one covid-19 case thus far [11] . three neuro-immunological entities related to covid-19 infection surfaced in our systematic review: acute transverse myelitis, gbs and its variants, and bell's palsy [9, 16, 28] . the time course of the disease is alike what is known for other viruses known to cause the above in that the symptoms of respiratory or gastrointestinal infection usually precede that of the neuroimmunological phenomena [63] . this was seen in all cases in this report with the only exception being the gbs case report from china [9] . this suggests that the underlying mechanism of such neuro-immunological phenomena in covid-19 patients is likely to be grounded by the hypothesis of molecular mimicry, where mimicry between microbial and nerve antigens is thought to be a major driving force behind the development of the disorder [63] . there are a number of limitations in our study. most of the studies included in this systematic review are case reports/series and retrospective observational studies. the larger retrospective studies included were limited to the documentation of common neurological symptoms, such as headache, myalgia, and a loss in sense of taste and/or smell. furthermore, the timeliness of our systematic review presents potential for premature analysis of data trends in the literature. given the current pandemic, the authors of this study felt that the benefits of systematic data retrieval and review outweighed current risks of inaccurate predications. our aim was to synthesize data to aid physicians currently treating the novel covid-19, knowing time constraints inhibited their own analysis of the evolving literature on neurological manifestations. our systematic review comprehensively detailed the neurological manifestations of covid-19 known to date. respiratory symptoms remain the hallmark of early identification, cohorting, and treatment of covid-19, bearing in mind that in a number of cases it has been observed that neurological manifestations may precede it in the course of the disease. clinical characteristics of coronavirus disease 2019 in china clinical features of patients infected with 2019 novel coronavirus in wuhan covid-19 in critically ill patients in the seattle region-case series neurologic complications of coronavirus infections neurologic manifestations of hospitalized patients with coronavirus disease the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration acute cerebrovascular disease following covid-19: a single 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biorxiv preprint neurotropism of sars-cov 2: mechanisms and manifestations preventing covid-19-induced pneumonia with anticytokine therapy inflammatory cytokines and ischemic stroke risk: the regards cohort aneta nitsch-osuch and ls. pathophysiology of clinical symptoms in acute viral respiratory tract infections hypogeusia, dysgeusia, hyposmia, and dysosmia following influenza-like infection covid-19: icu delirium management during sars-cov-2 pandemic nervous system involvement after infection with covid-19 and other coronaviruses surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (covid-19) prevalence of stroke and associated risk factors: a population based cross sectional study from northeast china prevalence, incidence, and mortality of stroke in china: results from a nationwide populationbased survey of 480 687 adults coagulopathy and antiphospholipid antibodies in patients with covid-19 severe neurologic syndrome associated with middle east respiratory syndrome corona virus (mers-cov) acute hemorrhagic leucoencephalitis guillain-barré syndrome publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none we received no funds for conducting this study. ethics approval and consent to participate not applicable. not applicable. none of the authors has any conflict of interest to disclose. we confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. key: cord-104180-f3hoz9bu authors: kirk-bayley, justin; venn, richard title: recently published papers: inflammation, elucidation, manipulation? date: 2003-07-03 journal: crit care doi: nan sha: doc_id: 104180 cord_uid: f3hoz9bu nan the search for the marker in sepsis and inflammation continues. perhaps when we do find it we may be able to alter and influence the underlying pathophysiology of sepsis. many reports from those who believe that this may lie in the hypothalamic-pituitary-adrenal axis have recently been published. manglik and colleagues [1] looked into secondary adrenocortical insufficiency in patients who present with severe sepsis. measuring maximal cortisol secretion after stimulation with adrenocorticotrophic hormone, those investigators found that 9% of their population failed an adrenocorticotrophic hormone stimulation test. four per cent had previously undiagnosed pituitary disease and 5% were suffering from sepsis-related adrenal dysfunction. they used absolute cortisol levels and not delta cortisol to define adrenocortical insufficiency, but until we have an established definition for adrenocortical insufficiency in sepsis the studies will continue to yield disparate results. looking at reduced endogenous steroid levels in sepsis, marx and coworkers [2] focused on the androgens dehydroepiandrosterone (dhea) and its sulphated precursor (dheas) and looked at disparity between survivors and nonsurvivors from severe sepsis. the cortisol levels of survivors reached upper normal limits and decreased significantly toward late sepsis. however, nonsurvivors had persistently lower cortisol levels (but within the normal physiological range) throughout sepsis. dheas paralleled this in survivors, with normal early levels reducing in late sepsis, but in nonsurvivors levels were persistently low throughout and to a significant degree. survivors had persistently elevated levels of dhea as compared with nonsurvivors. marx and coworkers showed that relative adrenocortical insufficiency extends to androgens, that dhea and dheas changes do not parallel each other, and that dheas levels may even predict survival in severe sepsis, which apache (acute physiology and chronic health evaluation) scores do not. so will stress doses of hydrocortisone attenuate severe systemic inflammatory response syndrome after cardiac surgery with cardiopulmonary bypass? kilger and coworkers [3] would suggest that in high-risk patients this is so. they found that severe systemic inflammatory response syndrome (serum interleukin-6 concentration >1000 pg/ml) was best predicted in their population by a bypass time in excess of 97 min and cardiac ejection fraction below 40%. thus, by targeting their predefined high-risk patients to receive hydrocortisone, they showed recipients to have significantly lower interleukin-6 levels, reduced duration of ventilation and catecholamine support, and reduced duration of stay in the intensive care unit and the hospital. nothing yet suggests a mortality benefit though. increased tissue factor is produced as part of the septic inflammatory process because the coagulation cascade is activated too. carraway and coworkers [4] have already shown that pretreating baboons with active site-inactivated factor vii and tissue factor pathway inhibitor at the onset of sepsis attenuates organ injury and is protective for lung and kidney. they have now shown that similarly blocking tissue factor in established gram-negative sepsis will attenuate this damage [5] . using a baboon model again, they blocked coagulation cascade initiation using active site-inactivated factor vii at the time of first antibiotic therapy after inducing sepsis. this resulted in reduced acute lung injury, renal injury, metabolic acidosis and sepsis-induced coagulopathy. can we manipulate this therapeutically in human sepsis? time and more research will tell. moving away from direct involvement of the inflammation/ coagulation process, soliman and colleagues [6] looked at how the ionized portion of serum magnesium varies in the critically ill. they found that ionized magnesium level at presentation did not affect outcomes (two-thirds of their population had normal levels), but that the development of reduced levels of ionized magnesium while in intensive care was associated with higher mortality and more severe organ dysfunction. sepsis was an independent risk factor for ionized hypomagnesaemia, but soliman and colleagues postulated that prolonged disease and diuretic administration may also be contributory. it may be that low levels contribute to critical illness, or that just the converse is true. which is true is unclear. what we need now is to discover how magnesium supplementation will alter these findings. inappropriate ventilatory strategies for patients with acute respiratory distress syndrome (ards) may have more consequences for the recipient than just lung abnormalities. imai and colleagues [7] indicated that remote cellular damage also occurs and that this may contribute to the multiple organ dysfunction that often accompanies ards. they looked at end-organ epithelial cell apoptosis in a rabbit model of ards and at the effects of plasma on epithelial cells from recipients of the injurious ventilatory strategy, and analyzed samples from a previous trial into lung protective ventilation [8] . they showed that kidney and small intestine damage occurred when ventilation with high tidal volumes and low positive end-expiratory pressures were used, and that plasma from rabbits in this group would induce apoptosis in cells in vitro. the fas-fas ligand system is involved in cell apoptosis, and they found elevated levels of soluble fas ligand in human patients who had not received a protective ventilatory strategy, which correlated well with elevations in creatinine levels. choosing the right ventilation strategy for ards patients has more benefits than just lung protection, and therapeutic targeting of these factors that induce end organ apoptosis may be the next step. choosing the right ventilation strategy may not be the only way to avoid lung problems in patients with ards. desirable strategies involve the prevention of over-distended alveoli and their de-recruitment. thus, it is not unreasonable to consider that periodic endotracheal suctioning might undermine these benefits. maggiore and colleagues [9] set out to find out whether this was so in patients with acute lung injury, and considered preventative measures. they found that closed suctioning systems reduced large lung volume falls and preserved positive end-expiratory pressure induced recruitment. recruitment was augmented by performing recruitment manoeuvres at the time of suctioning. repetitive shearing stresses on alveoli are injurious, and this study shows some ways to prevent this. using inhaled nitric oxide (no) in patients with ards improves oxygenation, but it has not been proven to improve outcome. why is this so? gerlach and coworkers [10] looked at dose-response characteristics when long-term no is used and found that these characteristics changed. patients could become sensitized to no, such that the number of responders to low no doses increased and some became nonresponders at higher no doses. it would seem that constant dose no is not right for all patients throughout their treatment, and that there is more inter-patient and intrapatient no dose-response variability than we had thought. titrating doses at each step may improve long-term benefits from no therapy. with respect to inotropes, which one should we use? the debate continues. de backer and colleagues [11] compared inotropes and their effects on the splanchnic circulation in sepsis. dopamine was used and then substituted for either adrenaline (epinephrine) or noradrenaline (norepinephrine) to achieve or maintain adequate arterial pressures depending on shock severity. the three inotropes were comparable in moderate shock, and dopamine would actually appear to have modest benefits for splanchnic circulation. however, in more severe septic shock adrenaline impaired splanchnic circulation, and de backer and colleagues suggested that it should be avoided in high doses in these patients. a larger, truly randomized trial should determine whether they are correct. however, if you use low dose dopamine in critically ill patients for renal protection, holmes and walley [12] tell us that the practice should be, "relegated to the place of hightidal volume ventilation and liberal transfusion practices". glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons blockade of tissue factor: treatment for organ injury in established sepsis development of ionized hypomagnesemia is associated with higher mortality rates injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experi-critical care effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial prevention of endotracheal suctioning-induced alveolar derecruitment in acute lung injury dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? bad medicine: low-dose dopamine in the icu on the physiologic and clinical relevance of lung-borne cytokines during ventilator-induced lung injury discrepancies between perceptions by physicians and nursing staff of intensive care unit end-of-life decisions a randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation activated protein c inhibits the expression of platelet-derived growth factor in the lung treatment of acute respiratory distress syndrome with recombinant surfactant protein c surfactant impact of randomized trial results on acute lung injury ventilator therapy in teaching hospitals none declared. as well as the references cited in the text, i also recommend the following. key: cord-336314-xf6zvvl8 authors: hu, lijuan; gong, linjing; jiang, zhilong; wang, qibing; zou, yunzeng; zhu, lei title: clinical analysis of sinus bradycardia in patients with severe covid-19 pneumonia date: 2020-05-26 journal: crit care doi: 10.1186/s13054-020-02933-3 sha: doc_id: 336314 cord_uid: xf6zvvl8 nan there were cases of sudden death in some patients infected with covid-19 including a few of young physicians, which had a huge impact on medical community and society [1] . the unexpected phenomenon lets us think about the underlying problems that caused the sudden death and some issues maybe ignored and that should be appropriately resolved. the initial manifestation of severe covid-19 pneumonia patients was hypoxemic respiratory failure, accompanied by rapid increased reactive heart rate and susceptibility to supraventricular arrhythmia [2] . it is notable that a proportion of these patients developed sinus bradycardia, which was significantly different from other patients with multiple types of respiratory failure. in addition to lung injury, cardiac injury has often been reported in patients with covid-19 [2] . some experts believed that the virus invasion into myocardium led to severe myocarditis or the severe "cytokine storm"induced acute myocardial injury may explain the sudden death in some affected patients [3] . it is noteworthy that about 1/3 of the patients with severe illness in our study developed sinus bradycardia (fig. 1) . the troponin and probnp were basically normal among these patients except for those with renal failure ( table 1 ). the clinical characteristics of explosive myocarditis and myocardial infarction were not presented among these patients, suggesting these are not the cause of sinus bradycardia in these patients. it was previously reported that no pathological evidence of myocarditis or myocardial microinfarction was observed in the heart of suffered patients [4] , consisting with our results. therefore, we speculated that sudden death among some severe patients with improved symptoms post-treatment may be caused by severe arrhythmia such as ventricular fibrillation induced by severe sinus delay. we found that sinus bradycardia often occurred during sleep. so, deep sleep or sedation may be an important risk factor for sinus bradycardia. a few patients had mild to moderate decreased thyroid function, which was consistent with secondary pathological thyroid syndrome and may also be one of the causes of sinus bradycardia. when viral nucleic acid tests gradually turned negative, the heart rate returned to normal no matter whether the patient's condition improved or worsened and the uses of catecholamine were gradually discontinued. according to the results, we speculated that the inhibitory effect of virus on sinus node activity was the main cause of sinus bradycardia in these patients. previous study indicated that covid-19 invaded host cells via the receptor angiotensin-converting enzyme 2 (ace2) [5] . zou et al. identified specific cell types including myocardial cells which were vulnerable to covid-19 infection through scrna-seq data analyses [5] . however, there was no severe myocardial damage or cardiac insufficiency in our patients with sinus bradycardia. we referred the gene ontology (go) enrichment analysis for ace2 gene in genecards database (https:// www.genecards.org/). biological processes (bp) for ace2 gene showed that it not only promoted the contraction of cardiac muscle, but also regulated the cardiac conduction. donoghue et al. demonstrated that cardiac ace2 overexpression in transgenic mice caused sudden death in a gene dose-dependent fashion; they also found that increased ace2 expression led to progressive conduction and rhythm disturbances with lethal ventricular arrhythmias via detailed electrophysiology [6] . in light of those evidences, it may be speculated that the toxic role of virus on cardiac conduction system instead of that generated myocardial damage resulted in a sudden death of patients infected with covid-19. taken together, heart rate monitoring of severe covid-19 pneumonia patients should be strengthened during treatment, and catecholamines should be appropriately applied when necessary. moreover, a possible inhibitory influence of the virus on activity of cardiac nervous conduction system including sinus node via ace2 should not be ignored when studying the pathogenic mechanisms among these patients. epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with 2019 novel coronavirus in wuhan critical care management of adults with community-acquired severe respiratory viral infection pathological findings of covid-19 associated with acute respiratory distress syndrome single-cell rna-seq data analysis on the receptor ace2 expression reveals the potential risk of different human organs vulnerable to 2019-ncov infection heart block, ventricular tachycardia, and sudden death in ace2 transgenic mice with downregulated connexins publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable authors' contributions lz and yzz conceived the study idea. lz, yzz, ljh, and ljg participated in the study design. zlj and qbw gathered the data and performed the data analyses. all authors interpreted the data analyses. all authors co-wrote and revised the manuscript for intellectual content. lz and yzz read and approved the final manuscript. the study was financially supported by the national natural science the data used to support the findings of this study are available from the corresponding author upon request.ethics approval and consent to participate ethical approval for this study was reviewed and approved by the ethics committee of zhongshan hospital, fudan university (shanghai, china). the authors declare no conflict of interest. all the authors listed have approved the manuscript.received: 23 april 2020 accepted: 30 april 2020 key: cord-310997-ulgemn42 authors: swai, joel title: letter to the editor—mortality rate of acute kidney injury in sars, mers, and covid-19 infection: a systematic review and meta-analysis date: 2020-09-11 journal: crit care doi: 10.1186/s13054-020-03239-0 sha: doc_id: 310997 cord_uid: ulgemn42 nan letter to the editor-mortality rate of acute kidney injury in sars, mers, and covid-19 infection: a systematic review and metaanalysis joel swai * dear editor, i have read with interest the published article entitled "mortality rate of acute kidney injury in sars, mers, and covid-19 infection: a systematic review and metaanalysis" by chen et al. [1] . the article is well written, and i have three concerns as explained below. firstly, the mortality rate for covid-19 patients with aki is different in the text (i.e., 76.5%; 95% ci 61.0-89.0) from one reported in the authors' figure 1 (i.e., 78.0%; 95% ci 63.0-90.0). the authors might need to clarify this discrepancy. secondly, the authors mistakenly made a duplicate entry of the study by chen et al. (2020) in the covid-19 forest plot. this mistake resulted in a pooled aki mortality rate of 78.0% (ci 63.0-90.0), i 2 = 97.1%, p < 0.0001, instead of 53.99% (ci 52.34-55.65), i 2 = 98.4%, p < 0.0001, had the authors sorted the duplicate-entry problem. thirdly, the authors concluded the mortality rate for covid-19 patients with aki from an otherwise a high heterogeneity of i 2 = 97.1%, p < 0.0001. this strongly impacts the reliability of the conclusion drawn [2] . i, on the other hand, reanalyzed authors' data and performed sensitivity analysis according to the cochrane library recommendation [3] [4, 5] . the nine remaining studies represented all-asian chinese hospitalized patients with covid-19 and aki. the newly obtained mortality rate for covid-19 patients with aki was 94.90% (ci 91.47-98.34), with nonstatistically significant heterogeneity, i 2 = 7.4%, p < 0.375, see fig. 1 . sensitivity analysis could not be conducted in mers and sars outcomes because of an insufficient number of studies. authors' response to "joel swai. letter to the editor-mortality rate of acute kidney injury in sars, mers, and covid-19 infection: a systematic review and meta-analysis" we thank dr. joel swai for the interest in our research letter. as the author pointed out, the reported results of mortality rate for coronavirus disease 2019 (covid-19) patients with acute kidney injury (aki) is different from the text and figure 1c in the original publication of our article [1] . the problem is that we mistakenly made a duplicate entry of the chen et al. (2020) study while performing the covid-19 forest plot. we have noticed this critical issue and sent the correct proof before the article publication; unfortunately, this mistake had not been accurately revised by the production team. we sincerely regret the inaccuracy may cause any inconvenience to the readers. however, there are no changes to the interpretation of the results, conclusions, and applications of our article. in details: 1. there was no evidence of statistical heterogeneity among studies reporting aki mortality in sars (i 2 = 0.0%, p = 0.589) and mers (i 2 = 0.0%, p = 0.758), but there was for covid-19 infection (i 2 = 97.0%, p < 0.0001). 2. figure 1c : in addition, our research letter aimed to overview the aki mortality in patients with different coronaviruses, but the clinical heterogeneity between studies should be also noted. one of the important factors may be the racial difference between studies as dr. joel swai noted. even if the recent study from fisher et al. indicated the races are not associated with mortality in covid-19 patients developing aki [6] , future large meta-analyses may be suggested to explore the clinical impacts from different races in aki mortality in covid-19 patients. mortality rate of acute kidney injury in sars, mers, and covid-19 infection: a systematic review and meta-analysis limitations of meta-analyses of studies with high heterogeneity updated guidance for trusted systematic reviews: a new edition of the cochrane handbook for systematic reviews of interventions covid-19 in racial and ethnic minority groups, inc.; c2020 [updated the association of race and covid-19 mortality aki in hospitalized patients with and without covid-19: a comparison study asn.2020040509 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.author's contributions js drafted the manuscript. js revised the manuscript critically for valuable intellectual content. js approved the final manuscript. there was no external funding regarding the letter.availability of data and materials not applicable. ethics approval and consent to participate not applicable. not applicable. the author has no conflict of interest to declare.received: 28 july 2020 accepted: 12 august 2020 key: cord-337444-pqoq8aew authors: doi, kent; ikeda, mahoko; hayase, naoki; moriya, kyoji; morimura, naoto title: nafamostat mesylate treatment in combination with favipiravir for patients critically ill with covid-19: a case series date: 2020-07-03 journal: crit care doi: 10.1186/s13054-020-03078-z sha: doc_id: 337444 cord_uid: pqoq8aew nan development of specific therapy against severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is urgently required. several drugs such as antimalarial and anti-ebola virus drugs are under investigation for coronavirus disease 2019 . transmembrane protease serine 2 (tmprss2) plays a crucial role for sars-cov-2 entry into the cytoplasm [1] . inhibition of tmprss2 protease activity is assumed to prohibit viral entry of sars-cov-2. through high-throughput screening of 1017 existing drugs, a clinically available serine protease inhibitor nafamostat mesylate was identified as a potent inhibitor of middle east respiratory syndrome coronavirus entry into human epithelial cells [2] . more recently, nafamostat mesylate was shown to inhibit the entry of sars-cov-2 into the human epithelial cells at ec 50 of~10 nm [3, 4] . nafamostat mesylate has been clinically used for the treatment of acute pancreatitis and disseminated intravascular coagulation in japan. by intravenous administration, its blood concentrations are maintained at 30-240 nm, which are sufficient to block the virus entry [3] . an anti-influenza a h1n1 virus drug favipiravir exhibits antiviral activity against other rna viruses and therefore is expected to have antiviral action against sars-cov-2. this drug has been approved in japan for novel influenza virus disease. eleven adults with reverse transcriptase polymerase chain reaction-confirmed sars-cov-2 infection were admitted to the intensive care unit (icu) at the university of tokyo hospital between april 6 and april 21, 2020, and treated with nafamostat mesylate in combination with favipiravir. the demographic and clinical characteristics and the laboratory and radiologic findings at icu admission are listed in table 1 . all the patients needed oxygen therapy. eight patients (73%) needed invasive mechanical ventilation (mv), and 3 patients (27%) needed venovenous extracorporeal membrane oxygenation (vv-ecmo). patients received combination treatment with nafamostat mesylate [0.2 mg per kg per hour by continuous intravenous infusion, median treatment 14 days (iqr, 10 to 14 days)] and favipiravir [3600 mg on day 1 and at 1600 mg per day on day 2 and subsequently median treatment 14 days (iqr, 12 to 14 days)]. no interruption of antiviral treatment occurred due to adverse drug reactions except for one patient who developed hyperkalemia on day 9 (by nafamostat mesylate). all 11 patients had at least 33 days of hospital follow-up. as of may 22, 1 patient, who had a do-not-resuscitate order, died on icu day 7. seven patients were successfully weaned from mv [median duration of mv 16 days (iqr, 10 to 19 days)] and 9 and 7 patients were discharged from the icu and the hospital, respectively (fig. 1) . this is the first report on nafamostat mesylate treatment in combination with favipiravir against covid-19. in comparison with previous reports about critically ill patients with covid-19, our case series also demonstrated a high number of patients (8 [73%]) who required mv requirement; however, the mortality rate was low (1 patient [9%]). patients with severe covid-19 often suffer from microvascular thrombosis and hemorrhage with extensive alveolar and interstitial inflammation in the lung [5] . nafamostat mesylate might thus be effective, because it inhibits intravascular coagulopathy, in addition to directly targeting the virus entry in host epithelial cells. in conclusion, nafamostat mesylate therapy in combination with favipiravir may allow blockade of virus entry and replication, as well as inhibition of pathogenic host response, i.e., hyper-coagulopathy. although the number of patients in this case series was very small, this low mortality rate suggests that combination treatment of favipiravir and nafamostat mesylate may be effective for critically ill covid-19 patients. a clinical trial for the combination treatment of nafamostat mesylate and favipiravir against covid-19 will be initiated in japan (jrcts031200026). sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor identification of nafamostat as a potent inhibitor of middle east respiratory syndrome coronavirus s protein-mediated membrane fusion using the split-protein-based cell-cell fusion assay the anticoagulant nafamostat potently inhibits sars-cov-2 infection in vitro: an existing drug with multiple possible therapeutic effects nafamostat mesylate blocks activation of sars-cov-2: new treatment option for covid-19 immune mechanisms of pulmonary intravascular coagulopathy in covid-19 pneumonia publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations collaborating author names from covid-uth study group, which will be searchable through their individual pubmed records: hiromu maehara, m.d. 1 authors' contributions kd, mi, and km designed the study and had full access to all data in the study and take responsibility for the integrity of data and the accuracy of the data analysis. nh contributed to the data collection, data interpretation, literature searches, and clinical management. mi and km had roles in the management of treatment of favipiravir and nafamostat mesylate. km and nm supervised this study and contributed to the writing of the manuscript. all authors contributed to the data acquisition, data analysis, or data interpretation, and reviewed and approved the final version of the manuscript. availability of data and materials full de-identified data of the analyses are available upon request to the corresponding author.ethics approval and consent to participate this case series was approved by the institutional review board at the university of tokyo (#3820). the institutional treatment board at the university of tokyo hospital approved the treatment protocol of antiviral agents of favipiravir and nafamostat mesylate (#2020001cl). informed consent for treatment was obtained from each patient or legal representative. one author (ji) has submitted a provisional application for a patent related to this work to uspto under the application no. 62988962. the other authors declare that they have no conflicts of interest with the contents of this article. key: cord-300897-lih5f6cj authors: du, bin; xi, xiuming; chen, dechang; peng, jinmin title: clinical review: critical care medicine in mainland china date: 2010-02-25 journal: crit care doi: 10.1186/cc8222 sha: doc_id: 300897 cord_uid: lih5f6cj critical care medicine began in mainland china in the early 1980s. after almost 30 years of effort, it has been recognized as a specialty very recently. however, limited data suggest that critical care resources, especially icu beds, are inadequate compared with those of developed countries. national critical care societies work together to set up good practice standards, and to improve academic levels with scientific meetings, education programs, and training courses. critical care research in mainland china is beginning to evolve, with great potential for improvement. although advanced life support techniques, especially positive pressure ventilation, inspired the development of critical care medicine in europe and north america in the 1950s, critical care medicine is still one of the newest disciplines of clinical medicine in mainland china. as in many other countries, critical care was initially practiced in a variety of postoperative recovery rooms and/or an isolation area within the general ward. it is well recognized that the fi rst icu in mainland china was set up in the peking union medical college hospital in 1982, in the form of a surgical icu with only one bed [4, 5] . two years later, it became the fi rst department of critical care medicine in mainland china, with a seven-bed general icu in the peking union medical college hospital, chaired by dr dechang chen, the well-recognized founding father of critical care medicine in mainland china. in november 1989, the ministry of health issued the regulation of hospital accreditation and management, which required the establishment of an icu as a prerequisite for accreditation as a tertiary hospital [4, 5] . many icus were set up in hospitals all over china following the release of this document. many physicians (including general surgeons, internists, emergency physicians, and anesthesiologists) were sent to other hospitals for critical care training, either abroad or domestically, before returning to practice as intensivists [4, 5] . in mainland china, physicians of other relevant specialties were the fi rst to be assigned to work in icus because of their familiarity with the necessary techniques (anesthesiologists), disease entities (surgeons and internists), and required urgency of treatment (emergency physicians). however, after years of hard work, the important role of intensivists, as a coordinator during patient evaluation and treatment, has gradually been recognized and respected by other specialties. junior physicians interested in critical care training can choose to be intensivists after they fi nish 3 or 4 years of fellowship training in surgery or internal medicine. however, the traditional specialties often still assume responsibility for or 'ownership' of patients, as well as have a desire to treat critically ill patients, as refl ected by the fact that the proposal for setting up a critical care society under the chinese medical association (cma) was rejected in 1996. public healthcare crises in china since 2003 have provided intensivists with an opportunity to demonstrate their knowledge and skills. epidemics of severe acute respiratory syndrome (sars) in 2003, of streptococcus suis in 2005, and of avian infl uenza, as well as the wenchuan earthquake in 2008, caused extreme anxiety in the public due to the vulnerability of the general population, the high communicability of the diseases, and the high case fatality rate. th erefore, intensivists were often convened by the government to be involved in crisis management very early [6] . th eir ability to coordinate, cooperate, and communicate with regard to both patient management and policy-making was well demonstrated during daily work, and recognised by the general public and healthcare authorities. as a result, critical care medicine was offi cially recognized as a specialty of clinical medicine in 2009 [7] . th ere is no census on critical care resources in china, including the number of icus, intensivists, icu nurses, and relevant facilities (for example, bedside monitors, artifi cial ventilators), because no national survey has ever been performed. we performed computerized literature searches of the china academic journals full-text database of the china national knowledge infrastructure. we used the search terms 'intensive care unit' or 'intensive care' or 'critical care unit' and 'survey' , and found only eight relevant papers concerning critical care resources in mainland china [8] [9] [10] [11] [12] [13] [14] [15] that were published within the past decade (table 2) . unfortunately, none of these eight papers selected a representative sample of icus in china. table 2 summarizes data from these eight papers [8] [9] [10] [11] [12] [13] [14] [15] , in addition to those of the china critical care clinical trial group (cccctg) [16] . based on the above data, we made a rough estimation that, in mainland china, icu beds might account for 1.8% (interquartile range 1.3% to 2.1%) of total hospital beds [8] [9] [10] [12] [13] [14] [15] [16] . in 2008, the ministry of health reported that there were a total of 2,882,862 beds in 19,712 hospitals in china [3] . th erefore, we estimate that there were 51,891 (37,477 to 60,540) icu beds in china in 2008, corresponding to 3.91 (2.82 to 4.56) icu beds per 100,000 population, with 217 hospital beds per 100,000 population. th is fi gure is comparable to that of the united kingdom (3.5 icu beds per 100,000 population), which was the lowest of eight countries in north america and western europe [17] . among all icus, about half were closed (mean 51.6%, range 45% to 73.5%), more than one-third were semiclosed (mean 36.3%, range 26.9% to 41.9%), and the others were open icus (mean 12.1%, range 0% to 18%) [8] [9] [10] [12] [13] [14] [15] . th e relative distribution of specialty icus versus general icus was not uniform across the country, with specialty icus making up from 35% (shandong) to 66% (jiangsu) of units, or 34% (shandong) to 53% (beijing) of icu beds [10, 11, 15] . in addition, the icu nurse-to-bed ratio ranged from 1.37 to 2.02 [8] [9] [10] [11] [12] [13] [14] [15] [16] , corresponding to 71,091 to 104,820 icu nurses in mainland china. according to limited data, there is no signifi cant diff erence in icu beds and nurse-to-bed ratios between coastal areas and inland areas. although there are usually more icu beds in tertiary hospitals than local hospitals, there is no diff erence in nurse-to-bed ratio. even few data are available for bedside monitors, mechanical ventilators, and dialysis machines, which preclude the possibility of making any estimation. th ere has been no large-scale observational study about case mix in chinese icus, although some data are available. among 443 patients receiving mechanical ventilation for more than 48 hours in 26 icus, mean age was 62.4 ± 19.5 years, and 298 (67.3%) were male [18] . medical reasons accounted for 58.2% of all icu admissions, followed by emergency surgery (22.8%), and elective surgery (19.0%) [18] . data from the cccctg showed that, among 38,922 patients admitted to 24 icus in 2007 and 2008, about two-thirds (66.2 ± 23.0%) were treated with invasive mechanical ventilation, pulmonary artery catheters or arterial pulse contour analysis was used in 2.9 ± 3.6% of patients, and continuous renal replacement therapy was used in 12.2 ± 11.4% of patients [19] . th e hospital mor tality rate was 13.1 ± 8.6% [19] . a 12-month prospective observational study in 10 surgical icus identifi ed 8.68% (318/3,665) of patients had severe sepsis, with a hospital mortality rate of 48.7% [20] . prospective and retrospective observational studies suggested that 2.0% to 25.1% of icu patients developed acute respiratory distress syndrome [18, [21] [22] [23] ; the hospital mortality rate ranged from 52.0% to 68.5% [21] [22] [23] . th e mean hospital cost for severe sepsis was usd 11,390 ± 11,455, and the mean daily cost was usd 502 ± 401 [20] , corresponding to 794% and 35% of annual income per capita in 2008 (table 1 ). as mentioned above, anesthesiologists, general surgeons, emergency physicians and pulmonologists are all involved in icu management in mainland china. th eir infl uence is well described by the presence of critical care sections although the cma refused to set up a critical care society in 1996, the fi rst national critical care society in mainland china was established in 1997, called the chinese society of critical care medicine (csccm), and currently has about 500 members. th e major objective of the csccm is to provide a multidisciplinary platform for promoting critical care medicine all over china, provide expert opinion to the government and other bodies, and encourage both national and international academic exchange. th e csccm organizes a 3-day biennial national conference, with attendees increasing from 200 in 1997 to more than 1,000 people in 2006, including physicians, nurses, and company representatives. in 2006, the csccm hosted the 14th international congress of the asia pacifi c association of critical care medicine (apaccm) in beijing. th e scientifi c program included 16 plenary lectures, 130 lectures and workshops by 57 speakers from 19 countries. th is was the fi rst time that an international conference on critical care medicine had ever been held in mainland china, a milestone demonstrating more involvement in the international community. since its establishment, the csccm has developed close relationships with multiple international profes sional societies, such as the society of critical care medicine (sccm), the european society of intensive care medicine, the société de réanimation de langue française, the apaccm, and the world federation of societies of intensive and critical care medicine (wfsiccm). right now, the csccm is the only member society representing mainland china in both the wfsiccm and apaccm. th e second national critical care society, the chinese society of intensive care medicine, was established in 2005 under the cma (csicm-cma). csicm-cma has been working actively to enact clinical practice guidelines, including nutritional support, mechanical ventilation, and sepsis management. th e third national critical care society, the chinese association of critical care physicians (caccp), was founded in july 2009. as an affi liation to the china medical doctors association, the aim of the caccp will include professional certifi cation of intensivists. th ese three societies have the common philosophy to cooperate with each other in the future because they share almost the same leadership. at present, there is no formal accredited critical care training program in china. residents can choose critical care medicine as their specialty after graduation from medical school. rotation in other departments, such as anesthesia or internal medicine, is not obligatory, and is organized according to institution and department requirements. on the other hand, residents may consider critical care medicine as a subspecialty after fi nishing a fellowship training program in internal medicine, anesthesia, general surgery, or emergency medicine. icu physicians can register as intensivists (for those working in general icus), or, alternatively, remain registered under their primary specialty of anesthesiology, internal medicine, general surgery or emergency medicine (for those working in specialized icus) [7] . in mainland china, most nursing education programs employ only a 3-year curriculum after senior high school. although colleague education programs have become more and more popular, there is still a signifi cant demand for professional education for nurses. in 2003, the beijing nursing association started to implement a critical care nurse certifi cation program, with around 150 trainees every year. th e program is composed of 1 month of lectures and 1 month of clinical practice, followed by examination of knowledge and skills. trainees are also required to fi nish a review before certifi cates are issued. in 2007, the china nursing association followed the same model in order to meet the need in other cities in mainland china. respiratory therapists are present in only a few icus. sichuan university set up the fi rst program of respiratory therapy in a medical school in mainland china in 2002 [24] . th e lack of a national accredited critical care training program is believed to be a major obstacle for improving professional education in china. although access to state-of-the-art advances might be available during national and international conferences, basic knowledge and skills are inadequately, and sometimes incorrectly, taught in many hospitals. for the past 5 years, the csccm has dedicated itself to promoting professional education with regard to basic knowledge and skills in critical care medicine. th e csccm successfully organizes a fundamental critical care support course, a funda mental disaster management course, and a multiprofessional critical care review course, with support from the sccm. in 2007, the csccm endorsed the basic assessment and support intensive care course, and promoted the course in mainland china. nine provider courses have been organized until november 2009, with more than 220 participants. however, an advanced training program is still under development, and the number of trainees is very limited compared with the large number of intensivists in mainland china. more over, a national board exam for critical care medicine is not yet available, which suggests that we do not have a minimum national standard for intensivists. critical care research in mainland china is in its infancy. most study results are published in national medical journals in the chinese language, while very few investigators succeed in publishing their studies in peerreviewed international medical journals. possible reasons might include: inadequate training and experience in clinical research; inadequate staffi ng dedicated to research; inadequate funding for critical care research; and inadequate language profi ciency. however, chinese intensivists have become more actively involved in international multicenter studies during recent years. for example, a total of 1,135 patients in 57 icus in mainland china were enrolled in an observational study, accounting for 21% of patients and 14% of icus (s finfer, unpublished data). th is suggests a great potential for future improvement in clinical research in mainland china. considering the above limitations and potential improve ment, we do believe that chinese intensivists may benefi t from academic exchange with the international medical community with regard to the following: development of a series of training programs fulfi lling international standards; development of a national board exam for critical care medicine; and conduction of multicenter trials compatible with good clinical practice. overall, critical care medicine in mainland china is still in a phase of development. after years of dedicated hard work, critical care medicine has been recognized as a specialty by the government and other specialties. however, due to scarce resources and limited experience, critical care training and clinical research are still underdeveloped, which also represents a great potential for future improvement. health systems: improving performance. geneva: world health organization statistical communique of the people's republic of china on the ministry of health: statistical communiqué of people's republic of china on the 2008 national healthcare development on exploration into critical care medicine and disciplinary construction the emergence and development of icu on behalf of the china critical care clinical trial group: natural disaster. in intensive and critical care medicine: wfsiccm world federation of societies of intensive and critical care medicine ministry of health of the people's republic of china the fi rst questionnaire survey of present situation of intensive care unit in whole country the survey of icu for neonates and children in china a questionnaire survey of present situation of icu in jiangsu province investigation on establishment and management of intensive care units in 64 hospitals in beijing a survey of general intensive care units in guangxi survey of present situation of intensive care unit in hospitals and construction of intensive care network in guangdong province a survey of present situation of general intensive care unit in second grade hospitals and construction of intensive care network in guangdong province the questionnaire survey of present status of intensive care units in shandong province china critical care clinical trials group; cccctg participating centers: summary of clinical information variation in critical care services across north america and western europe an investigation on current practice of nutrition support for critically ill in chinese icu china critical care clinical trials group; cccctg participating centers: summary of icu admissions epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in china a 12-month clinical survey of incidence and outcome of acute respiratory distress syndrome in shanghai intensive care units retrospective analysis on acute respiratory distress syndrome in icu epidemiological investigation on acute respiratory distress syndrome occurring in anonymous: introduction of program on respiratory therapy critical care medicine in mainland china the authors declare that they have no competing interests.published: 25 february 2010 key: cord-292335-al6v3b9x authors: crotty, matthew p.; meyers, shelby; hampton, nicholas; bledsoe, stephanie; ritchie, david j.; buller, richard s.; storch, gregory a.; kollef, marin h.; micek, scott t. title: impact of antibacterials on subsequent resistance and clinical outcomes in adult patients with viral pneumonia: an opportunity for stewardship date: 2015-11-18 journal: crit care doi: 10.1186/s13054-015-1120-5 sha: doc_id: 292335 cord_uid: al6v3b9x introduction: respiratory viruses are increasingly recognized as significant etiologies of pneumonia among hospitalized patients. advanced technologies using multiplex molecular assays and polymerase-chain reaction increase the ability to identify viral pathogens and may ultimately impact antibacterial use. method: this was a single-center retrospective cohort study to evaluate the impact of antibacterials in viral pneumonia on clinical outcomes and subsequent multidrug-resistant organism (mdro) infections/colonization. patients admitted from march 2013 to november 2014 with positive respiratory viral panels (rvp) and radiographic findings of pneumonia were included. patients transferred from an outside hospital or not still hospitalized 72 hours after the rvp report date were excluded. patients were categorized based on exposure to systemic antibacterials: less than 3 days representing short-course therapy and 3 to 10 days being long-course therapy. results: a total of 174 patients (long-course, n = 67; short-course, n = 28; mixed bacterial-viral infection, n = 79) were included with most being immunocompromised (56.3 %) with active malignancy the primary etiology (69.4 %). rhinovirus/enterovirus (23 %), influenza (19 %), and parainfluenza (15.5 %) were the viruses most commonly identified. a total of 13 different systemic antibacterials were used as empiric therapy in the 95 patients with pure viral infection for a total of 466 days-of-therapy. vancomycin (50.7 %), cefepime (40.3 %), azithromycin (40.3 %), meropenem (23.9 %), and linezolid (20.9 %) were most frequently used. in-hospital mortality did not differ between patients with viral pneumonia in the short-course and long-course groups. subsequent infection/colonization with a mdro was more frequent in the long-course group compared to the short-course group (53.2 vs 21.1 %; p = 0.027). conclusion: this study found that long-course antibacterial use in the setting of viral pneumonia had no impact on clinical outcomes but increased the incidence of subsequent mdro infection/colonization. interactions between viral and bacterial respiratory pathogens have been recognized dating back to the 1918 influenza pandemic [1] . bacterial pneumonia is a wellrecognized serious complication of influenza infections and coinfections are commonplace [2] [3] [4] [5] [6] [7] [8] [9] [10] . respiratory syncytial virus (rsv), parainfluenza viruses, rhinoviruses, and adenoviruses have also been linked to bacterial coinfections in humans [11] [12] [13] [14] [15] [16] [17] [18] . animal studies have suggested synergism between bacterial pathogens and other respiratory viruses [19, 20] . the relationship between viral and bacterial respiratory infections creates a difficult situation for clinicians determining the appropriate use of antimicrobials as they treat hospitalized patients with pneumonia while also trying to minimize the development and selection of resistant organisms. respiratory viruses are increasingly recognized as the primary etiology of pneumonia among patients requiring hospitalization (2.7-5 % of pneumonia cases) [21, 22] . advanced technologies using multiplex molecular assays and pcr improve the diagnostic ability to identify viral pathogens in a timely manner and may impact the use of antibacterials in patients with no bacterial infection identified. several studies have investigated the impact of respiratory viral pathogen identification on antibacterial exposure [23] [24] [25] [26] . decreased antibiotic use was observed in two pediatric studies assessing the impact of rapid viral diagnostic tests for respiratory tract infections; however, these results were not mirrored in similar adult studies [23] [24] [25] . these studies all used immunofluorescent staining as the primary diagnostic technology. to our knowledge, only one study using pcr-based respiratory virus detection has been reported and found no change in antibacterial use with improved diagnoses for lower respiratory tract infections [26] . broad-spectrum antibacterial exposure increases the risk of subsequent infections with multidrug-resistant organisms (mdros) and leads to a vicious cycle of empiric broad-spectrum antibacterials to combat increasingly resistant organisms [27] . we and others have previously shown that patients with culture-negative pneumonia frequently receive treatment with broadspectrum antibiotics, usually in excess of 5-6 days of therapy despite lack of evidence for a bacterial etiology of infection [28, 29] . it is important to recognize that these studies were performed prior to the availability of rapid viral diagnostics which may have influenced how antibiotics were used during those study periods. use of new diagnostic technologies for respiratory virus detection could decrease unnecessary antibacterial exposures and subsequent mdro infections. this study aimed to describe the use of continued empiric antibacterials in patients with known viral pneumonia and to determine the impact of such therapies on subsequent bacterial infections/colonization and clinical outcomes. this was a single-center, retrospective cohort study of patients with a positive respiratory virus panel (rvp) at barnes-jewish hospital (bjh) (a 1300-bed urban academic medical center in st. louis, mo, usa) between 1 march 2013 and 7 november 2014. the study protocol was approved by the bjh, washington university, and st. louis college of pharmacy institutional review boards. consecutive patients who were ≥19 years of age and admitted to bjh for ≥24 hours were assessed for study inclusion. patients were identified through a query of an internal database which tracks respiratory viruses. patient admissions in which a respiratory virus was identified by filmarray ® respiratory panel (farp) assay (biofire diagnostics, salt lake city, ut, usa) were screened for inclusion in this study. included patients had to meet the study definition of viral pneumonia. patient admissions were excluded if rhinovirus or enterovirus was identified by nasopharyngeal (np) swab alone but could also be included if identified from lower respiratory tract specimens. additionally, patients were excluded if there was a virus identified by rvp within the previous 90 days or if a bacterial pathogen was identified by the respiratory panel. patients who were transferred from an outside hospital and those who were discharged/died or were made comfort care less than 72 hours after the index rvp report date were also excluded to better evaluate continued empiric antibacterial use in this population. the farp assay is a multiplexed nucleic acid test capable of simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids. viral pneumonia was defined as identification of a respiratory virus by farp and a new or progressive radiographic infiltrate within 48 hours of the index rvp. short-course antibacterial administration was defined as treatment with systemic antibacterials for less than 3 days while long-course therapy was defined as 3-10 days of antibiotics after the index rvp report date with no bacterial infection identified at any point during the admission. mdros were defined as methicillin-resistant staphylococcus aureus (mrsa), vancomycin-resistant enterococci (vre), or a bacterium exhibiting in vitro resistance to at least one drug in ≥3 classes of antibacterials for which the organism is not intrinsically resistant [30] . subsequent isolation of a mdro was defined as isolation of a study-defined mdro or a positive epidemiologic screen (mrsa np swab; vre stool specimen) ≥10 days after the report date of the index rvp. positive epidemiologic screens for mrsa or vre were only considered to be subsequent colonization of an mdro if the patient had at least one screen in the previous 180 days and all screening tests were negative prior to the index rvp. immunocompromised status was defined as a diagnosis of human immunodeficiency virus (hiv), active malignancy (stem cell transplant or receiving chemotherapy), solid organ transplant, or currently on immunosuppressive therapy (prednisone 20 mg/day for at least 30 days or equivalent). information regarding the farp including time of collection/report, type of specimen, patient location at time of collection, and resulting findings were obtained from an internal database. additionally, all available aerobic and anaerobic bacterial cultures were evaluated based on electronic medical record (emr) query. in vitro susceptibilities of isolated bacterial pathogens were evaluated as reported per institutional practices. urine legionella antigen, direct-fluorescent antibody for pneumocystis jiroveci, and clostridium difficile toxin assay were also evaluated. data collected to describe patient groups included demographic information, comorbid conditions, and clinical outcomes. charlson's comorbidity index was used as a summative score of underlying disease states [31] . antibacterial exposures were calculated using emr orders for systemic antibacterials. days of therapy (dot) and dot normalized per 1000 patient-days (dot/1000pd) were calculated as described previously [32] . emr queries were used to acquire patient information where possible. manual chart review was used to validate and supplement all emr queries. the primary endpoint was subsequent isolation of a mdro ≥10 days after the index rvp report date. inhospital mortality and readmission at 30, 90, and 180 days were secondary endpoints. dichotomous variables were compared using the chisquare test or fisher's exact test as appropriate. continuous variables were compared using the mann-whitney u test. all tests were two-tailed and p <0.05 was considered significant. univariate analyses were performed to compare the group that received long-course antibacterials and the group that received short-course antibacterial therapy. kaplan-meier survival analysis was used to compare risk of in-hospital mortality between comparator groups while censoring for patient discharge. all statistical analyses were performed using spss software (ibm spss statistics, version 22.0; chicago, il, usa). a total of 174 consecutive patients (long course, n = 67; short course, n = 28; mixed bacterial-viral infection, n = 79) were included in this study (fig. 1 ). demographic and clinical characteristics are summarized in table 1 . the median age was 57 years and 46.0 % were male. a majority of patients in the cohort were deemed to be immunocompromised (56.3 %), with active malignancy the most common etiology (69.4 %). only 5 of 174 patients had been admitted within the 90 days prior to the index admission. figure 2 provides a breakdown of the subgroup of patients screened in the emergency department setting according to the presence of pure viral and mixed infections. rhinovirus/enterovirus (23.0 %), influenza (19.0 %), and parainfluenza (15.5 %) were the viruses most commonly identified in the cohort ( table 2 ). of the total 174 patients, 11 had multiple respiratory viruses identified by rvp: rsv (5 of 11), rhinovirus/enterovirus (5 of 11), influenza (4 of 11), human metapneumovirus (3 of 11), parainfluenza (2 of 11), coronavirus (2 of 11), and adenovirus (2 of 11). specimens resulting positive for a respiratory virus in the cohort included np swabs (40.8 %), bronchoalveolar lavage (25.9 %), tracheal aspirates (18.4 %), bronchial washes (9.8 %), and sputum samples (4.0 %). the rvp identified a respiratory virus from multiple specimens in 25 patients. among the 25 patients with multiple positive specimens, the most common were bronchoalveolar lavage (19 of 25 patients) and tracheal aspirates (13 of 25 patients). no significant differences in comorbidities between groups were identified ( table 1) . patients with mixed viral-bacterial infection had statistically greater apa-che ii scores and were more likely to require vasopressor support compared with patients with pure viral infection. there was no significant difference in the number of immunocompromised patients between groups, although numerically more patients who received long-course antibacterials had an active malignancy or solid organ transplant compared with patients receiving short-course therapy. virus types identified by farp assay were similar in all three patient groups ( table 2 ). the bacterial coinfecting organisms identified in patients with mixed viral-bacterial infection are presented in table 3 . respiratory coinfection with a bacterial pathogen was most common, with s. aureus, streptococcus pneumoniae, and pseudomonas aeruginosa accounting for the most frequent respiratory coinfecting bacteria. a total of 13 different systemic antibacterials were used as empiric treatment in patients with viral pneumonia without bacterial coinfection for a total of 466 dot. vancomycin (50.7 %), cefepime (40.3 %), azithromycin (40.3 %), meropenem (23.9 %), and linezolid (20.9 %) were the most frequently used empiric antibacterials in patients with viral pneumonia without bacterial coinfection (fig. 3) . the most common regimens used in viral pneumonia without bacterial coinfection were vancomycin plus cefepime (28.4 %) and vancomycin plus meropenem (13.4 %). a total of 44 (65.7 %) patients with viral pneumonia without bacterial coinfection received empiric mrsa coverage with vancomycin or linezolid. empiric antibacterial therapy was continued for a median of 4.1 days (interquartile range, 2.5-6.1 days) in viral pneumonia without bacterial coinfection, with most (69 %) being days on intravenous antibacterials. total antibacterial exposure differed between the longcourse and short-course groups at 2116 and 484 dot/ 1000pd, respectively ( the number of patients with subsequent mdro colonization or infection was not significantly different between groups (table 4 ). however, in instances of subsequent infection or colonization, where a single patient could have more than one organism, there was a higher rate of mdro identification among isolates from the group that received long-course antibacterials compared with the group receiving short-course therapy (53.2 vs. 21.1 %; p = 0.027) ( table 4) in-hospital mortality was statistically higher for the mixed-infection group compared with the long-course therapy group (table 4) . kaplan-meier survival analysis showed that the mixed-infection group had the lowest overall survival, but these differences were not statistically icu admit was determined to be oncology related if the patient fit the study definition for active malignancy *statistically significant difference (p <0.05) between long-course and mixed-infection groups **statistically significant difference (p <0.05) between short-course and mixed-infection groups bmi body mass index, cci charlson's comorbidity index, copd chronic obstructive pulmonary disease, esrd end-stage renal disease significant (fig. 4) . icu mortality was also significantly higher for patients in the mixed-infection group compared with the long-course therapy group. patients receiving long-course therapy or those with mixed infection had statistically longer icu length of stay compared with patients receiving short-course therapy. hospital readmission rates were similar between groups at 30, 90, and 180 days after index hospitalization discharge. this study compared a cohort of 174 patients with viral pneumonia and mixed viral-bacterial infection based on exposure to continued empiric antibacterials after respiratory virus identification. more of the subsequent infecting or colonizing bacterial isolates from the group with pure viral pneumonia who received continued long-course antibacterials were defined as mdros compared with the short-course group (p = 0.027). these findings suggest that more prolonged exposure to broad-spectrum antibacterials in patients with viral pneumonia may have promoted resistance in these patients. no benefit of continued empiric antibacterials for patients with pure viral pneumonia was seen in this study. the risk of bacterial coinfection in the setting of viral pneumonia, especially with influenza, creates a challenging situation for clinicians. the potential detrimental impact of not treating a bacterial pathogen weighs data expressed as number (% of total) or median (interquartile range) los length of stay, mdro multidrug-resistant organism, mrsa methicillin-resistant staphylococcus aureus, vre vancomycin-resistant enterococci *statistically significant difference (p <0.05) between short-course and long-course groups **statistically significant difference (p <0.05) between long-course and mixed-infection groups ***statistically significant difference (p <0.05) between short-course and mixed-infection groups heavily on the decision process and downstream effects of such therapies may be disregarded. our findings of similar clinical outcomes between patients with pure viral pneumonia who received long-course antibacterials after virus recognition and those who did not may suggest opportunity for de-escalation of empiric antibacterial therapy when viral pneumonia is identified. a previous randomized controlled trial by oosterheert et al. [26] evaluated implementation of real-time pcr rapid diagnostics for respiratory pathogen identification. they found increased diagnostic yield with the assay but no difference in antibiotic use, and hypothesized that reluctance to change treatment based on testing results may have inhibited cost-effectiveness from being demonstrated. in our study, systemic antibacterials were discontinued following identification of a respiratory virus by rvp for several patients; however, whether virus identification directly led to discontinuation of antibacterials cannot be determined. the willingness of prescribers to de-escalate and stop antibacterials in this setting may suggest increased recognition of the role of viral pathogens in pneumonia. additionally, the expanded panel of viruses detected may have factored into how results were perceived, as prescribers may have been more likely to attribute pneumonia to newly detectable viruses such as human metapneumovirus. however, it is not possible to definitively determine the rationale for stopping antibacterial therapy. timely antibiotic administration is crucial for treating hospitalized patients with suspected pneumonia [33] . antimicrobial de-escalation attempts to balance the use of these essential drugs up front with the emergence of resistance [34] . the optimal strategy for de-escalation of antibacterials in the setting of viral pneumonia without an identified bacterial coinfection is unclear. our study found no difference in clinical outcomes based on antibiotic duration of therapy in patients with viral pneumonia despite significantly different total antibacterial exposure (dot/1000pd) between groups. byington et al. [24] found previously that improved diagnostic technologies enhancing detection of respiratory viruses decreased antibacterial use at a children's hospital. the authors concluded that improved diagnostics are an important tool in decreasing unnecessary antibacterial prescribing. our study similarly illustrated the potential impact of respiratory virus diagnostics on antibacterial use in an adult population. c. difficile infection is a major cause of morbidity and mortality in us hospitals and has been directly linked to exposure to broad-spectrum antibiotics [35, 36] . in a cohort of hospitalized adult patients, shiley et al. [37] found that significantly more patients who continued to receive antibacterials after diagnosis of a viral respiratory tract infection developed c. difficile infection. one patient in our study who was treated with long-course antibacterials after identification of a respiratory virus also developed c. difficile infection. strategies to best limit the use of unneeded antibacterials are important to curtail against the growing issues of c. difficile and resistance, and may be aided by de-escalation approaches using enhanced viral diagnostic technologies. limitations of this study should be noted. first, this was a small retrospective cohort study of patients at a single institution and may not be representative of all settings. it is important to note that bjh is a regional specialty referral hospital and not a community hospital. this accounts for the case mix with a high prevalence of immunosuppressed patients and the low prevalence of narrow spectrum empiric antibiotic utilization. the small number of patients meeting inclusion criteria did not allow for definitive conclusions to be made regarding group comparison as a lack of statistically significant differences being found could be due to the lack of sample size. second, patients were determined to have viral pneumonia based on virus identification and radiographic findings but other markers of illness, such as white blood cell count and fever, were not considered and the retrospective nature of the study did not allow evaluation of what drove continuation of antibacterials in some patients but not others. moreover, we did not attempt to identify risk factors associated with pure viral pneumonia. third, although coinfecting bacterial pathogens were not identified in patients with pure viral pneumonia, it is impossible to prove that they were not present. receipt of antibacterials prior to obtaining bacterial cultures could have limited the diagnostic yield of bacterial cultures in some cases and yield from bacterial cultures is not perfect. finally, all of the viral pneumonia cases occurred in a 20-month period. viral epidemiology during this time may not be representative of all seasons. influenza h1n1 p2009 was the primary influenza virus identified in our study (85 %). incidence rates of bacterial coinfection and coinfecting organisms may differ from year to year and from virus type to virus type, which may hinder application of de-escalation strategies using the results of this study. it is not possible to directly link the development of subsequent mdro infections/colonization and c. difficile infection seen in our study to the continued empiric antibacterials administered. all of the patients included in the cohort received antibacterials at some point during their index hospitalization and infection control measures were not directly assessed in these patients. additionally, hospitalization itself probably increases the risk of these patients being colonized with mdros. use of cephalosporins and vancomycin, two of the most commonly administered empiric agents in our study, have been implicated as increasing the prevalence of vre, the most commonly identified subsequent mdro in this study [38, 39] . decreasing exposure to broad-spectrum antibacterials such as third-generation and fourth-generation cephalosporins and vancomycin would be expected to lessen the incidence of vre and other mdros as was seen in this study, but the risk of development and transmission of resistance in the hospital cannot be completely eliminated. antibacterials are extraordinarily important in the treatment of many hospitalized patients and their use is often warranted. decreasing unnecessary use may help curb acquirement of resistant organism in healthcare settings but even appropriate use can lead to the development of resistance. only through multifaceted efforts of infection control and antimicrobial stewardship can the spread of mdros between patients, clinicians, workers, and visitors be diminished. this study highlights the potential benefits of improved diagnostics for respiratory viruses, primarily the potential for decreased antibacterial exposure and thus decreased selective pressure for resistant bacterial isolates. antibacterial exposure applies selective pressure and promotes colonization/infection by resistant organisms including mrsa and vre [40, 41] . halting this process is essential to maintain effective therapeutic options in the future and may be aided by discontinuation of antibacterials in cases of viral pneumonia. in our study, patients with viral pneumonia exposed to long-course antibacterials had more occurrences of subsequent infection or colonization with mdro isolates. in contrast, the number of patients with subsequent mdro infection or colonization was not different between groups although this may be due to the small number of patients in each group. no differences in clinical outcomes, including in-hospital mortality and readmission rates, were observed between patient groups. in the setting of viral pneumonia and no coinfecting bacterial pathogens, discontinuation of antibacterials is reasonable in many if not most cases, and may allow for decreased overall antibacterial use. enhanced diagnostic technologies can potentially be incorporated into antimicrobial stewardship practices to allow for de-escalation of unnecessary antibacterials. these findings warrant further investigation to determine the applicability of an antibacterial deescalation approach in the setting of viral pneumonia. in this single-center retrospective cohort, patients with viral pneumonia who continued to be treated with systemic antibacterials 3 days after virus identification were more likely to have a subsequent infection or colonization with a mdro than were patients in whom systemic antibacterials were stopped. in-hospital mortality based on kaplan-meier survival analysis and readmission rates were not different between 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staphylococcus aureus (mrsa) isolation? a systematic review and meta-analysis vancomycin-resistant enterococcal infections submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution submit your manuscript at www authors' contributions mpc and stm conceived the study. mpc, stm, djr, mhk, rsb, and gas participated in the study design. nh and sb performed the electronic medical record queries. mpc and sm conducted data collection and managed the data, including quality control. mpc and stm analyzed the data and interpreted the results. mpc, stm, and djr drafted the manuscript, and all authors contributed substantially to its revision. all authors read and approved the manuscript. key: cord-331700-5rfgyiit authors: martin, greg title: epidemiology studies in critical care date: 2006-04-04 journal: crit care doi: 10.1186/cc4897 sha: doc_id: 331700 cord_uid: 5rfgyiit epidemiology studies are an essential part of clinical research, often forming the foundation for studies ranked more highly in the hierarchy of evidence-based medicine. studies of sepsis to date have been conducted on local, regional, national and international scales, with the majority conducted in the past 5 years. longitudinal epidemiology studies convey an important additional aspect of the healthcare burden from disease, and may additionally serve to compare the effectiveness and efficiency of healthcare systems, to examine specific patient care strategies and to perform quality control analyses. critical care epidemiology studies, of which the current study from the intensive care national audit and research center database is a good example [1] , serve a variety of purposes that advance the mission of both practicing intensive care unit (icu) physicians and scientific researchers. at the most basic level, epidemiology studies convey important information about disease characteristics, the type of patients affected, and the frequency and outcomes of the disease. importantly, these studies keep medical events in perspective. epidemiology studies report and reinforce the frequency of deaths related to atherosclerotic disease, cancer and sepsis in developed countries, and of deaths from a variety of infectious diseases and sepsis in developing countries. these reminders are essential in an era of increasing media attention on diseases such as severe acute respiratory syndrome and avian influenza that are less immediate public health concerns. descriptive epidemiology studies also inform intensivists about the type of conditions they should expect to encounter in their icu (i.e. the frequency of disease) and they guide clinicians in treating patients by reporting information on relative causality (such as streptococcus pneumoniae being the most common cause of community-acquired pneumonia). local and regional epidemiology data have long been disseminated to tailor therapy for infectious diseases based on local organism resistance patterns. in contrast, larger epidemiology studies are invaluable for determining healthcare resource allocation and for the design and conduct of both observational and interventional clinical trials. longitudinal studies add a vitally important characteristic to point-prevalence or time-limited epidemiology studies. they permit characterization of temporal changes in affected patients and in disease characteristics, such as in the frequency, complications and outcomes of a disease. longitudinal studies also permit more detailed planning for healthcare resource allocation, in particular by matching temporal changes in disease or disease-specific outcomes with known changes in underlying patient populations (e.g. hiv-positive) or according to rendered treatments (e.g. antibiotics, chemotherapeutics). longitudinal epidemiology studies on a local level can be utilized for quality control purposes, to assess the impact of changes in healthcare delivery. in general, longitudinal studies are invaluable for understanding how a disease is changing and how it affects patients in the studied healthcare system. division of pulmonary and critical care, emory university school of medicine, atlanta, georgia, usa, and medical and coronary intensive care, grady memorial hospital, atlanta, georgia, usa epidemiology studies that cross physical and geopolitical borders permit broader comparisons than would be possible for observations that are geographically constrained. most simply, they allow comparisons to be drawn for diseases according to different pressures, such as differing underlying patient populations and different risk factors for disease. more broadly, when epidemiology studies are conducted they longitudinally create the ability to examine healthcare quality and effectiveness of resource utilization on a regional scale or a national scale in relation to scientific advances. data of this kind are essential for determining the optimal icu utilization for a given condition, tracking the effectiveness and efficiency of healthcare systems according to changes in disease incidence or outcome, and for planning research studies according to the characteristics of the disease. in the present issue of critical care, investigators from the intensive care national audit and research center report the results of a longitudinal study of severe sepsis encompassing england, wales and northern ireland in the past 10 years [1] . these data are indispensable as a baseline assessment for a common and lethal condition in the respective countries, where severe sepsis occupies more than one-quarter of icu beds and carries fatality rates approaching 50%. the data confirm previous secular trends in the incidence and mortality of sepsis [2] [3] [4] and define the severity of disease and heterogeneity of case-mix typical of sepsis. with these data in hand, scientists and healthcare administrators may assess the impact of community interventions designed to reduce the incidence of sepsis or medical therapies that may improve outcomes with sepsis. the value of these data is even more apparent in a system of national healthcare insurance, where tracking of health-related outcomes related to resource allocation is necessary to ensure appropriate healthcare delivery. other large-scale epidemiology studies exist for sepsis, either by sampling locally, [5] regionally [3, [6] [7] [8] [9] , nationally [4, [10] [11] [12] [13] [14] [15] or internationally [16, 17] . few available studies cross systems of care or permit direct comparisons of healthcare delivery strategies. those studies that include longitudinal data provide important additional insights into sepsis epidemiology while minimizing seasonal influences. continued investigation is necessary to optimize healthcare quality and to compare the effectiveness and efficiency of different icu utilization and care strategies, both nationally and internationally. secondary analysis of a high quality clinical database, the icnarc case mix programme database episepsis: a reappraisal of the epidemiology and outcome of severe sepsis in french intensive care units facing the challenge: decreasing case fatality rates in severe sepsis despite increasing hospitalizations the epidemiology of sepsis in the united states from 1979 through 2000 the natural history of the systemic inflammatory response syndrome (sirs). a prospective study academic medical center consortium sepsis project working group: epidemiology of sepsis syndrome in 8 academic medical centers adult-population incidence of severe sepsis in australian and new zealand intensive care units epidemiology of severe sepsis in the united states: analysis of incidence, outcome, and associated costs of care epidemiology of severe sepsis in intensive care units in the slovak republic incidence, risk factors, and outcome of severe sepsis and septic shock in adults. a multicenter prospective study in intensive care units. french icu group for severe sepsis epidemiology of sepsis in victoria, australia epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in england, wales, and northern ireland brazilian sepsis epidemiological study group: brazilian sepsis epidemiological study (bases study) prevalence and incidence of severe sepsis in dutch intensive care units epidemiology of sepsis in norway in 1999 the prevalence of nosocomial infection in intensive care units in europe. results of the european prevalence of infection in intensive care (epic) study. epic international advisory committee sepsis occurrence in acutely ill patients investigators: sepsis in european intensive care units: results of the soap study the author declares that they have no competing interests. key: cord-303893-47lxq8pi authors: jalkanen, juho; hollmén, maija; jalkanen, sirpa title: interferon beta-1a for covid-19: critical importance of the administration route date: 2020-06-12 journal: crit care doi: 10.1186/s13054-020-03048-5 sha: doc_id: 303893 cord_uid: 47lxq8pi nan interferon beta-1a for covid-19: critical importance of the administration route juho jalkanen 1 , maija hollmén 2 and sirpa jalkanen 2* type i interferons, especially ifn-beta, have been appointed as potential leading therapeutics to tackle severe covid-19 and are currently being evaluated in remap-cap and the who's solidarity trial. as a most recent example, combination treatments with ifn-beta, lopinavir-ritonavir, and ribavirin showed that the arm containing ifn-beta was superior in eliminating the virus from the nasopharyngeal swabs in phase ii clinical trial [1] . recent papers on the matter unfortunately fall short of differentiating between subcutaneous (s.c.) and intravenous (i.v.) administration, which are completely different treatments concerning drug exposure and wanted effects in the lung endothelium, which is under attack in covid-19 [2] . we wish to highlight the differences of these two treatment methods and also other crucial aspects of ifn-beta treatment for covid-19 and acute respiratory distress syndrome (ards). a recent report concluded that the pharmacological effects of s.c. vs. i.v. ifn-beta-1a are the same, because they produce similar anti-viral responses [3] . importantly, however, the pharmacokinetics of s.c. vs. i.v. ifn-beta are complete mirror images, "flip-flops" [4] . maximum serum concentrations (cmax) and total exposure through serum concentrations are significantly higher after i.v. than s.c. injections (p = 0.0001). prior corner stone pk studies investigating s.c. vs. i.v. administration of ifn-beta-1a conclude that s.c. administration produces significantly lower drug concentrations and incomplete bioavailability compared to i.v. dosing. the bioavailability via the s.c. route is about one third of that obtained by i.v. injections [4] . for critically ill patients on vasopressors and with very limited peripheral microcirculation, the bioavailability of s.c. dosed ifn-beta becomes even more questionable. ifn-beta is cleared almost solely through its receptor (ifnar). with s.c. dosing, ifn-beta is slowly taken up by the lymphatic system, from which it enters the blood during a number of hours with modest peak concentrations. in contrast, i.v. dosing achieves high serum concentration and efficiently reaches vast capillary beds of central organs, where it is taken up by its receptors without saturating the body and causing unwanted adverse events. this is an important aspect as endothelial dysfunction is connected to covid-19 infection [2, 5] . nonetheless, the purpose of i.v. administered ifn-beta for the treatment of covid-19 and ards is to maximise bioavailability of the drug at the lung vasculature, as well as other vascular beds. this is hardly achieved with s.c. dosing in critically ill patients. ifn-beta increases cd73 in pulmonary capillaries. this is of utmost importance as cd73 is the key enzyme for vascular integrity under hypoxic conditions. the protective effect of ifn-beta on the lung is attributed to the clearance of pro-inflammatory atp and prothrombotic adp from circulation and converting them into highly anti-inflammatory adenosine via amp step by cd73 [6] . it is well known that corticosteroids as immunosuppressors dampen our natural anti-viral responses, and the direct inhibitory effect of corticosteroids on ifn signalling has been reported [7] . still corticosteroids are widely used to treat ards and severe viral respiratory infections even though several studies have shown that corticosteroid use is associated with harm in viral outbreaks such as h1n1 and mers [8] . in fact, reports on using type i ifns for the treatment of mers reveal that the majority of these patients received systemic corticosteroids with ifn. for example, 60% of mers patients received corticosteroids with type i ifn [9] . in the recent interest study investigating the use of i.v. ifnbeta-1a for ards, the primary analyses did not show any benefit for ifn-beta over placebo [10] . however, nearly 60% of the patients received corticosteroids with ifn-beta. further studies revealed that corticosteroids block ifn signalling and the upregulation of cd73 expression in human pulmonary endothelial cells, and combining i.v. ifn-beta with systemic corticosteroids may be even more detrimental than corticosteroids alone [11] . these findings suggest that the different anti-inflammatory pathways triggered by ifn-beta and corticosteroids should not be induced at the same time. immunomodulation is complex, and timing of the treatments is critical. there are a limited number of direct studies on the timing of immunomodulatory treatments such as ifn-beta, but given our basic understanding of human biology and viral defence, we suggest that ifn-beta should be given early to covid-19 patients. in mild cases such as in the recent clinical trial, even s.c. administered ifn-beta was effective [1] , but in more severe cases, i.v. injections are needed to rapidly reach the endothelium. as ards rises together with a cytokine storm, corticosteroids may play a beneficial role during the later fibrotic phase or just by calming down the cytokine storm after ifns have had their impact. this is supported by villar et al. who showed that the use of dexamethasone was associated with better survival in ards [12] . a notable feature of this study is that the enrolled patients were not on steroids when entering the trial. thus, initial endogenous ifn responses had not been tampered. sequential treatment strategy may be the future once we are able to reliably understand the time course of patients' immunological responses. severely ill covid-19 patients with increased levels of plasma cytokines (especially il-6) show signs of immune exhaustion and poor ifn responses [13] . even in such cases, these patients would most likely benefit from ifnbeta, because it is the most potent anti-viral and antiinflammatory agent of all interferons. it can induce the desired immune boost, but simultaneously downregulate il-6 and il-8 [14] and impair extravasation of neutrophils into lungs [15] . ifn-beta is now among the leading candidates to treat covid-19 in various clinical trials, and i.v. and s.c. routes of administration are considered to be equal. this is not the case due to the different bioavailabilities of ifn-beta via i.v. and s.c. injections in target organs. this aspect needs to be taken seriously, when critically ill patients with compromised peripheral circulation are treated. gastrointestinal manifestations of sars-cov-2 infection and virus load in fecal samples from the hong kong cohort and systematic review and meta-analysis pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19 type 1 interferons as a potential treatment against covid-19 receptor-mediated pharmacokinetic/ pharmacodynamic model of interferon-beta 1a in humans endothelial cell infection and endotheliitis in covid-19 purinergic signaling during inflammation the type i interferon signaling pathway is a target for glucocorticoid inhibition clinical evidence does not support corticosteroid treatment for 2019-ncov lung injury ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: a multicenter observational study effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: a randomized clinical trial glucocorticoids inhibit type i ifn beta signaling and the upregulation of cd73 in human lung dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial imbalanced host response to sars-cov-2 drives development of covid-19 ifn-beta-mediated inhibition of il-8 expression requires the isgf3 components stat1, stat2, and irf-9 ifn-beta protects from vascular leakage via up-regulation of cd73 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions all authors contributed to the writing of this comment; the funding agencies did not have any role. the authors read and approved the final manuscript. key: cord-326874-rdwvsm4s authors: wu, chaomin; hou, dongni; du, chunling; cai, yanping; zheng, junhua; xu, jie; chen, xiaoyan; chen, cuicui; hu, xianglin; zhang, yuye; song, juan; wang, lu; chao, yen-cheng; feng, yun; xiong, weining; chen, dechang; zhong, ming; hu, jie; jiang, jinjun; bai, chunxue; zhou, xin; xu, jinfu; song, yuanlin; gong, fengyun title: corticosteroid therapy for coronavirus disease 2019-related acute respiratory distress syndrome: a cohort study with propensity score analysis date: 2020-11-10 journal: crit care doi: 10.1186/s13054-020-03340-4 sha: doc_id: 326874 cord_uid: rdwvsm4s background: the impact of corticosteroid therapy on outcomes of patients with coronavirus disease 2019 (covid-19) is highly controversial. we aimed to compare the risk of death between covid-19-related ards patients with corticosteroid treatment and those without. methods: in this single-center retrospective observational study, patients with ards caused by covid-19 between january 20, 2020, and february 24, 2020, were enrolled. the primary outcome was 60-day in-hospital death. the exposure was prescribed systemic corticosteroids or not. time-dependent cox regression models were used to calculate hazard ratios (hrs) and 95% confidence intervals (cis) for 60-day in-hospital mortality. results: a total of 382 patients [60.7 ± 14.1 years old (mean ± sd), 61.3% males] were analyzed. the median of sequential organ failure assessment (sofa) score was 2.0 (iqr 2.0–3.0). of these cases, 94 (24.6%) patients had invasive mechanical ventilation. the number of patients received systemic corticosteroids was 226 (59.2%), and 156 (40.8%) received standard treatment. the maximum dose of corticosteroids was 80.0 (iqr 40.0–80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0–12.0) days in total. in cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days after adjusting for age, sex, sofa score at hospital admission, propensity score of corticosteroid treatment, comorbidities, antiviral treatment, and respiratory supports (hr 0.42; 95% ci 0.21, 0.85; p = 0.0160). corticosteroids were not associated with delayed viral rna clearance in our cohort. conclusion: in this clinical practice setting, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within 60 days in covid-19 patients who developed ards. the world health organization (who) declared that the outbreak of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) constitutes a pandemic [1] . since the first confirmed case on january 22, 2020, the virus has been emerged in 216 countries. more than 14,765,000 laboratory-confirmed cases were reported, with an average mortality approaching 4.1% as of july 22, 2020 [2] . the spread of sars-cov-2 has led to serious socioeconomic consequences worldwide. currently, there is no specific treatment or vaccine for coronavirus disease 2019 . up to 29% of the covid-19 patients developed acute respiratory distress syndrome (ards) [3] [4] [5] as a consequence of cytokine storm. ards was the major cause of morbidity [6] . adjunctive corticosteroids may be theoretically beneficial [7] , and has been widely used by clinicians to suppression of hyperinflammation in covid-19 patients, especially those with critical illness [3, 5, 8] . however, there was comprehensive controversy on its efficacy [9, 10] , due to the results of observational studies that showed corticosteroid treatment was associated with increased mortality and nosocomial infections for influenza and delayed virus clearance for severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers) [11] . in the early pandemic of covid-19, lower mortality was reported among the critically ill subgroup of sars patients treated with corticosteroids in a retrospective study [12] . since then, evidence is growing that corticosteroid treatment is beneficial for some covid-19 patients. the randomized evaluation of covid-19 therapy (recovery) trial from the uk reported reduced mortality in patients treated with oral or intravenous dexamethasone 6 mg/d for up to 10 days [13] . the efficacy was significant only in severe patients who receiving oxygen or invasive mechanical ventilation. a prospective meta-analysis of 7 rcts of critically ill patients with covid-19 also showed the association between systemic corticosteroids and lower all-cause mortality [14] . other two randomized controlled trials (rcts) did not show benefit on mortality from intravenous dexamethasone or methylprednisolone treatment, but corticosteroid treatment increased ventilator-free days and number of days alive in patients with moderate to severe ards [15, 16] . a meta-analysis of corticosteroids on the mortality of ards showed beneficial effects of corticosteroids on short-term mortality may be counteracted by the delayed onset of adverse effects [17] , such as secondary infection due to immunosuppression and altered tissue repair. a follow-up period of 28 days in these randomized trials may underestimate the late adverse effects of corticosteroids on all-cause mortality. in addition, most of the aforementioned trials studied dexamethasone, and evidence for methylprednisolone was limited. in this observational study, we thoroughly examined the associations of corticosteroid treatment with 60-day in-hospital mortality among a population of covid-19 patients who have developed ards. this single-center, retrospective, cohort study was conducted at the jin yin-tan hospital, wuhan, china. we identified all adult patients with confirmed covid-19 according to who interim guidance [18] and patients were admitted between january 20, 2020, and february 24, 2020. then, we identified those who developed ards according to the who definition for analysis [18] . among these patients, 84 have been described previously by wu et al. [8] , and 91 participated in the open-label trial of lopinavir-ritonavir [19] . to avoid the influence of early mortality before cortical steroid presenting treatment efficacy, patients who died or discharged within 2 days on hospital admission were excluded. other exclusion criteria were: (1) participating in any double-blind clinical trial, (2) under long-term corticosteroid therapy for at least 1 month as part of treatment for chronic underline diseases, or (3) could not provide valid medical history because of mental disease. the jin yin-tan hospital ethics committee approved the study (no. ky-2020-44.01) and granted a waiver of informed consent from study participants. in jin yin-tan hospital, systemic corticosteroids were considered if patients had progressive respiratory failure or laboratory findings indicated the presence of hyperinflammatory response. in patients receiving mechanical ventilation, preventive ventilation strategy of tidal volume 4-8 ml/kg of predicted body weight, inhale positive airway pressure < 30 cmh 2 o, and peep > 5 cmh 2 o was followed. administration of corticosteroids was defined as systemic use (oral or intravenous) of corticosteroids, including methylprednisolone, dexamethasone, hydrocortisone, and prednisone. the primary outcome was keywords: corticosteroids, coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, mortality, propensity score, methylprednisolone 60-day in-hospital mortality. patients were followed to death or discharge from hospital up to 60 days since hospital admission (last clinical outcome was observed on march 21, 2020). the secondary outcomes were time to sars-cov-2 viral clearance since symptom onset. data on demographics, medical history, laboratory findings, chest radiology, medication use, and clinical outcomes were extracted retrospectively from electronic medical records using a standardized data collection form. all data were checked independently by two physicians (dh and xc). from january 11, 2020, to monitor the clearance of viral rna, sars-cov-2 rna was tested using polymerase chain reaction from throat-swab specimens for every other day after clinical remission of symptoms, including fever, cough, and dyspnea [8] . viral clearance was defined as two consecutive negative results. the definitions of ards and other diseases were described in emethods (additional file 1). baseline characteristics were compared between patients with and without corticosteroid treatment. data were reported as percentage for categorical variables and as mean ± standard deviation (sd) or median with interquartile range (iqr, 25-75%) for continuous variables. categorical variables were compared by fisher's exact test or pearson chi-square test, as appropriate, and continuous variables were compared by mann-whitney u test or student's t test. to reduce the effect of steroids treatment bias and potential confounding factors, we performed propensity score analysis [20] to adjust the differences in baseline characteristics. for each patient, a propensity score indicating the likelihood of receiving systemic corticosteroid treatment was calculated by a logistic regression model. the model included 10 pre-selected baseline variables based on the clinical guidelines from national health commission of china, which recommended corticosteroids for patients with progressive respiratory failure and hyperinflammation response. specifically, spo 2 /fio 2 ratio and respiratory rate were included for indicating severe respiratory failure; temperature, heart rate, sofa score, blood lymphocyte count, blood neutrophil count, and level of crp at hospital admission were included for indicating systemic inflammatory response syndrome; age and sex were included as basic characteristics of each patient. the outcome variable was whether or not the patient received corticosteroid therapy in the current hospital stay. goodness of fit was evaluated by the c-statistic and the hosmer-lemeshow test. the effect of corticosteroid treatment on risk of 60-day in-hospital all-cause death was analyzed using a series of cox proportional-hazard regression models. first, we constructed a univariable cox regression model on hospital death by 60 days since hospital admission with corticosteroid treatment treated as a time-varying covariate. then, we constructed a multivariable cox model of 60-day hospital death with corticosteroid treatment as time-varying covariate and incorporated the individual propensity score into the model as a covariable to calculate the propensity adjusted hazard ratio (hr). in the final model, the effects of corticosteroids on 60-day in-hospital death were adjusted for propensity score of corticosteroid treatment, as well as the following pre-selected covariates: age, sex, sequential organ failure assessment (sofa) score at hospital admission, comorbidities (diabetes, hypertension, coronary artery disease, chronic pulmonary disease, chronic renal or liver disease, solid malignant tumor, hematologic malignancy, and immunosuppressive status), antiviral treatment (lopinavir-ritonavir, oseltamivir, and ganciclovir), and respiratory supports (high-flow oscillation oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation) in hospital [9] . several sensitivity analyses were performed to assess the robustness of our findings. to test whether the findings were influenced by the time point of baseline variables used in propensity score analysis, cox proportional-hazard regression models were repeated in sensitivity analyses: (1) comparing patients receiving corticosteroids within 2 days after hospital admission versus no corticosteroids; (2) comparing patients receiving corticosteroids versus no corticosteroids using ards onset date as baseline, where values of spo 2 /fio 2 ratio, respiratory rate, temperature, heart rate, respiratory rate, sofa score, blood lymphocyte count, blood neutrophil count, and level of crp at ards onset were used; (3) comparing patients receiving corticosteroids within 2 days after ards diagnosis versus no corticosteroids with ards onset as baseline. to test whether the findings might be influenced by ards definition, we conducted survival analysis using the same model among patients diagnosed with ards by berlin definition [21] . the difference between berlin definition and who definition was that the latter included patients with spo 2 /fio 2 ≤ 315 when pao 2 is not available, and did not restrict to ventilated patients. differences in the time to sars-cov-2 rna clearance were analyzed using cox proportional-hazard regression adjusted for the same covariables with corticosteroid therapy as a time-varying covariate. patients died without viral shedding or discharged alive before they had two consecutive negative sars-cov-2 rna tests were censored. the associations between c-reactive protein with corticosteroids treatment after ards onset were analyzed using the interaction between corticosteroids and days after ards onset based on a linear regression model. results were analyzed with sas (version 9.4, sas institute, cary, nc). unadjusted and adjusted hazard ratios and their 95% confidence intervals (cis) were reported. two-sided p values less than 0.05 were considered statistically significant. a total of 1147 patients with covid-19 were screened for the study. forty patients were excluded for participating in any double-blind clinical trial (n = 15), death or discharge from the hospital within 2 days after hospital admission (n = 21), underwent long-term corticosteroid therapy for chronic kidney disease or rheumatic disease (n = 3), or no valid medical history provided because of mental disease (n = 1). from 1107 patients remained, 382 patients were identified as ards (additional file 1: fig. s1 ). baseline characteristics of the ards patients at hospital admission by receiving systemic corticosteroid treatment are shown in table 1 . in the entire cohort, the mean age was 60.7 ± 14.1 years, and 234 (61.3%) patients were male. 147 (38.5%) were treated with nimv, 94 (24.6%) with imv, and 11 (2.9%) with ecmo. all but one of the patients reached end point of decease (53.1%) or discharge (46.6%) during the follow-up period of 60 days. the median duration of follow-up was 12.0 (iqr 7.0-18.0) days. a total of 226 (59.2%) ards patients had a prescription of systemic corticosteroids. corticosteroids were more likely prescribed to the younger (p = 0.0077) and males (p = 0.0135). corticosteroids group had lower lymphocyte count and higher levels of crp and lactate dehydrogenase at hospital admission than non-corticosteroids group, indicating a propensity in prescribing corticosteroids to patients with more severe immune dysfunction and inflammatory response ( table 1 ). the 60-day hospital death in patients who ever used corticosteroids was higher than the patients who did not use corticosteroids among patients prescribed corticosteroids, methylprednisolone was the most frequently administered corticosteroids (213/226, 94.2%) ( table 2) in the logistic regression model generating propensity score, the pre-selected variables most closely correlated with prescription of systemic corticosteroids included age, blood lymphocyte count, heart rate and crp (etable 2, additional file 1). the multivariable regression model of propensity for corticosteroid treatment had area under the receiver operating characteristic curve (roc) of 0.71. in survival analysis, univariable time-dependent cox regression model showed the prescription of corticosteroids was associated with a lower risk of death (hr 0.48; 95% ci 0.25, 0.93; p = 0.0285) ( table 3 ). in full model adjusted for age, sex, sofa score, propensity score, comorbidities, antiviral drugs, and respiratory supports, the association remained (hr 0.42; 95% ci 0.21, 0.85; p = 0.0160) (fig. 1) . in sensitivity analysis, narrowing to patients meet the berlin definition of ards did not alter the association between corticosteroids and lower risk of death (hr 0.43; 95% ci 0.21, 0.88; p = 0.0208). the hr of corticosteroids on risk of death was constant when using hospital admission as baseline and excluding patients received corticosteroids 2 days after hospital admission (hr 0.37; 95% ci 0.18, 0.76; p = 0.0072). when using ards onset date as baseline, the associations between corticosteroids and the risk of death were also significant ( blood crp level decreased among corticosteroids group on the first 4 days after ards onset (fig. 2) , all of the models assessed the effects of corticosteroids as a time-varying covariate ards acute respiratory distress syndrome, fio 2 fraction of inspired oxygen, sofa sequential organ failure assessment, spo 2 pulse oxygen saturation a adjusted for age, sex, sofa score at hospital admission, propensity score of corticosteroid treatment, comorbidities (diabetes, hypertension, chronic pulmonary disease, chronic renal or liver disease, solid malignant tumor, hematologic malignancy, and immunosuppressive status), antiviral treatment (lopinavir-ritonavir, oseltamivir, and ganciclovir), and respiratory supports (high-flow oscillation oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation). propensity score was calculated by a non-parsimonious logistic regression model that included: age, sex, sofa score, temperature, respiratory rate, spo 2 /fio 2 ratio, blood lymphocyte count, blood neutrophil count, and level of c-reactive protein at hospital admission b using values of spo 2 /fio 2 ratio, respiratory rate, temperature, heart rate, respiratory rate, sofa score, blood lymphocyte count, blood neutrophil count, and level of crp at ards onset while an increase was found in non-corticosteroids group. crp levels were significantly lower in corticosteroids-treated group after 2 days of ards onset (p for interaction = 0.0434). in this observational study, prescription of low-to-moderate dose systemic corticosteroids was associated with lower risk of 60-day in-hospital death among covid-19 patients who developed ards. the efficiency of corticosteroids was further supported by the reduction of crp, as the marker for suppressed systemic inflammation responses. no associations between corticosteroid treatment with viral shedding were found in our study. our study demonstrates the association between corticosteroid treatment with long-term (60 days) risk of death in severe covid-19 patients. it is biologically plausible that suppression of inflammatory response by corticosteroids may be beneficial for patients with ards, which was caused by dysregulated systemic inflammation [3] [4] [5] and proved the main cause of death. the recov-ery trial and a metanalysis of ongoing rcts showed reduced 28-day mortality and longer ventilation-free days in patients with corticosteroid treatment [13] . we used 60-day in-hospital death as primary endpoint. to our knowledge, it was longer than previously reported rcts. the results showed significant association between corticosteroids and risk of death, which further provide evidence on the long-term benefit of corticosteroids. it was compatible with studies that indicated corticosteroid treatment was not associated with increases in secondary infections in covid-19-related ards patients [15, 16] . type, dosage, and duration of corticosteroids therapy were fundamental variables of corticosteroid treatment regimens. different from the most of the published rcts using dexamethasone, most of the patients in our study were treated with methylprednisolone. methylprednisolone is a rapid onset glucocorticoid with shorter half-life and less mineralocorticoid effects than dexamethasone, which indicate shorter effects on systemic immunity and preventing corticosteroids-related fluid retention. meduri et al. [22] firstly promoted the early use of corticosteroids in ards. they found that methylprednisolone reduced the duration of mechanical ventilation, icu stay, and icu mortality in early severe ards patients. in our study, a similar maximum dose (equivalent to methylprednisolone of 1-2 mg/kg) of corticosteroids was used, which was also close to the dose in recovery trial and recommended by society of critical care medicine (sccm) and european society of intensive care medicine (esicm) for ards patients [23, 24] . our results were in line with the rcts of covid-19 [13, 14] and previous studies of other ards patients, which showed low-dose corticosteroid treatment (equivalent to methylprednisolone of 1-2 mg/kg) accelerates the resolution of ards [23, 25, 26] , indicating low-dose methylprednisolone as an alternative to dexamethasone in covid-19-related ards. higher dose may increase risks of cox regression model with corticosteroid treatment was time-varying variable, adjusting for age, sex, sofa score at hospital admission, propensity score of corticosteroid treatment, comorbidities (diabetes, hypertension, chronic pulmonary disease, chronic renal or liver disease, solid malignant tumor, hematologic malignancy, and immunosuppressive status), antiviral treatment (lopinavir-ritonavir, oseltamivir, and ganciclovir), and respiratory supports (high-flow oscillation oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation). propensity score was calculated by a non-parsimonious logistic regression model that included: age, sex, sofa score, temperature, respiratory rate, spo 2 /fio 2 ratio, blood lymphocyte count, blood neutrophil count, and level of c-reactive protein at hospital admission. ards, acute respiratory distress syndrome; sofa, sequential organ failure assessment immune-suppression and corticosteroid-induced complications [27] [28] [29] . in this cohort, tapering strategy was performed as has been suggested by the guidelines for the ards-related corticosteroid insufficiency (circi) to reduce deterioration from the development of a reconstituted inflammatory response and febrile response. of note, a randomized trial included mild covid-19 patients using a similar dose and shorter course of methylprednisolone (0.5 mg/kg twice daily for 5 days) than in the regimens of our study found no benefit on mortality. more research is needed to determine the best duration of corticosteroid therapy. a recent analysis of four trials showed prolonged corticosteroids therapy reduced mortality [25] . however, chronic side effects of corticosteroids including secondary infection and osteoporosis may occur in prolonged course of treatment. delayed virus clearance was reported in corticosteroidtreated patients with both sars, mers, and influenza [30] [31] [32] , which was a major concern for the immune suppressive effects of corticosteroids, albeit its uncertain clinical relevance. we found no difference in viral shedding duration from symptom onset between corticosteroid and non-corticosteroid groups, which may explain the heterogeneity in efficacy of corticosteroids between covid-19 and other virus infections. of note, positive sars-cov-2 test results have been reported after two consecutive negative results [33] . viral tests of throat swabs were not monitored after two consecutive negative tests in our cohort. more evidence is needed for assessing the effects of corticosteroids on clearance of sars-cov-2 rna. we used rigorous statistical method to control for survival and indication bias. survivors-treated bias exists in observational studies that assess exposure after the start of follow-up, where only patients survived long enough had an opportunity to receive the intervention. therefore, the patients died early are more likely to be misclassified to the no-treatment group, leading to overestimation of the effectiveness of medicine [34] . this study was specifically designed to address survivors-treated bias of corticosteroid treatment, by using a time-dependent variable for corticosteroids initiation to define corticosteroids group and non-corticosteroids group [35] . in addition, there was a propensity of clinicians to give corticosteroids to patients who were critically ill in non-randomized clinical condition. the imbalance in baseline characteristics may introduce confounders in comparison of mortality between corticosteroids and non-corticosteroids group. in this cohort, lymphopenia and elevation of crp and lactate dehydrogenase levels were more severe in patients who received corticosteroids therapy. propensity score is a validated method to account for baseline confounding and control selection bias in this case [36] . in this study, we performed a rigorous propensity adjustment analysis accounting for the baseline variables related to propensity of corticosteroid treatment. these added to the strength of our results that found associations between corticosteroid treatment and risk of death. our study had some limitations. first, unlike randomized controlled trials, the selection bias and potential confounding effects might exist. we used propensity analysis rather than standard multivariable analysis to rigorously adjust for selection bias, and time-dependent model to avoid survivors-treated bias. nonetheless, only measured factors were controlled for due to the nature of observational study design. second, secondary infections were not monitored in this study, because microbiological culture results needed for definite diagnosis of secondary infection were possibly affected by antibiotic treatment the patients received simultaneously. to include the delayed effects of secondary infections on mortality, a longer follow-up period of 60 days was used. third, this study was single center and patients were sicker and transferred from other hospital, so might lacking of generality. forth, some of the patients were treated with lopinavir-ritonavir; it might be a confounder because the efficacy of lopinavir-ritonavir in covid-19 was unclear. fifth, our cohort was collected in the early outbreak of covid-19; thus, the mortality was relatively higher than other studies, which limited generalization of our results. our findings suggest administration of low dose of corticosteroids might reduce the risk of death in covid-19 patients who developed ards. supplementary information accompanies this paper at https ://doi. org/10.1186/s1305 4-020-03340 -4. additional file 1: emethods, etable 1 and 2, and efigure 1 were included. director-general's opening remarks at the media briefing on covid-19-11 coronavirus disease 2019 (covid-19) situation report-156 clinical characteristics of coronavirus disease 2019 in china clinical features of patients infected with 2019 novel coronavirus in wuhan clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19 activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china on the use of corticosteroids for 2019-ncov pneumonia clinical evidence does not support corticosteroid treatment for 2019-ncov lung injury corticosteroid administration for viral pneumonia: covid-19 and beyond treatment of severe acute respiratory syndrome with glucosteroids: the guangzhou experience dexamethasone in hospitalized patients with covid-19-preliminary report association between administration of systemic corticosteroids and mortality among critically ill patients with covid-19: a meta-analysis effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and covid-19: the codex randomized clinical trial methylprednisolone as adjunctive therapy for patients hospitalized with covid-19 (metcovid): a randomised, double-blind, phase iib, placebo-controlled trial exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome: a systematic review and meta-analysis clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: a propensity analysis convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold open access which fosters wider collaboration and increased citations maximum visibility for your research: over 100m website views per year • at bmc, research is always in progress. learn more biomedcentral.com/submissions ready to submit your research ready to submit your research ? choose bmc acute respiratory distress syndrome: the berlin definition methylprednisolone infusion in early severe ards: results of a randomized controlled trial corticosteroid guideline task force of s, esicm: guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (circi) in critically ill patients (part ii): society of critical care medicine (sccm) and european society of intensive care medicine (esicm) 2017 the clinical practice guideline for the management of ards in japan prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study steroid-induced osteonecrosis in severe acute respiratory syndrome: a retrospective analysis of biochemical markers of bone metabolism and corticosteroid therapy glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients corticosteroid therapy for critically ill patients with middle east respiratory syndrome viral loads and duration of viral shedding in adult patients hospitalized with influenza dynamic profile of rt-pcr findings from 301 covid-19 patients in wuhan, china: a descriptive study a most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies quantifying the impact of survivor treatment bias in observational studies invited commentary: propensity scores national institutes of health nhl, blood institute an: comparison of the spo 2 /fio 2 ratio and the pao 2 /fio 2 ratio in patients with acute lung injury or ards publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-317729-ruvx9zwd authors: wilson, darius cameron; schefold, joerg c.; baldirà, jaume; spinetti, thibaud; saeed, kordo; elke, gunnar title: adrenomedullin in covid-19 induced endotheliitis date: 2020-07-09 journal: crit care doi: 10.1186/s13054-020-03151-7 sha: doc_id: 317729 cord_uid: ruvx9zwd nan darius cameron wilson 1* , joerg c. schefold 2 , jaume baldirà 3 , thibaud spinetti 2 , kordo saeed 4 and gunnar elke 5 despite the exponential growth in research following the rapid spread of sars-cov-2 and subsequent covid-19 pandemic, the underlying pathophysiological mechanisms in covid-19 patients remain poorly understood. the increased incidence of cardiovascular and thromboembolic complications, immune cell deactivation and sepsis-like multiple organ failure suggests the involvement of multiple pathways. accordingly, recent studies have proposed that virus-induced endothelial dysfunction and damage, resulting in impaired vascular blood flow, coagulation and leakage, may partially explain the development of organ dysfunction and oedema [1] . hence, the development of endotheliitis may be a prominent, yet partly under recognised, feature of covid-19 induced critical illness. whilst numerous pro-inflammatory cytokines and blood biomarkers have already been compared in patients with different severities of covid-19 -to date -no study, report or editorial has described the potential role of adrenomedullin (adm) during the host response to covid-19. this is surprising, since adm has been shown to play a key role in reducing vascular (hyper) permeability and promoting endothelial stability and integrity following severe infection [2] . thus, adm may also be of interest within covid-19 induced endotheliitis. indeed, a recent study investigating gene upregulation in patients with systemic capillary leak syndrome (scls), characterised by plasma leakage into peripheral tissue and transient episodes of hypotensive shock and oedema, found that adm was not only one of the most upregulated genes, but that subsequent application to endothelial cells resulted in a protective effect on vascular barrier function [3] . furthermore, recent clinical studies on sepsis patients upon emergency department (ed) presentation and during intensive care (icu) treatment using the stable protein surrogate, mid-regional proadrenomedullin (mr-proadm), found that its assessment could accurately identify disease progression in patients with nonsevere clinical signs and symptoms, safely increase outpatient treatment with decreased readmission rates and no subsequent mortalities [4] , and identify patients requiring a rapid administration of antibiotics or triage to the icu [5] . despite the low number of severe viral cases within each of these studies (between 2.1% [3] and 3.4% [4] ), similar hypotheses can also be formulated for patient populations with covid-19. the assessment of mr-proadm in future covid-19 studies may therefore provide important information into the pathophysiological mechanisms underlying endotheliitis and subsequent organ dysfunction. the early identification of patients likely to develop severe clinical symptoms requiring subsequent hospitalisation, as well as the safe discharge of those already hospitalised, may be of particular importance in regions where healthcare systems are used to full capacity. abbreviations adm: adrenomedullin; ed: emergency department; icu: intensive care unit; mr-proadm: mid-regional proadrenomedullin; sars-cov-2: severe acute respiratory syndrome coronavirus 2; scls: systemic capillary leak syndrome endothelial cell infection and endotheliitis in covid-19 the use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis -a secondary analysis of a large randomised controlled trial adrenomedullin surges are linked to acute episodes of the systemic capillary leak syndrome (clarkson disease) the early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study biomarkers and clinical scores to identify patient populations at risk of delayed antibiotic administration or intensive care admission publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions dcw was the primary author and editor of the manuscript. all authors critically reviewed and approved the final manuscript. dcw takes responsibility for the paper as a whole. key: cord-304070-jw1lxwyd authors: lapinsky, stephen e; wax, randy; showalter, randy; martinez-motta, j carlos; hallett, david; mehta, sangeeta; burry, lisa; stewart, thomas e title: prospective evaluation of an internet-linked handheld computer critical care knowledge access system date: 2004-10-14 journal: crit care doi: 10.1186/cc2967 sha: doc_id: 304070 cord_uid: jw1lxwyd introduction: critical care physicians may benefit from immediate access to medical reference material. we evaluated the feasibility and potential benefits of a handheld computer based knowledge access system linking a central academic intensive care unit (icu) to multiple community-based icus. methods: four community hospital icus with 17 physicians participated in this prospective interventional study. following training in the use of an internet-linked, updateable handheld computer knowledge access system, the physicians used the handheld devices in their clinical environment for a 12-month intervention period. feasibility of the system was evaluated by tracking use of the handheld computer and by conducting surveys and focus group discussions. before and after the intervention period, participants underwent simulated patient care scenarios designed to evaluate the information sources they accessed, as well as the speed and quality of their decision making. participants generated admission orders during each scenario, which were scored by blinded evaluators. results: ten physicians (59%) used the system regularly, predominantly for nonmedical applications (median 32.8/month, interquartile range [iqr] 28.3–126.8), with medical software accessed less often (median 9/month, iqr 3.7–13.7). eight out of 13 physicians (62%) who completed the final scenarios chose to use the handheld computer for information access. the median time to access information on the handheld handheld computer was 19 s (iqr 15–40 s). this group exhibited a significant improvement in admission order score as compared with those who used other resources (p = 0.018). benefits and barriers to use of this technology were identified. conclusion: an updateable handheld computer system is feasible as a means of point-of-care access to medical reference material and may improve clinical decision making. however, during the study, acceptance of the system was variable. improved training and new technology may overcome some of the barriers we identified. the rate of expansion of medical knowledge is increasing rapidly, and it is frequently difficult for clinicians to keep abreast of important new literature. for example, several recently published randomized controlled trials in critical care have demonstrated mortality benefits [1] [2] [3] [4] [5] , but uptake of new knowledge into clinical practice is often delayed [6] [7] [8] . improving access to this knowledge base at the point of care may lead to better clinical decision making, which could improve patient outcome, reduce costs and optimize bed utilization [9] . in critical care, rapid access to medical reference information may be particularly important in facilitating timely management decisions and avoiding errors [10] . computing technology can allow point-of-care access to upto-date medical reference material [11] . a study evaluating a mobile computerized cart to make evidence available to clinicians in an internal medicine setting [12] demonstrated that evidence-based medicine was more likely to be incorporated into patient care when the computerized system was used. because of their portability, handheld devices may be more practical tools for disseminating knowledge to the point of care. despite the popularity of handheld devices in medicine, few studies have evaluated the usefulness of this technology [13] . before widespread dissemination of this type of technology can be encouraged, its impact must be thoroughly evaluated [14] . in the present study we evaluated whether it would be feasible and effective to provide updateable reference information from a central academic centre to handheld computers used by critical care specialists in community hospitals. a total of 17 intensivists at four community hospital intensive care units (icus) in the greater toronto area participated in the present prospective interventional study. after training, each physician was equipped with a handheld computing device (palm m505; palm inc., milpitas, ca, usa) loaded with medical reference material pertinent to the critical care physician. this information included a customized critical care information handbook ('critical care'), which was previously developed for use by residents and physicians at our centre (additional file 1). commercially available medical reference software was also incorporated, namely pepid ed (pepid llc, skokie, il, usa) and medcalc http://med calc.med-ia.net/. the handheld devices were able to receive literature updates on a regular basis, using customized software (iqsync; infiniq software, mississauga, ontario, canada), which accessed an internet-based server using either a connection via desktop computer or infrared data transfer to a telephone modem (fig. 1 ). new information was sent to the handheld devices and appeared in a file called 'what's new'. these updates, provided every 2-3 weeks, comprised brief reviews of relevant new literature including a short summary, a commentary and the article abstract. all handheld devices were equipped with backup software that allowed the content to be rapidly restored in the event of a hardware failure (backupbuddy vfs; blue nomad software, redwood city, ca, usa). the devices were also equipped with software capable of generating a log of the applications used (appusage; benc software production, slavonski brod, croatia). between september and november 2002 the handheld devices were distributed to participating physicians, at which time they each received a 1-hour training session on the use of the handheld device and the internet link (fig. 2) . after training, the participants were able to utilize the devices in clinical practice for 12 months. we provided 24-hour support by telephone and e-mail, with a website for independent review. feasibility feasibility of the system was assessed by tracking physicians' use of the handheld device and tracking their access of the individual handheld applications during the study period. physicians who updated their handheld computers at least once a month for 6 months were identified as 'regular users'. a qualitative assessment of the system was achieved through surveys and focus group methodology. participants completed surveys at baseline to identify their prior familiarity with handheld devices, and at the end of the study period to evaluate subjectively the handheld reference system and the individual handheld applications. survey data were scored on a 7-point scale, in which 'poor' scored 1 and 'excellent' scored 7. an independent company (the nrc+picker group, markham, canada) conducted the focus group evaluations at the end of the intervention period, to determine the perceived utility of the information system. each hospital physician group participated in one focus group meeting. information sources that physicians accessed to make clinical decisions were evaluated during simulated patient care scenarios, completed in the physicians' own icu utilizing a computerized patient simulator (simman; laerdal medical corporation, wappingers falls, ny, usa). each physician completed one scenario before the handheld device was introduced (baseline scenario) and one at the end of the intervention period (final scenario), when the handheld device could be used (fig. 2) . a small pool of five scenarios with equivalent complexity was developed, such that physicians would likely need to access information sources in order to make management decisions. the scenarios involved unusual but important conditions, namely thyroid storm, myasthenia gravis, methanol toxicity, malaria and methemoglobinaemia. they were allocated to study participants in such a way as to avoid participants from the same site receiving the same scenario at the same time point, and to avoid repetition of scenarios among individual participants. each scenario concluded with the physician writing admission orders for the simulated patient. during the scenarios we tracked all medical reference sources utilized by the physicians, who were encouraged to use a 'think the internet-based data transfer system the internet-based data transfer system. updated information is downloaded to the handheld device from a study server. connection to the internet can take place via hardwire synchronization with a desktop computer or using infrared (ir) data transmission to a dial-up modem. isp, internet service provider. the study time course the study time course. aloud' process [15] . an audiovisual recording was made of the scenarios for later analysis, and when the handheld was used real-time screen capture was incorporated into the recording (additional file 2). this allowed us to document which handheld applications were accessed, the time taken to access information and the time taken to complete the scenario. we developed an objective scoring system for the admission orders generated at each scenario. the admission orders were assigned a score (range 0-100) by a critical care physician (sm) and critical care pharmacist (lb), who were blinded as to whether the physician used the handheld device. the scenario-specific scoring system allocated points for all necessary diagnostic and therapeutic interventions, weighted according to relative importance. negative points were given for potentially harmful orders. data are presented as median and interquartile range (iqr), and permutation tests were used for comparisons because numbers were small and not normally distributed. the differences between the final and baseline admission order scores and the time to completion of scenarios were calculated for each participant. a two-sample permutation test was used to compare these differences between the group of physicians who chose to use the handheld in the final scenario and those who did not use the device. admission order scores obtained for each of the five scenarios were compared. outcomes were considered statistically significant at α < 0.05. the sas system for window version 8.2 (sas institute, inc., cary, nc, usa) was used for all analyses. focus groups were recorded, transcribed verbatim and subsequently analyzed. themes were identified and unique perspectives on key issues noted [16] . the handheld information system functioned well during the study period. tracking of the deployment of handhelds identified 10 regular users (59%), four physicians (23%) who used the system variably and three physicians (18%) who never used their handheld device. the regular users accessed the personal information management applications more commonly (median 32.8 times/month, iqr 28.3-126.8) than the medical software (median 9/month, iqr 3.7-13.7; p = 0.028), although significant variation was noted (table 1) . baseline survey data identified that, of the 17 critical care physicians participating, 12 (71%) had previous experience with handheld devices (nine had used the palm operating system, and three had used windows ce) for a median duration of 1 year (range 1 month to 3.8 years). seven participants (41%) reported using handhelds for accessing medical information before the study. of the 16 final survey respondents, seven (44%) felt that the handheld system had had a positive impact on their clinical practice. the handheld medical applications (critical care, what's new, medcalc and pepid) received similar ratings, with overall evaluation scores ranging from 4.1 to 5.3 on the 7-point scale. four focus group meetings, involving a total of 13 participants (76%), identified the benefits and barriers to use of handhelds for information access, and made suggestions for improvement ( table 2 ). the overall impression of participants was that there is a role for handhelds for mobile information access, but that in situations away from the bedside other electronic media such as desktop computers were preferable. not all study physicians were able to participate in the simulated clinical scenarios on the pre-assigned day. fourteen physicians (82.3%) participated in the baseline scenarios and 13 (76.5%) in the final scenarios. information sources utilized during the baseline scenarios included the internet (50% of participants; e.g. medline searches and electronic textbooks), textbooks (43%), telephoning colleagues, the icu pharmacist or poison control centre (71%), and other sources such as pocket guides (21%). in the final scenarios, the handheld device was used as the primary source of information by eight participants (62%; table 3 ). of 14 information searches on the handheld device, 11 searches (79%) were successful and the median time to access information was 19 s (iqr 15-40 s). the information sources of those participants not using the handheld device were similar to those in the baseline surveys ( fig. 3 ). when scores recorded for each of the five clinical scenarios were compared, no significant difference was noted, reducing the likelihood that scenario assignment influenced outcomes. this study demonstrates the feasibility of using an electronic knowledge translation system to provide high quality, regularly updated medical reference information from a central academic centre to multiple peripheral users. user acceptance of this technology was not uniform, with just over half of the participants using their handheld devices to access information on a regular basis. nevertheless, the availability of point-ofcare access to information may have improved the quality of clinical decision-making. although mobile computing devices have potential beneficial roles to play in clinical medicine, few publications describe formal evaluation of this technology [13] . because the present study was an early hypothesis-generating evaluation of this technology, multiple quantitative and qualitative outcomes were measured. we generated novel data on the use of handheld devices in a clinical situation, but the study has several limitations. the number of physicians involved was relatively small, with a significant proportion not utilizing the technology. the allocation of clinical scenarios was not randomized, because they were allocated predominantly to avoid using the same scenario at the same site and time point. however, the analysis performed compared participants who used the handheld with those who did not; because it was not known which participant would use the handheld at the time of allocation of scenarios, potential bias was minimized. furthermore, the scenarios appeared to be equivalent in difficulty because no difference was noted when scores for the individual scenarios were compared. a confounding factor in the study was the outbreak of sars (severe acute respiratory syndrome) from march to may 2003, which had a significant impact on the study icus [17] . participants were advised to avoid using their handhelds during patient contact because of the potential to transmit infection, and this affected continuity of the study. had we not encountered this event, utilization might have been higher. the lack of universal acceptance of this technology is not surprising and may be due to a number of factors, including inadequate training and the lack of familiarity with the technology [18] . training is essential when introducing handheld computing technology [19, 20] and, although all users underwent a training programme, the surveys and focus groups indicated a need for improvement. familiarity with handhelds is increasing, with 33% of all canadian physicians and 53% of under 35year-olds using these devices in 2003, but these levels of utilization remain relatively low when compared with use of the internet, at 88% [21] . increasing familiarity with the technology will probably increase acceptance of such a system. other potential barriers to use of the handheld system may be addressed by the rapidly developing technology, including improved screen resolution, ease of data entry and wireless connectivity. acceptance may be increased through the development of an all-in-one package on the handheld, allowing additional functionality such as decision support, billing, electronic prescribing and communication. the study demonstrated the potential role of an updateable handheld information system for knowledge translation in critical care. rapid access to current clinical guidelines may be a valuable component of a comprehensive solution to reducing error and improving efficiency. information access may be most beneficial in areas without full-time critical care physicians, particularly given the current imbalance between demand and supply with critical care physicians, which is expected to worsen [9, 10] . recent recommendations highlight the importance of leveraging information technology to standardize practice and promote efficiency in critical care [10] . handheld information access alone is unlikely to change clinical practice, but it should be considered a component of an electronic knowledge translation system. in many situations other media, such as desktop or tablet computers, may be preferable for information access. although the study was carried out in a critical care environment, such a system is probably applicable to other specialties in which clinicians are mobile and may not have ready access to a desktop computer (for example, anaesthesia, emergency medicine, home care). this study provides insight into the potential impact of this technology in improving health care outcomes [14] . nevertheless, further study that builds on our findings is essential to determine how these new technologies can best be incorporated into the patient care setting. a handheld computer system is feasible as a means of providing point-of-care access to medical reference material in the icu. during this study acceptance of this system was variable, and improved training and more advanced technology may be required to overcome some of the barriers we identified. in clinical simulations, use of such a system appeared to improve clinical decision-making. the acute respiratory distress network: ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome efficacy and safety of recombinant human activated protein c for severe sepsis bouillon r: intensive insulin therapy in critically ill patients effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock early goal-directed therapy collaborative group: early goal-directed therapy in the treatment of severe sepsis and septic shock publication of study results does not increase use of lung protective ventilation in patients with acute lung injury introduction of sedative, analgesic, and neuromuscular blocking agent guidelines in a medical intensive care unit: physician and nurse adherence dreyfuss d: ventilator circuit and secretion management strategies: a franco-canadian survey physician staffing patterns and clinical outcomes in critically ill patients the critical care crisis in the united states: a report from the profession improving safety with information technology finding and applying evidence during clinical rounds: the 'evidence cart handheld computing in medicine what next for electronic communication and health care? analysis of complex decision-making processes in health care: cognitive approaches to health informatics qualitative evaluation and research methods 2nd edition critically ill patients with severe acute respiratory syndrome (sars) doctors' experience with handheld computers in clinical practice: qualitative study introduction of handheld computing to a family practice residency program surgical procedure logging with use of a handheld computer more than half of mds under 35 age now using pdas we acknowledge the contributions of the intensive care physicians from william osler health centre (brampton memorial campus), scarborough general hospital, north york general hospital and trillium health centre (mississauga). this study would not have been possible without the financial support of the change foundation of the ontario hospital association (grant 01011) and bayer canada inc. we acknowledge the technical support provided by infiniq software (http://www.infiniq.com; mississauga, ontario, canada) and would like to thank dr arthur slutsky and dr allan detsky for reviewing the manuscript and providing valuable comments. stephen lapinsky, randy wax and thomas stewart were responsible for study design. stephen lapinsky, randy wax, randy showalter and carlos martinez implemented the handheld system and collected study data. sangeeta mehta and lisa burry were responsible for data collection and interpretation. stephen lapinsky and david hallet analyzed the data. the manuscript was written by stephen lapinsky, randy showalter and thomas stewart, with all authors participating in revisions and giving approval to the final draft for submission for publication. the author(s) declare that they have no competing intrests. • this study demonstrated that an updateable handheld computer information resource is a feasible means for providing point-of-care access to medical reference information in the icu.• acceptance of this system was variable and may be improved by enhanced training and newer technological innovations.• in clinical simulations, this system appeared to improve clinical decision making. key: cord-334117-8gadvw16 authors: hassanian-moghaddam, hossein; zamani, nasim; kolahi, ali-asghar; mcdonald, rebecca; hovda, knut erik title: double trouble: methanol outbreak in the wake of the covid-19 pandemic in iran—a cross-sectional assessment date: 2020-07-09 journal: crit care doi: 10.1186/s13054-020-03140-w sha: doc_id: 334117 cord_uid: 8gadvw16 nan iran has been the epicenter of covid-19 in the middle east, with a total of 120,198 infected cases and 8556 deaths as of june 10 [1]. the pandemic has been complicated by the co-occurrence of a large methanol outbreak in iran, seemingly triggered by false claims that consumption of disinfectants and alcohols could prevent and treat covid-19 infection. according to local news, the ensuing rise in ethanol demand made bootleggers decolorate industrial alcohols containing pyridine (to deter from consumption) using bleach, before selling them as regular ethanol to iranians. in this research letter, we describe the scale of the iranian methanol outbreak, based on hospitalization and mortality data collated from databases of the iranian ministry of health (moh) and legal medicine organization (lmo) for the period of february 23 (first documented covid-19 case in iran) until may 2, 2020. moh records indicate 5876 hospitalizations for methanol poisoning, occurring in geographical clusters, with just three (tehran, fars, khuzestan) out of the total 31 iranian provinces accounting for the majority (52.2%; n = 3068) of cases (see table 1 ). in terms of mortality, moh reported that 534 patients with methanol poisoning were confirmed dead in the hospital setting, equivalent to an estimated case fatality rate of approximately 9% (534/5876). lmo registered 800 deaths from methanol poisoning during the same period (see table 1 and fig. 1 ), comprising both in-hospital and community-based fatalities. this 33% discrepancy in deaths between moh and lmo data (i.e., (800-534)/800 × 100) may have several explanations. for instance, lmo data also includes out-of-hospital deaths and is likely more accurate. moreover, a hospitalbased diagnosis of methanol poisoning is difficult and complicated by the lack of diagnostic equipment or physician knowledge. therefore, methanol poisoning may go undetected in hospitals, and accurate diagnosis is-best case scenario-only assigned during a post-mortem examination, which then enters lmo statistics. in the absence of formate analyses, late presenters can become false negatives. despite these inconsistencies, the number of iranian poisoning cases (5876 hospitalizations from late february until early may),\ is already five times higher than the second-largest methanol outbreak in history, which was recorded in libya in march 2013 and affected 1066 patients [2] . from our data, it is unclear how many iranians drank adulterated alcohol for recreational purposes or as gastrointestinal "disinfectant" to prevent-or treat-covid-19 infection. with no end to the covid-19 pandemic in sight, it is thus paramount to educate the general public that alcohol does not protect against covid-19, as already initiated by the who [3] . the united nations rightly recognizes the international spread of "fake news" related to covid-19 as a threat to human lives [4] , as health care systems have to contend with medical misinformation of the general public. in methanol poisoning, the efficacy of treatment is markedly reduced in delayed presentations. with 534 methanol deaths registered by moh and 800 deaths by lmo, alongside 5876 hospitalizations, we report an estimated mortality rate in the range of 9-14%. however, this figure is preliminary and should be interpreted with great caution, until lmo and moh release their final data. additionally, in many more non-fatal methanol poisoning cases, adults and children are now visionimpaired or blind from this toxic alcohol. during situations like pandemics, healthcare institutions may seem dangerous settings, which could pose a risk of viral infection. it is possible that fear of covid-19 kept methanol poisoning victims from seeking and obtaining timely care. this highlights the importance of early identification and initiation of treatment, which can be supplemented by "active case finding" by treating physicians and public health agencies [5] . public health messaging and strategic planning are crucial to prevent future methanol outbreaks [6] . correction: the methanol poisoning outbreaks in libya 2013 and kenya alcohol and covid-19: what you need to know during this coronavirus pandemic, 'fake news' is putting lives at risk: unesco methanol mass poisoning in iran: role of case finding in outbreak management consensus statements on the approach to patients in a methanol poisoning outbreak publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we want to acknowledge the novel initiative by medécins sans frontières (msf/doctors without borders) which looks at mechanisms to improve the survival of methanol poisoning victims globally. methanol poisoning is an under-recognized issue, especially in low-and middle-income countries. for more information on the work of msf regarding methanol poisoning, please visit https://msf.no/mpi. authors' contributions hhm helped in the conception and design of the study. aak, hhm, and nz contributed to the data collection. nz helped in writing the first draft. rm and keh composed the final draft. all authors contributed to the final approval of the version to be submitted. all authors read and approved the final manuscript. availability of data and materials all the data is presented in the text. this study is a preliminary report and was approved by the ethics committee of shahid beheshti university of medical sciences (ir.sbmu.retech.rec.1398.872). the authors declare that they have no competing interests. key: cord-300135-iwvkvs3k authors: lemay, francois; cooper, jeremy title: description of an alternative method for optimal and comfortable two-handed face mask ventilation: the transverse mandibular technique date: 2020-05-26 journal: crit care doi: 10.1186/s13054-020-02999-z sha: doc_id: 300135 cord_uid: iwvkvs3k nan description of an alternative method for optimal and comfortable two-handed face mask ventilation: the transverse mandibular technique francois lemay 1,2* and jeremy cooper 3 to the editor, recent recommendations stress the importance of avoiding aerosolization while attempting rescue facemask ventilation (fmv) with covid-19 patients [1] . in addition, major difficult airway algorithms already highlight the importance of oxygenation rather than intubation, and many include best attempts at facemask ventilation (fmv) while progressing in cannot intubate cannot oxygenate situations [2, 3] . best attempt at fmv may be challenging, and two major techniques have been so far well described for two-handed fmv: the double ce-grip and the thenar eminence techniques, or ve-grip [4] . we would like to share an alternative technique that provides good fmv conditions through improved jaw thrust, mask seal and ergonomic comfort. we would describe this technique as the transverse mandibular technique (fig. 1) , for which we have not found any description in the literature. we believe it is already performed by some clinicians and that its use and potential benefits should be discussed. in this technique, emphasis is on mandibular advancement and mask seal. fingers of both hands (mainly through the index and middle fingers) are placed transversally under the angle of the mandible to achieve an optimal jaw thrust. the thumbs are positioned transversely over the middle of a standard facemask on both sides, pushing down to achieve proper facial seal. we believe the transverse mandibular technique has some advantages: 1. the strongest fingers in both hands are used to make an appropriate jaw thrust. 2. the thumb grip is potentially less tiring. in other techniques, lateral pressure must be used with the thumbs, which can be difficult especially in smaller hands. 3. the wrists are kept straight over a wide range of table height. this is relevant as the hands have been shown to have a stronger grip with the wrists in a neutral position [5] . 4. the position of the hands fits a wide range of facemasks and patients' sizes and can be used in both adult and paediatric patients. 5. it can be performed standing in front of the patient, which can be useful in critical situations when many practitioners are managing the airway. it is important that one uses a technique that he or she is comfortable with. whatever the primary fmv technique, tiring practitioners might want to alternate or combine techniques. we would suggest that practitioners consider the technique advocated in this correspondence as they may find it useful in difficult fmv contexts. consensus guidelines for managing the airway in patients with covid-19 difficult airway society 2015 guidelines for management of unanticipated difficult intubation in adults practice guidelines for management of the difficult airway an updated report by the american society of anesthesiologists task force on management of the difficult airway comparison of effectiveness of two commonly used two-handed mask ventilation techniques on unconscious apnoeic obese adults the effect of wrist position, angular velocity, and exertion direction on simultaneous maximal grip force and wrist torque under the isokinetic conditions publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' information none. none.availability of data and materials not applicable.ethics approval and consent to participate not applicable. written consent has been obtained for images provided by the theatre staff involved in fig. 1 . none.author details key: cord-325626-r7k7u7ro authors: yu, xia; sun, shanshan; shi, yu; wang, hao; zhao, ruihong; sheng, jifang title: sars-cov-2 viral load in sputum correlates with risk of covid-19 progression date: 2020-04-23 journal: crit care doi: 10.1186/s13054-020-02893-8 sha: doc_id: 325626 cord_uid: r7k7u7ro nan the pandemic of coronavirus diseases 2019 (covid-19) imposes a heavy burden on medical resources [1] . whether there is correlation between viral load and disease severity has not been clarified. in the study, we retrospectively collected the virological data, as well as demographic, epidemiological clinical information of 92 patients with confirmed covid-19 in a single hospital in zhejiang province, china. we compared the baseline viral loads between severe patients and those mild to moderate at admission and also between those developing severe disease during hospitalization and those not. we studied 92 patients with confirmed covid-19 who were admitted from january 19, 2020, to march 19, 2020, in the first affiliated hospital of zhejiang university. the sputum specimens were collected from the lower respiratory tract of each patient at admission and the levels of viral nuclei acid were determined by a real-time pcr (rt-pcr) approach and indicated by the cycle threshold (ct) values of rt-pcr assays [2] . other demographic, epidemiological and clinical information were collected and inputted into a pre-designated electronic data collection form. all patients followed up to march 15, 2020. all the statistical analyses were performed using graphpad prism 5 (graphpad software inc.; san diego, ca, usa) and spss 20.0 (spss inc.; chicago, il, usa). of the 92 patients, 30 were severe on admission. of the other 62 mild-moderate cases at admission, 11 cases became severe during hospitalization. the demographic, epidemiological and clinical information was shown in table 1 . all patients were tested for sars-cov-2 nucleic acid on sputum specimens from the lower respiratory tract at admission. as shown in fig. 1a , severe patients had significantly lower ct values than mildmoderate cases at admission (25 vs. 28, p = 0.017), suggesting a higher viral load in the lower respiratory tract. furthermore, a higher viral load was observed in sputum specimens from patients who became severe during the hospitalization than those did not (24 vs. 29, p = 0.008). as shown in fig. 1b , the ct values of rt-pcr assays negatively correlated with the probability of progression to severe type in all the patients representing mild-tomoderate at admission. we found that the viral load of the sputum specimen in the lower respiratory tract tested at baseline is closely related to the severity of covid-19. more importantly, patients with a higher baseline viral load are more likely fig. 1 a comparison of baseline sputum viral load between severe and mild-to-moderate patients at admission or between those becoming severe and those did not during the hospitalization. b relationship between the estimated probability of disease progression during the hospitalization and baseline sputum viral load. viral load is indicated by the ct value of rt-pcr assay. the asterisk indicates a p value < 0.05 to become severe. this finding apparently justifies the concept that early antiviral treatment, if effective, would reduce the risk of progression and thereby the mortality, which has been demonstrated in influenza [3] . in our study, sputum specimens were used, instead of nasopharyngeal and oropharyngeal swabs because it has been shown that samples from lower respiratory tract generally contain a higher level of viral load than nasopharyngeal and oropharyngeal swabs [4] and acquiring swabs is uncomfortable for patients. in summary, we found a positive association between sputum viral load and disease severity as well as risk of progression. potential association between covid-19 mortality and health-care resource availability sars-cov-2 viral load in upper respiratory specimens of infected patients viral load of sars-cov-2 in clinical samples publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.authors' contributions j.s conceptualized the idea and designed the study. x.y and s.s drafted the manuscript and j.s revised it. x.y, s.s, y.s, h.w, and r.z participated in the data collection, analysis, and interpretation. the authors read and approved the final manuscript. this work was supported by grants from chinese national natural science foundation (no. 81670567 and 81870425) and the fundamental research funds for the central universities. the datasets and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request. this study is reviewed and approved by the ethics committee of the first affiliated hospital of zhejiang university. following a full explanation of the study, written consent was obtained from each patient or his/her authorized representatives. not applicable. the authors declare that they have no competing interests.received: 26 march 2020 accepted: 14 april 2020 key: cord-319101-2vdd10mu authors: abrams, darryl; lorusso, roberto; vincent, jean-louis; brodie, daniel title: ecmo during the covid-19 pandemic: when is it unjustified? date: 2020-08-17 journal: crit care doi: 10.1186/s13054-020-03230-9 sha: doc_id: 319101 cord_uid: 2vdd10mu nan darryl abrams 1,2 , roberto lorusso 3 , jean-louis vincent 4 and daniel brodie 1,2* the coronavirus disease 2019 (covid-19) pandemic has led to a critical shortage of resources in the hardest-hit areas around the world [1] . intensive care units (icus) overwhelmed by critically ill patients may create non-conventional icu spaces and even consider triaging invasive mechanical ventilation to those most likely to benefit [2] . in the most severe cases of refractory hypoxemia, extracorporeal membrane oxygenation (ecmo) may be considered, as recommended by the world health organization for severe covid-19. early data suggest there may be a benefit from ecmo in certain patients with covid-19-associated respiratory failure, though outcomes are likely to be highly dependent on patient selection and timing of ecmo initiation [3] . whether certain phenotypes of covid-19 (if present) have differential responses to and prognoses with ecmo remains to be determined [4] . an important question then is whether a resource-intensive therapy is warranted when systems are already strained [5] . the high severity of the respiratory failure in some patients with covid-19 anticipates the need for ecmo in a large number of patients. however, circumstances that limit otherwise readily available resources raise the threshold for initiating more complex therapies. therefore, in the context of the covid-19 pandemic, adherence to evidence-based algorithms is necessary to optimize the allocation of limited resources. every effort should be made to apply established, less invasive strategies, including prone positioning and optimization of volume status, prior to consideration of ecmo in these patients [6] , but ecmo may still be required. in fact, the limited availability of ecmo, due in part to shortages in ecmo equipment and insufficient capacity at ecmocapable centers, may lead to the unanticipated benefit of more widespread adoption of these proven therapies that often go underutilized [7] . perhaps the initial question should not be when, but whether to use ecmo at all in the covid-19 pandemic. analyses have demonstrated a benefit from ecmo in severe forms of the acute respiratory distress syndrome (ards) [8] , though such benefit comes at real costs, and not simply financial ones. in the case of a pandemic requiring crisis standards of care, every resource has the potential to become critical to the functioning of an icu or the care of critically ill patients. most prominently, staffing may emerge as a critical bottleneck. the use of ecmo taxes many resources, but none more so than staffing-increased nursing ratios, need for ecmo specialists, disproportionate medical provider time, not to mention other staff, such as respiratory or physical therapists, who would be needed elsewhere for the care of other patients [9] . given that staffing may already be maximally strained, the excess resources needed for the ecmo patient will negatively and disproportionately impact the care of non-ecmo patients relative to the addition of another critically ill patient not receiving ecmo. during a crisis, ecmo may not be a zero-sum game. the inability to manage this strain will likely be greatest among lower-volume, less-experienced ecmo centers, providing rationale for the regionalization of ecmo [9] , an approach which itself may be further limited by excess patient volume at all centers, resulting in suboptimal provision of care to ecmo patients in general. in this context, can ecmo be justified in the epicenter of a pandemic? during non-pandemic times, in hospitals or regions with sufficient staffing reserves and provider availability, it may be understandable why clinicians might attempt ecmo in a candidate with a low, but acceptable, probability of benefit (e.g., a post-partum patient with refractory shock in multisystem organ failure). yet, one would be hard-pressed to justify the same approach if it meant a tangible sacrifice in the care of other patients in whom there is greater likelihood of favorable outcomes. effectively, at times of substantially increased strain on hospital and healthcare systems, there needs to be more judicious patient selection, reserving ecmo only for those patients who are most likely to derive benefit, assuming an acceptable level of care can be maintained for other patients, in an attempt to achieve the greatest benefit for the greatest number of patients-a utilitarian standard that may apply under crisis standards of care. beyond withholding ecmo, the most dire of situations may seem to necessitate the withdrawal of ecmo from those in whom there is no perceived chance of meaningful recovery-regardless of the opinion of the patient or surrogate decisionmaker [10, 11] . triage committees may be helpful to help determine the allocation of resources under such circumstances [12] . the use of ecmo in a pandemic can be seen following a u-shaped curve (fig. 1) , rising as the number of cases rises, decreasing as resources become increasingly scarce, and possibly rising again as strain eases on the back-end of the crisis or trailing off as the number of patients qualifying for ecmo likewise tapers down. of course, under the most extreme of circumstances (at the bottom of the curve), ecmo may have to be abandoned altogether [13] . therein lies the key principle: the use of ecmo should not be considered in a vacuum; the consequences of choosing to initiate ecmo in a crisis are not just borne by that patient alone. fig. 1 potential curve of ecmo case volume during the covid-19 pandemic. during surge conditions, ecmo usage will be variable (red dashed line), including the potential of being abandoned altogether. as the pandemic resolves and patient volume decreases, there may be increasing resource availability and ecmo use (blue arrow) or decreasing demand (green arrow) epidemiology, clinical course, and outcomes of critically ill adults with covid-19 in new york city: a prospective cohort study considerations for ventilator triage during the covid-19 pandemic the role of ecmo in covid-19: can it provide rescue therapy in those who are critically ill? covid-19-associated acute respiratory distress syndrome: is a different approach to management warranted? who clinical management of severe acute respiratory infection (sari) when covid-19 disease is suspected: interim guidance ecmo for ards: from salvage to standard of care? unproven and expensive before proven and cheap: extracorporeal membrane oxygenation versus prone position in acute respiratory distress syndrome venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients ethical aspects of the covid-19 crisis: how to deal with an overwhelming shortage of acute beds ethical dilemmas encountered with the use of extracorporeal membrane oxygenation in adults the toughest triage -allocating ventilators in a pandemic understanding pathways to death in patients with covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions da and db wrote the first draft of the manuscript. rl and jvl reviewed and edited the manuscript. all authors read and approved the final manuscript. key: cord-344965-h945xi7y authors: wang, ying; shi, li; yang, haiyan; duan, guangcai; wang, yadong title: pooled prevalence of deep vein thrombosis among coronavirus disease 2019 patients date: 2020-07-28 journal: crit care doi: 10.1186/s13054-020-03181-1 sha: doc_id: 344965 cord_uid: h945xi7y nan to the editor, the article by ren et al. reported that there was an extremely high incidence (85.4%) of lower extremity deep venous thrombosis (dvt) among 48 patients with severe coronavirus disease 2019 in wuhan, china [1] . as the global pandemic of covid-19, there have been several studies on the incidence, risk factors, and preventive strategies of dvt [1] [2] [3] [4] . however, the incidence of dvt has been reported diversely among different clinical centers. thus, we performed a meta-analysis to estimate the pooled prevalence of dvt in confirmed covid-19 patients. we searched pubmed, embase, web of science, and medrxiv databases until june 22, 2020, for relevant studies, using the keywords ("coronavirus" or "covid-19" or "sars-cov-2" or "2019-ncov") and ("thrombosis" or "thrombi" or "thrombus"). in addition, we screened out the relevant potential articles in the references of selected studies. articles reporting the prevalence of dvt in confirmed covid-19 patients were included. the pooled prevalence and its 95% confidence interval (ci) were used to estimate the combined effects. we calculated the prevalence estimates with the variance stabilizing double arcsine transformation [5, 6] . the heterogeneity among studies was assessed with the i 2 statistic and cochran's q test. the meta-regression and subgroup analysis were used to investigate the potential heterogeneity sources (such as sample size, prevalence of prophylaxis in covid-19 patients, location, design of studies, screening methods of dvt, and covid-19 patients in intensive care unit (icu)). we chose egger's test and begg's test to assess publication bias. all analyses were performed using the stata 11.2 (statacorp, college station, tx), and a twotailed p value < 0.05 was considered to be statistically significant. a total of 1202 records were initially identified by our searches. we finally included 28 articles in our meta-analysis. the basic characteristics of included studies are shown in table 1 . there were 397 dvt cases in a total of 4138 covid-19 patients. the pooled estimate of the prevalence for dvt was 16% by using a random-effects model (95% ci 10-23%, p < 0.01, i 2 = 96.81, q = 846.41, p < 0.01) (fig. 1a ). according to patients' geographic location, the much higher pooled prevalence of dvt was found in covid-19 patients from china (30%, 95% ci 2-72%, p = 0.02, i 2 = 98.73%, q = 313.90, p < 0.01) compared with those from western countries (13%, 95% ci 8-19%, p < 0.01, i 2 = 95.62%, q = 502.07, p < 0.01) (fig. 1b) . twenty articles clearly reported the prevalence of dvt in covid-19 patients treated in icu or non-icu. the pooled prevalence of dvt in table 1 characteristics of the included studies covid-19 patients treated in icu was 23% (95% ci 11-38%, p < 0.01, i 2 = 96.44%, q = 421.29, p < 0.01), which was significantly higher than in covid-19 patients treated in non-icu (5%, 95% ci 1-11%, p < 0.01, i 2 = 92.17%, q = 89.42, p < 0.01) (fig. 1c, d) . we found significant publication bias by egger's test (p < 0.001) and begg's test (p < 0.001). the subgroup analysis showed that none of these factors could explain the significant heterogeneity. however, the meta-regression analysis of multiple covariates indicated that the geographic location of patients could partially explain heterogeneity (p = 0.036). in conclusion, more attention should be paid to the prevention and clinical management of dvt, especially for covid-19 patients in icu, and timely assessment of dvt is essential. however, there was considerable heterogeneity in our meta-analysis. in addition, there was significant publication bias in our meta-analysis, although we searched four databases as many and as carefully as possible. finally, we included non-survival patients who were seriously ill and may exaggerate the prevalence of dvt in covid-19 patients. extremely high incidence of lower extremity deep venous thrombosis in 48 patients with severe covid-19 in wuhan deep vein thrombosis in hospitalized patients with coronavirus disease 2019 (covid-19) in wuhan, china: prevalence, risk factors, and outcome incidence of venous thromboembolism in hospitalized patients with covid-19. j thrombosis haemostasis occupational health outcomes among international migrant workers: a systematic review and meta-analysis two-sided confidence intervals for the single proportion: comparison of seven methods publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. ying wang, li shi, and yadong wang designed the study, performed the analyses, and wrote the manuscript; ying wang, li shi, haiyan yang, and guangcai duan performed the statistics; and all authors critically reviewed and approved the manuscript. this work was supported by the national natural science foundation of china (no. 81973105). the funder has no role in the preparation of manuscript and decision to submission. availability of data and materials all data generated or analyzed during this study are included in this article.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no conflict of interests.received: 30 june 2020 accepted: 15 july 2020 key: cord-323601-qzruawe1 authors: dufranc, etienne; del bello, arnaud; belliere, julie; kamar, nassim; faguer, stanislas title: il6-r blocking with tocilizumab in critically ill patients with hemophagocytic syndrome date: 2020-04-22 journal: crit care doi: 10.1186/s13054-020-02878-7 sha: doc_id: 323601 cord_uid: qzruawe1 nan to the editor, hemophagocytic lymphohistiocytosis (hlh) is a rare life-threatening hematological disorder characterized by uncontrolled activation of cd8 + t cells and nk cells, cytokine storm (including overproduction of interleukine-6 (il6)), and uncontrolled hemophagocytosis leading to severe organ dysfunction [1] . several causes of hlh have been identified, including infection, cancer, drugs, and autoimmune diseases [1] . diagnosis of hlh is challenging, and the h-score may help to better identify patients with reactive hlh [2] . a combination of dexamethasone, etoposide, and treatment of the underlying cause is the cornerstone of treatment for severe forms of hlh [1] . because some patients may develop refractory or relapsing hlh, alternative treatments targeting specific immune pathways or cytokine signaling have been tested [1] . these approaches also aim to avoid long-lasting etoposide-induced neutropenia in patients with bone marrow failure or after transplantation. tocilizumab, a monoclonal antibody targeting the receptor of il6, fully reverses the multi-organ failure and the cytokine profile of the car-t cell-induced cytokinerelease syndrome [3] . this prompted some groups including ours to treat severe hlh secondary to acute autoimmune disease with tocilizumab [4] . targeting one of the major cytokines that orchestrate the cytokine storm may be an alternative to etoposide in patients with hlh not related to hematological malignancies. in the herein study, we reviewed the outcomes of nine critically ill patients who received tocilizumab to treat hlh ( table 1 ). eight of them received at least one organ support. median h-score was 208 (probability of hlh according to the score, 92.5%), and all patients had at least 4 to 7 criteria of the modified 2009 hlh criteria (genetic testing and nk cell activity were not available; scd25 was tested in one patient). causes of hlh were multiples: autoimmune diseases in four, infection (bacterial or viral) in three, and idiopathic in two. in addition to tocilizumab (8 mg/kg once, intravenously), five patients received concomitant treatment with dexamethasone (n = 4), cyclophosphamide (n = 2), or intravenous immunoglobulins (n = 1). remission was observed in 8/9 patients after tocilizumab (88.9%) whereas one developed refractory hlh, also unresponsive to rescue therapy with etoposide. ferritin progressively decreased over the first 2 weeks (fig. 1 ). one patient relapsed during the hospitalization and successfully received etoposide, but she ultimately died from unrelated gut ischemia. no patient developed profound neutropenia (< 500 cells/mm 3 ), except one who had also received cyclophosphamide. during the hospitalization, four patients died (sepsis-related multi-organ failure n = 1; refractory hlh n = 1; organ support limitation n = 2). none developed hlh relapse beyond the current hospitalization. cytomegalovirus prophylaxis was pursued at least 3 months in transplant recipients. in critically ill patients with severe forms of hlh, etoposide rapidly reverses cytokine storm and improves clinical condition [1] . hlh 94 and 2004 protocols were developed for children with primary hlh (50% successes), but adult patients may be more at risk to develop chemotherapy toxicities [1] . alternatives should thus be discussed in adult patients with chemotherapy-induced bone marrow failure, underlying autoimmune diseases requiring cytotoxic agents, or with a moderate form of hlh not related to hematological malignancies. in line with this need, the jak1/2 inhibitor ruxolitinib was tested in a mouse model of genetic hlh. its benefits were confirmed in patients with reactive hlh [5] , but the oral administration may preclude its pharmacokinetic in critically ill patients requiring mechanical ventilation. due to its intravenous administration, tocilizumab may thus be a valuable alternative after ruling out on-going bacterial or fungal sepsis. in conclusion, il-6-r blockade with tocilizumab may be an alternative in critically ill patients with moderate forms of hlh. whether such beneficial effects may also be observed in the subset of patients with a cytokinerelated syndrome induced by the recently emerging sars-cov2 virus remains to be addressed. [3] . he was first hospitalized for thrombotic microangiopathy associated with autoimmunity and symptoms of rheumatoid arthritis, anti-synthetase syndrome, systemic lupus erythematosus, cryoglobulinemia, and sjogren syndrome recommendations for the management of hemophagocytic lymphohistiocytosis in adults development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome cytokine release syndrome after chimeric antigen receptor t cell therapy for acute lymphoblastic leukemia tocilizumab added to conventional therapy reverses both the cytokine profile and cd8+granzyme+ t-cells/nk cells expansion in refractory hemophagocytic lymphohistiocytosis ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank the practitioners that followed the patients before and after their course in the icu. taidi (toulouse acquired immune deficiency and infection) study group: etienne dufranc, arnaud del bello, julie belliere, nassim kamar and stanislas faguer. authors' contributions sf designed the study; ed collected the data; sf, nk, and adb wrote the manuscript. all authors followed the patients. the authors read and approved the final manuscript. none. the authors stated that all the data are available upon request.ethics approval and consent to participate there are no ethical/legal conflicts involved in the article. not applicable. the authors have no conflicts of interest to disclose. key: cord-319936-5uze06rp authors: dixon, barry; santamaria, john d; campbell, duncan j title: a phase 1 trial of nebulised heparin in acute lung injury date: 2008-05-06 journal: crit care doi: 10.1186/cc6894 sha: doc_id: 319936 cord_uid: 5uze06rp introduction: animal studies of acute lung injury (ali) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. no human studies have been undertaken to date. we assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ali. methods: an open label phase 1 trial of four escalating doses of nebulised heparin was performed. a total of 16 ventilated patients with ali were studied. the first group was administered a total of 50,000 u/day, the second group 100,000 u/day, the third group 200,000 u/day and the fourth group 400,000 u/day. assessments of lung function included the pao(2)/fio(2 )ratio, lung compliance and the alveolar dead space fraction. monitoring of anticoagulation included the activated partial thromboplastin time (aptt) and the thrombin clotting time. bronchoalveolar lavage fluid was collected and the prothrombin fragment and tissue plasminogen activator levels were assessed. analysis of variance was used to compare the effects of dose. results: no serious adverse events occurred for any dose. the changes over time for the pao(2)/fio(2 )ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses. a trend to increased aptt and thrombin clotting time levels was present with higher doses (p = 0.09 and p = 0.1, respectively). for the highest dose, the aptt reached 64 seconds; following cessation of nebulised heparin, the aptt fell to 39 seconds (p = 0.06). in bronchoalveolar lavage samples a trend to reduced prothrombin fragment levels was present with higher doses (p = 0.1), while tissue plasminogen activator levels were similar for all doses. conclusion: administration of nebulised heparin to mechanically ventilated patients with ali is feasible. nebulised heparin was not associated with any serious adverse events, and at higher doses it increased aptt levels. larger trials are required to further investigate the safety and efficacy of nebulised heparin. in these trials due consideration must be given to systemic anticoagulant effects. trial registration: australian clinical trials registry actrn12606000388516. acute lung injury (ali) is a serious clinical problem. estimates are that 190,600 cases of ali develop in the united states each year, which are associated with 74,500 deaths and 3.6 million hospital days [1] . the 28-day mortality for ali is 32% [2] . there is currently no method to prevent or treat ali ali is characterised by the rapid onset of respiratory distress in the setting of an inflammatory insult to the lungs [3, 4] . inflammatory insults include sepsis, trauma, hypotension, cardiopulmonary bypass, pancreatitis, aspiration and multiple transfusions. septic insults are by the commonest cause of ali. pneumonia triggers 30% of cases, and sepsis elsewhere in the body causes 32% of cases [2] one mechanism by which inflammation causes ali is deposition of fibrin in the alveolar space and microcirculation. fibrin deposition in the alveolar sacs gives rise to a hyaline membrane, and deposition in the microvasculature results in thrombosis [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] . nebulised heparin may limit fibrin deposition in the alveolar space and microcirculation through heparin's anticoagulant and fibrinolytic actions [15] [16] [17] [18] . studies in animal models of ali have demonstrated that nebulised heparin improved the pao 2 /fio 2 ratio and reduced histological ali = acute lung injury; aptt = activated partial thromboplastin time; bal = bronchoalveolar lavage; elisa = enzyme-linked immunosorbent assay; pao 2 /fio 2 = arterial oxygen partial pressure to inspired oxygen fraction ratio; ptf = prothrombin fragments; tct = thrombin clotting time; t-pa = tissue plasminogen activator. (page number not for citation purposes) damage [19, 20] . in addition, in the setting of lung injury triggered by cardiac surgery, a preoperative heparin infusion reduced evidence of pulmonary microvascular thrombosis [21] . we are unaware of previous trials of nebulised heparin in patients with ali. we therefore undertook the present trial to assess the feasibility, safety and potential anticoagulant effects of nebulised heparin in mechanically ventilated patients with ali. in addition, we assessed the effects on intrapulmonary coagulation activation and fibrinolysis. the study was approved by the st vincent's hospital human research ethics committee. consent was obtained from the patient or next of kin before participation in the study. the present study was an open-label, escalating-dosage phase 1 trial of nebulised heparin (heparin sodium, 25,000 u/ ml; cp pharmaceuticals ltd, wrexham, uk) in mechanically ventilated patients with ali. four doses were studied. each dose was assessed in four patients over 2 days. the first group was administered 50,000 u/day, as 25,000 u 12 hourly (four nebulisations); the second group received 100,000 u/ day, as 50,000 u 12 hourly (four nebulisations); the third group received 200,000 u/day, as 100,000 u 12 hourly (four nebulisations); and the fourth group was administered 400,000 u/day, as 100,000 u 6 hourly (eight nebulisations). the final nebulisation of heparin was administered at 36 hours from baseline in the 50,000 u/day, 100,000 u/day and 200,000 u/day groups, and at 42 hours in the 400,000 u/day group. we studied patients admitted to the intensive care unit that met the following inclusion and exclusion criteria. the inclusion criterion was the initiation of mechanical ventilation for acute respiratory dysfunction characterised by a pao 2 / fio 2 ratio < 300 mmhg, where the acute respiratory dysfunction was primarily due to a direct or indirect inflammatory insult to the lung. the exclusion criteria were > 48 hours since the inclusion criterion was met; hypoxemia predominantly due to a cause other than ali, such as congestive heart failure, pulmonary embolism, chronic obstructive airways disease or asthma; systemic anticoagulation (including activated protein c), potential need for haemofiltration and therefore anticoagulation; pulmonary haemorrhage in the previous 3 months, uncontrolled bleeding, significant bleeding disorder; allergy to heparin, including heparin-induced thrombocytopenia; age < 18 years or > 85 years; patient unlikely to survive 96 hours; bronchoscopy not possible due to severe hypoxia; previous intubation and venti-lation during current admission; noninvasive ventilation for more than 36 hours prior to intubation; or pregnancy. heparin was nebulised with an aeroneb pro nebulizer (aerogen ltd, galway, ireland) over 30 minutes. the nebuliser was placed in the inspiratory line 12 cm from the y of the circuit. the heat and moisture exchanger was removed during nebulisation. patients were ventilated in a pressure-support mode of ventilation and upper pressure levels were maintained at or below 35 cmh 2 o. the p a o 2 /f i o 2 ratio, lung compliance and the alveolar dead space fraction were measured at baseline and at 2, 6, 10, 14, 18, 22, 26, 30, 34, 28, 42 and 46 hours. we measured the alveolar dead space fraction because previous studies have suggested this variable may reflect the extent of microvascular thrombosis in ali [21, 22] . evidence of blood staining of respiratory secretions was assessed by the bedside nurse following routine pulmonary suctioning. the activated partial thromboplastin time (aptt) and the thrombin clotting time (tct) were assessed at the same time points as those of lung function, and at 50, 54 and 58 hours in the 400,000 u/day group. prothrombin fragments (ptf) and tissue plasminogen activator (t-pa) levels in bronchoalveolar lavage (bal) fluid were assessed at baseline and following the final nebulisation (bal was undertaken on average 7.6 ± 5 hours following the final nebulisation). standard formulae were used to calculate lung compliance. the alveolar dead space fraction was measured with the cosmo plus respironics monitor (novametrix medical systems, wallingford, ct, usa) [21] . the bronchoscope was wedged in the distal airway. the initial 25 ml of warm saline injected was discarded. five further 25 ml aliquots were instilled and aspirated. a portion of the aspirated fluid was spun at 1,500 × g for 10 minutes at 4°c. the supernatant was stored at -80°c. samples were assayed by elisas for ptf levels (enzygnost f1 + 2 monoclonal assays; behring, marburg, germany) and for t-pa antigen levels (tin-telize tpa, biopool international, ventura, ca, usa). based on previous studies we determined that four patients in each group would be adequate to detect a major anticoagulant effect [23, 24] . analysis of variance was used to compare the effect of heparin dose on the p a o 2 /f i o 2 ratio, lung compliance, the alveolar dead space fraction, the aptt, the tct and intrapulmonary ptf and t-pa levels. fisher's exact test compared categorical variables. student's t test compared normally distributed variables. data are reported as the mean ± standard deviation. statistical analysis was performed with the jmp program (sas institute, inc., cary, nc, usa). sixteen patients were enrolled. the mean patient age was 58 ± 14 years, and the acute physiology and chronic health evaluation score ii was 21 ± 7. the baseline p a o 2 /f i o 2 ratio was 183 ± 66 mmhg, lung compliance was 26 ± 14 ml/ cmh 2 o and the alveolar dead space fraction was 0.23 ± 0.1. prophylactic subcutaneous heparin was administered to 14 of the 16 patients studied. the commonest aetiological factor for ali was pneumonia ( table 1) . the time from intubation to initial heparin nebulisation was 22 ± 15 hours. the mean mechanical ventilation time was 10 ± 9 days, the intensive care length of stay was 12 ± 8 days and the hospital length of stay was 28 ± 14 days. the tracheostomy rate was 63% and the hospital mortality was 43%. the changes over time in the p a o 2 /f i o 2 ratio, lung compliance and the alveolar dead space fraction were similar for all doses studied. there were no statistically significant differences found for the dosage or for the interaction between dosage and time (figures 1 to 3 ). one patient in the 400,000 u/day group developed bloodstained respiratory secretions after the seventh dose. this was not associated with any deterioration in lung function. the blood staining resolved following withdrawal of nebulised heparin. the mean aptt for each group following the final nebulisation, in order of increasing dose, was 34 seconds (normal range < 35 seconds), 41 seconds, 48 seconds and 64 seconds (p = 0.09, analysis of variance, comparison by dose) (figure 4 ). the mean tct for each group following the final nebulisation, in order of increasing dose, was 18 seconds (normal range < 21 seconds), 23 seconds, 50 seconds and 48 seconds (p = 0.1, analysis of variance, comparison by dose) ( figure 5 ). for the higher dose groups, both the aptt and tct fell following cessation of nebulised heparin. for the highest dose, the aptt fell from 64 seconds to 39 seconds (p = 0.06) (figure 4 ). the ptf levels in bal fluid in the 50,000 u/day group were higher following the final nebulisation, while in the 100,000 u/ day, 200,000 u/day and 400,000 u/day groups the ptf levels remained similar to baseline levels following the final nebulisation (p = 0.1, analysis of variance, comparison by dose) (figure 6 ). the t-pa levels were similar to baseline levels for all doses following the final nebulisation ( figure 7 ). changes in arterial to inspired oxygen ratio with nebulised heparin dosage changes in arterial to inspired oxygen ratio with nebulised heparin dosage. percentage change from baseline in the arterial to inspired oxygen ratio (p a o 2 /f i o 2 ) (mean ± standard deviation). changes in lung compliance with nebulised heparin dosage changes in lung compliance with nebulised heparin dosage. percentage change from baseline in the lung compliance over time for each dose (mean ± standard deviation). (page number not for citation purposes) changes in alveolar dead space fraction with nebulised heparin dosage changes in alveolar dead space fraction with nebulised heparin dosage. percentage change from baseline in the alveolar dead space fraction (adsf) (mean ± standard deviation). we assessed the feasibility, safety and potential anticoagulant effects of nebulised heparin in mechanically ventilated patients with ali. we found administration of nebulised heparin to mechanically ventilated patients with ali was feasible, was not associated with serious adverse events, and increased aptt levels at higher doses. the changes in the pao 2 /fio 2 ratio, lung compliance and the alveolar dead space fraction were similar for all doses. in one patient in the 400,000 u/day group, blood staining of the respiratory secretions was present after the seventh dose. this staining resolved following withdrawal of heparin. we found evidence of dose-dependent effects on aptt and tct levels. for the 50,000 u/day group, the levels remained within the normal range; however, for the 100,000 u/day, 200,000 u/day and 400,000 u/day groups, the aptt and tct levels were raised on the second day. peak levels were reached following the final nebulisation, and thereafter levels fell. for the 400,000 u/day group, the aptt reached the therapeutic range (64 seconds) and fell acutely to 39 seconds following cessation of nebulised heparin. previous clinical studies have investigated the potential of systemic anticoagulation using nebulised heparin -to date, without success [23, 24] . unlike these studies we used repeated doses of nebulised heparin. our finding that the aptt and tct levels increased only after repeated doses suggests that pulmonary processes, such as storage of heparin in endothelial cells and metabolism by heparinases, may initially limit heparin reaching the systemic circulation. these processes may, however, become saturated following repeated heparin doses [25] . in future trials of nebulised heparin, due consideration must be given to this systemic anticoagulant effect. we also examined whether nebulised heparin limited coagulation and increased fibrinolysis in the lungs. for the 50,000 u/ day group, the ptf levels in bal fluid doubled from baseline levels following the final nebulisation. for the 100,000 u/day, 200,000 u/day and 400,000 u/day groups, however, the ptf levels did not increase. previous trials in patients with ventilated-associated pneumonia also found a doubling of coagulation levels in bal fluid over the first few days [26, 27] . while inconclusive, our findings raise the possibility that nebulised heparin, at higher doses, limited coagulation activation in the lungs. nebulised heparin did not increase t-pa levels in bal fluid for any of the doses studied. one of the strengths of the present study was the nebulisation system used. the evidence of a dose-related effect on systemic aptt and tct levels suggested significant amounts of heparin reached the alveolar spaces. this finding is consistent with previous studies [28] . another strength of the study was the inclusion of genuinely high-risk patients with ali. the aver-age p a o 2 /f i o 2 ratio at baseline was 183 mmhg, the tracheostomy rate was 63% and the hospital mortality was 43%. limitations of the present study included the absence of a control group, the small number of patients enrolled and the relatively short time (2 days) over which heparin was nebulised. the size of the study reflected the need for caution, as nebulised heparin had not previously been administered to patients with ali. furthermore, we determined that four patients in each group would provide adequate power to detect a major anticoagulant effect. our study was consequently too small to draw conclusions regarding efficacy or potential infrequent deleterious effects. previous studies in animal models of ali have demonstrated significant improvements in pulmonary function with inhaled heparin and other glycosaminoglycans [19, 20, 29] . heparin has a range of anticoagulant actions and also promotes fibrinolysis through increased t-pa levels [15] [16] [17] [18] . compared with the intravenous route, nebulisation delivers high concentrations of heparin to the alveolar space with a reduced risk of adversely effecting systemic coagulation. administration of nebulised heparin to mechanically ventilated patients with ali is feasible. the heparin administration was not associated with any serious adverse events, and increased aptt levels at higher doses. larger trials are required to further investigate the safety and efficacy of nebulised heparin in ali. in these trials, due consideration must be given to systemic anticoagulant effects. (page number not for citation purposes) ies had no role in the study design, data collection, analysis and interpretation of the data or in the writing and publication of the manuscript. incidence and outcomes of acute lung injury incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three australian states the acute respiratory distress syndrome definitions, mechanisms, relevant outcomes, and clinical trial coordination pathophysiology of the respiratory distress syndrome lung pathology of fatal severe acute respiratory syndrome case records of the massachusetts general hospital. weekly clinicopathological exercises. case 22 -1977 disseminated intravascular coagulation in newborn infants. prevalence in autopsies and significance as a cause of death the pulmonary vascular lesions of the adult respiratory distress syndrome intravascular coagulation associated with the adult respiratory distress syndrome pulmonary pathology in acute respiratory insufficiency: lung biopsy as a diagnostic tool the microembolism syndrome pathological manifestations of septic shock infection and disseminated intravascular coagulation heparin reverses the procoagulant properties of stimulated endothelial cells neri serneri gg: tissue factor reduction and tissue factor pathway inhibitor release after heparin administration tissue factor and plasminogen activator inhibitor type 2 expression in human stimulated monocytes is inhibited by heparin the effect of heparin and other glycosaminoglycans on levels of tissue plasminogen activator and plasminogen activator inhibitor in cultured human umbilical vein endothelial cells heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits elevated pulmonary dead space and coagulation abnormalities suggest lung microvascular thrombosis in patients undergoing cardiac surgery pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome effect of inhaled heparin on lung function and coagulation in healthy volunteers anticoagulant effects and tissue factor pathway inhibitor after intrapulmonary low-molecular-weight heparin endothelial sequestration of heparin administered by the intrapulmonary route clinical and hemostatic responses to treatment in ventilator-associated pneumonia: role of bacterial pathogens poll t van der: local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia lung deposition and clearance of inhaled (99m)tc-heparin in healthy volunteers the effects of aerosolized dextran in a mouse model of pseudomonas aeruginosa pulmonary infection the present study was supported by the st vincent's hospital research endowment fund and the intensive care foundation. the funding bodthe authors declare that they have no competing interests. bd designed the study, collected the data, performed the statistical analysis and drafted the manuscript. jds and djc participated in its design, and coordinated and helped to draft the manuscript. all authors read and approved the final manuscript. key: cord-353344-tzyu6j6n authors: van berkel, miranda; kox, matthijs; frenzel, tim; pickkers, peter; schouten, jeroen title: biomarkers for antimicrobial stewardship: a reappraisal in covid-19 times? date: 2020-10-06 journal: crit care doi: 10.1186/s13054-020-03291-w sha: doc_id: 353344 cord_uid: tzyu6j6n nan on initial presentation, differentiation between earlystage coronavirus disease 2019 (covid-19) and classical bacterial community-acquired pneumonia can be challenging. furthermore, covid-19 patients may develop a hyperinflammatory phase later in their disease process, which is particularly difficult to distinguish from a secondary bacterial infection. as a consequence, 72% of covid-19 patients receive empirical antibiotic therapy during hospital stay [1] . antibiotic overuse undoubtedly leads to an exacerbation of another-slowly progressive-pandemic: antimicrobial resistance [2] . procalcitonin (pct) has proven useful in the early diagnosis of lower respiratory tract infections of bacterial origin [3] . furthermore, in the icu setting, serial measurement of pct can safely guide the withdrawal of antibiotic therapy [4] . in patients with covid-19, c-reactive protein (crp) is usually increased on presentation while pct is often low [5] . pct appears to increase in covid patients with severe disease and/or in those presenting with secondary bacterial infections [6] . longitudinal data on both biomarkers in covid-19 infections are currently lacking. also, it is unclear to what extent pct and crp predict the occurrence of secondary infections in these patients. data from 66 covid-19 icu patients were recorded in the good clinical practice (gcp)-compliant data management system castor (castor edc, amsterdam, the netherlands). pct was determined using the elecsys brahms procalcitonin assay (thermo fisher scientific), whereas crp was determined using an immunoturbidimetric assay, both on a cobas 8000 immunoanalyzer (roche diagnostics). secondary infection was defined as "any infectious episode" evidenced by the presence of positive cultures and time-stamped at the day the culture was performed. infectious episodes were independ-ently determined by two icu physicians (js and ht). in case of incongruency, a third icu physician (pp) was consulted. in case of multiple secondary infections, only the first infectious episode was analyzed. half of the patients (n = 33) developed a secondary infection during icu admission. no significant differences in characteristics were observed between patients who did or did not develop a secondary infection (table 1 ). in patients without secondary infection, both pct and crp decreased over time (fig. 1a) , with pct values lower (peak geometric mean [95% ci] of 0.64 [0.32-1.27] μg/l) than crp (peak geometric mean [95% ci] of 192 [107-342] mg/l) compared to their respective cutoff values for bacterial infection (< 0.5 μg/l and < 100 mg/l, respectively). a significant increase in both pct and crp levels was observed in case of the occurrence of a secondary infection (fig. 1b) . the receiver operating curve analysis of pct and crp yielded aucs of 0.80 and 0.76, respectively (fig. 1c) . in patients with pct < 0.25 μg/l, the negative predictive value was 81%, whereas pct levels of > 1.00 μg/l had a positive predictive value of 93%. intermediate pct levels were of limited diagnostic value. for crp, predictive values were less robust (fig. 1c) . the use of biomarkers to predict secondary infections in icu patients warrants reappraisal in times of covid-19. we demonstrate that covid-19 patients who do not develop a bacterial infection present with high initial crp levels and lowmoderate pct levels that gradually decrease over time. furthermore, our data show that, during icu admission, pct levels of > 1.00 μg/l rule in, whereas concentrations of < 0.25 μg/l rule out secondary bacterial infections with good predictive values. with regard to icu antimicrobial stewardship, initiation of empirical antibacterial therapy in icu patients with low pct levels should probably not be started. as crp is consistently elevated, this biomarker does not have predictive value for bacterial infections in the initial phase of covid-19. later on during icu stay, serial pct and, to a lesser extent, crp may help to identify or rule out nosocomial bacterial infections and prompt appropriate use of antibiotic therapy. . data are aligned on the day of the start of covid symptoms, which is designated day 0. the arrows indicate the median day of hospital admission (day 7, interquartile range [5] [6] [7] [8] [9] [10] [11] ) and the median day of icu admission (day 10, interquartile range [6] [7] [8] [9] [10] [11] [12] [13] [14] ). data are expressed as geometric means with 95% confidence interval. when biomarker variables were not measured daily, data were binned into bins spanning 2 days using a custom script made in r-studio v3.6.2 (www.r-project.org). if more than one value was present in these 2-day bins, the mean value was used. b serial values of pct (left panel) and crp (right panel) in patients (n = 33) with covid-19 who did develop (n = 33) or did not (n = 33) develop a secondary infection. data are aligned on the day of secondary infection, which is designated day 0. for the "no secondary infection" group, data are aligned on the median day of infection in the "secondary infection" group (day 14 after icu admission). data are expressed as geometric means with 95% confidence interval. data were binned into bins spanning 2 days (see a for details). the groups were compared using mixed-models analysis (time × group interaction factor) on log-transformed data. p values placed under graph titles reflect between-group differences over the entire time period (day − 10 until day 14). p values for day − 10 until day 0 and day 0 until day 14 are shown on the top left and right. c receiver operating curve to illustrate sensitivity and specificity of pct (left panel) and crp (right panel) levels to predict secondary infection. binned pct/ crp data of day − 1 and day 0 were used (see a for details). positive predictive value (ppv), negative predictive value (npv), and incidence are provided for the depicted concentrations bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid-19 antimicrobial prescribing covid-19: don't neglect antimicrobial stewardship principles! procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial « laboratory abnormalities in patients with covid-2019 infection » clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in wuhan publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-351264-zp41u14l authors: quah, pipetius; li, andrew; phua, jason title: mortality rates of patients with covid-19 in the intensive care unit: a systematic review of the emerging literature date: 2020-06-04 journal: crit care doi: 10.1186/s13054-020-03006-1 sha: doc_id: 351264 cord_uid: zp41u14l nan mortality rates of patients with covid-19 in the intensive care unit: a systematic review of the emerging literature pipetius quah 1* , andrew li 1 and jason phua 1, 2 the understanding of outcomes in the intensive care unit (icu) for the coronavirus disease 2019 (covid-19) remains poor. studies have reported close to 100% mortality amongst patients requiring mechanical ventilation [1] , and this together with the hypothesis that covid-19 may not cause classic acute respiratory distress syndrome (ards) has led to concerns regarding the use of mechanical ventilation [2, 3] . we thus aimed to review the outcomes of icu patients with covid-19 from the existing literature. we searched pubmed for studies published between dec 1, 2019, and may 8, 2020, with at least ten icu patients with covid-19 and reported icu mortality data. we excluded studies that had duplicate patients from other reports, did not provide data on icu survival, enrolled only decedents, and excluded patients who were still hospitalised ( fig. 1 and electronic supplementary material). several lessons can be surmised from table 1 , which outlines the 15 included studies conducted largely in countries worst hit by the pandemic. first, 56.1% of patients were still in the icu at the time of study publication, and attempts to calculate mortality based on a sample of only deceased or discharged patients risk painting a skewed picture of reality [4] . second, with the prior limitation in mind, the overall icu mortality rate was 25.7%. in china, with 14.1% of patients still in the icu, the mortality rate was 37.7%. these figures are not higher than the mortality rates of 35 to 45% seen in ards. third, 29% of the icu patients who died in the chinese studies did not receive mechanical ventilation, and where systems experienced a surge of critically ill patients, up to 53.2% of patients who required icu care were unable to receive it because of resource constraints [5] . in new york, 262 deaths occurred in hospital wards and outside the icu, compared to 291 deaths in the icu [4] . we hypothesise that rationing of ventilators and icu beds in overwhelmed health systems may have resulted in attempts at postponing intubation, with a significant minority of patients received high-flow nasal cannula (13.7%) and noninvasive ventilation (11.3%) based on available data, despite uncertainty surrounding their roles. we conclude that while there is a need for further studies which capture patients' final dispositions, the current preliminary data does not suggest unusually high icu mortality rates for covid-19. the poor outcomes seen in various studies may be related to rationing of resources in overwhelmed icus. clinical course and outcomes of 344 intensive care patients with covid-19 covid-19 pneumonia: different respiratory treatments for different phenotypes? intensive care med acute respiratory failure in covid-19: is it "typical presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area hospitalization and critical care of 109 decedents with covid-19 pneumonia in wuhan, china publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.author details 1 division of respiratory and critical care medicine, department of medicine, national university hospital, national university health system, singapore, singapore. 2 fast and chronic programmes, alexandra hospital, national university health system, singapore, singapore.received: 12 may 2020 accepted: 19 may 2020 additional file 1. electronic supplementary material. all authors did the literature search. pq and al reviewed the articles and drafted the manuscript, which jp edited and supervised. all authors subsequently revised the manuscript. the author(s) read and approved the final manuscript. this review was not funded by any organisation. the datasets generated during and/or analysed during the current study are available in the pubmed repository. the full list of included studies is available in the electronic supplementary data (appendix). no ethics approval and no patient consent were required for this study. not applicable. all authors declare no competing interests. key: cord-297863-ou432md0 authors: ye, lei; yang, shulan; liu, caixia title: infection prevention and control in nursing severe coronavirus disease (covid-19) patients during the pandemic date: 2020-06-12 journal: crit care doi: 10.1186/s13054-020-03076-1 sha: doc_id: 297863 cord_uid: ou432md0 nan with covid-19 patients in health care, household, and community settings were all detected [7] . covid-19 infections among health workers are common and fatal to the health system. infection among health workers may cause widespread transmission within the system and even lead to the collapse of the whole services. and this was what exactly happened in harbin in the past weeks; a persisting cluster centered on an 87-year-old inpatient infected more than eighty people, including 8 health workers. the affected hospital urgently suspended routine medical services as a result. based on wuhan's experience, it is critical to develop tailored infection prevention and control (ipc) protocols for both workplace and non-occupational settings and to conduct effective ipc training. thus, the following suggestions were summarized based on the first-hand experience of a national medical team from zhejiang, to facilitate the development of ipc protocols in critical care settings. generally, all health workers should implement appropriate personal protective equipment (ppe) regarding contact and droplet precautions based on recommendations by who [8] . for health workers in icu, advanced protections are required during routine intensive care and airborne precautions are considered as airborne transmission may happen during aerosol-generating procedures. the implementation of ppe may be different by option in certain practices. in our experience, the most protective choices were made and the "zero" medical infection rate was treated as the top priority that all staff were equipped from head to toe. compared to official recommendations, we selected some additional ppe during intensive care, such as an extra medical face mask outside the respirator, and both face shield and goggles (see fig. 1 ). additional ppe may increase the risk of sharp injuries and increase the difficulty of donning and doffing. to lower the incidence of adverse events, sequences of donning and doffing ppe were carefully developed based on the above selections through thorough group discussions and agreement was reached among the team. donning and doffing ppe under the three-zone double-channel structure the ward was reconfigured into a three-zone doublechannel structure before accepting covid-19 patients. in this design, the ward was divided into several working areas according to cleanliness and the moving lines of patients and medical staff were fixed (see fig. 2 ). the patient care area was identified as contaminated, and all staff were fully equipped with ppe before entering the buffer area. when doing doffing, all staff took off the additional ppe during intensive care (such as the fluidresistant gown and face shield) in the first buffer area that was near the patient care area. in the second buffer area, staff doffed the coverall and goggles. finally, in the clean area, all staff removed the remaining ppe and conducted personal hygiene. we also developed reasonable shift rotations determined by the most tolerable shift lengths to prolong the use of ppe. in a 4-6 h shift, health care workers avoided eating, watering, and toileting. to strengthen ipc, an inspector was set to facilitate the routine ipc management by on-site monitoring. basically, the inspector was responsible for supervising the adherence of donning and doffing procedures of each health worker and real-time surveillance. in this way, some highrisk intensive interventions were identified and improvement measures were implemented promptly. covid-19specific precautions were drawn among the team consequently, such as waste management. according to recent reports, not only respiratory specimens but also serum, urine, and stool specimens might be positive for covid-19. even though no further ipc advice was provided, advanced procedures for waste managing were necessary, such as collecting respiratory and non-respiratory wastes in covered containers filled with chlorinated disinfectants and discarding in fastened double-layered medical waste garbage bags. timely after arriving wuhan, we established the icp team and developed our own practical icp procedures in non-occupational settings as well. we strictly ruled our behaviors during traffic routes and in the residential region and facilitated the whole team with a remote communication and collaboration platform using cellphone applications to strengthen communication. same as what we do in the ward, we established the three-area double-channel structure and fixed our moving line. besides, we developed behavior codes among the team, such as limiting gatherings and personnel contacts, routine disinfection of contact surfaces (handphone, doorknob, handle, etc.), and frequent hand hygiene on certain occasions. all information provided in this paper is to strengthen the clinical practice in critical care settings and to better protect front-line health workers in nursing severe covid-19 patients. the "zero" medical infection rate in our experience was hard won but worth fighting for. clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan coronavirus disease 2019 (covid-19) in italy covid-19) in italy: analysis of risk factors and proposed remedial measures characteristics and outcomes of 21 critically ill patients with covid-19 in washington state tribute to health workers in china: a group of respectable population during the outbreak of the covid-19 characteristics of health vare personnel with covid-19 -united states infection prevention and control during health care when covid-19 is suspected: interim guidance publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.authors' contributions shulan yang and lei ye were the major contributors in writing and revising the manuscript. all authors read and approved the final manuscript. not applicable. availability of data and materials data sharing not applicable to this article as no datasets were generated or analyzed during the current study.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests.author details key: cord-307512-70j4vn78 authors: worku, elliott; gill, denzil; brodie, daniel; lorusso, roberto; combes, alain; shekar, kiran title: provision of ecpr during covid-19: evidence, equity, and ethical dilemmas date: 2020-07-27 journal: crit care doi: 10.1186/s13054-020-03172-2 sha: doc_id: 307512 cord_uid: 70j4vn78 the use of extracorporeal cardiopulmonary resuscitation (ecpr) to restore circulation during cardiac arrest is a time-critical, resource-intensive intervention of unproven efficacy. the current covid-19 pandemic has brought additional complexity and significant barriers to the ongoing provision and implementation of ecpr services. the logistics of patient selection, expedient cannulation, healthcare worker safety, and post-resuscitation care must be weighed against the ethical considerations of providing an intervention of contentious benefit at a time when critical care resources are being overwhelmed by pandemic demand. extracorporeal cardiopulmonary resuscitation (ecpr) describes the emergent use of extracorporeal membrane oxygenation (ecmo) to restore circulation in patients during cardiac arrest [1] . optimal patient selection, timing of initiation, post-ecpr patient management, and logistical feasibility of providing an ecpr service remain ongoing challenges to securing good outcomes [2, 3] . among patients suffering either an out-of-hospital or an in-hospital cardiac arrest (ohca or ihca), few meet established and generally agreed upon eligibility criteria, and even fewer can be successfully cannulated for ecmo within acceptable timeframes. this makes ecpr a low-volume, high-risk, and resource-intensive intervention, of contentious benefit. with mainly observational data to support the use of ecpr, much remains to be studied in the field. the coronavirus disease 2019 (covid-19) pandemic poses additional challenges to the safe and appropriate use of ecpr. prioritising healthcare worker safety whilst facilitating expedient cannulation is fraught with complexity and presents a considerable barrier to the effective implementation of ecpr in this setting [4] . appropriate candidate selection is a prerequisite for successful ecpr and is challenging under the best of circumstances [5] . currently, identifying patients with the greatest potential to benefit from this resourceintense intervention is limited by the evolving understanding of the natural history of covid-19 and the ability to prognosticate at an individual patient level. finally, increased demand for critical care resources, the institution of crisis standards, and limitations on staffing and equipment are forcing the critical care community to confront the ethical boundaries between individual patient benefit, distributive justice, and resource allocation [6] [7] [8] . rational decision-making must prevail in order to maximise both individual patient, and societal benefits. interventions pertaining to the resuscitation of a patient in cardiac arrest are time critical. when cardiac arrest occurs, blood flow ceases and the resulting "no-flow" state rapidly produces irreversible neurological and multiorgan damage, if not promptly ameliorated. conventional cpr (ccpr) produces a "low-flow" state that can temporarily sustain organ function. however, the longer the patient remains in cardiac arrest receiving ccpr, the less likely the patient is to achieve return of spontaneous circulation (rosc), even when advanced life support measures are applied [9] . the application of ecmo to maintain organ perfusion is a well-established technique extrapolated from the use of cardiopulmonary bypass in cardiothoracic surgery, where an anesthetised patient is cannulated and mechanical circulatory support is initiated before the heart is arrested. in the case of ecpr, the patient is unconscious due to loss of cardiac output, and in this uncontrolled situation, the cannulation and establishment of mechanical circulatory support must occur rapidly. the american heart association (aha), in their 2019 update, support consideration of ecpr for those failing ccpr, where it can be "expeditiously implemented, and supported by skilled providers" [10] . however, even with well-performed ecpr under non-pandemic conditions, the majority of patients will fail to survive with a good neurological outcome [11, 12] . there are currently two main models of ecpr provision [3] (fig. 1 ). the first is in-hospital cannulation, whereby patients suffering an ihca or ohca who fail to achieve rosc with standard ccpr and advanced cardiac life support (acls) may be cannulated for ecpr. the site of cannulation is often the emergency department (ed), or cardiac catheterisation laboratory for ohca, or the intensive care unit (icu), operating theatre, or cardiac catheterisation laboratory for patients with ihca. the second is pre-hospital cannulation of patients suffering ohca refractory to acls and who are attended at scene by a mobile ecpr cannulation team. current data suggest that time to cannulation is a more important determinant of ecpr outcome than the site where cannulation occurs per se [13] , and that stringent selection criteria applied rapidly at the scene may improve the yield of this intervention [14] . identifying the group of patients who might benefit from ecpr is difficult. having a reversible (predominantly cardiac) underlying aetiology for the arrest [3] , the receipt of effective bystander cpr, the presenting arrest rhythm, and the time to initiation of ecpr [12] are important determinants of ecpr outcome [14] . patients should also be free from precluding conditions, such as untreatable metastatic malignancy or life-limiting, endstage, chronic disease [3] . the timing of transition from ccpr to the institution of ecpr is not universally agreed on. this conversion may be facilitated by the application of a mechanical cpr device to continue chest compressions whilst cannulation for ecpr is performed. following restoration of organ perfusion with ecpr, a targeted intervention to address the underlying aetiology of arrest must be performed. cardiac arrests of presumed cardiac origin have been disproportionately represented in ecpr studies; hence, high rates of angiography and subsequent percutaneous coronary intervention (pci) are often seen [15] . this reflex resort to coronary angiography (intraarrest pci) may be challenged during the current pandemic, particularly in the absence of compelling st elevation [16, 17] . severe acute respiratory syndrome coronavirus 2 (sars-cov-2) may lead to a multisystem illness, covid-19, in many patients. the majority of infected individuals either are asymptomatic or suffer a mild respiratory tract infection. approximately 15% of individuals with covid-19 will develop a more severe illness, and 5-6% will develop critical illness characterised by severe respiratory failure with acute respiratory distress syndrome (ards) [18] . additionally, sars-cov-2 can directly infect and impair other organ systems including the cardiac, gastrointestinal, renal, and central nervous systems, with the angiotensin-converting enzyme 2 (ace2) receptor possibly implicated in viral tropism for these tissues. other sequelae of covid-19 disease may include a prothrombotic state, or immunodepression with superinfection, which in turn may potentiate acute pulmonary embolism, with ensuing acute cor pulmonale, or septiclike circulatory compromise. the number of critically unwell patients with covid-19 who require icu admission and organ support has overwhelmed health services in many countries globally, necessitating the rationing of critical care resources [19] . ecpr is complex, and efficient deployment relies on finely honed processes that may be significantly impacted by pandemic conditions. in acknowledging these circumstances, the current guidance on ecpr provided by elso [20] states the following: a) centres with lesser experience or without established ecpr programmes are discouraged from initiating ecpr for ohca during surge situations. b) experienced centres may offer ecpr for ihca for highly selected non-covid-19 patients depending on resource availability, whilst ecpr use in covid-19-positive patients requires reflection on the risk-benefit ratio. c) emergency conversion of venovenous ecmo to venoarterial ecmo in the setting of a cardiac arrest in a patient receiving venovenous ecmo or during cannulation is not recommended-due to the poor outcomes anticipated. there are two scenarios that might be used to describe the aetiology of cardiac arrest during the covid-19 pandemic. first, a cardiac arrest occurring in a patient who does not have covid-19 would be presumed to be due to one of the currently understood aetiologies of ohca and ihca. these patients would be eligible for consideration of ecpr based on currently used criteria where resources are not constrained by the pandemic. the second is cardiac arrest in a patient who is known, or suspected, to have covid-19. in this case, the aetiology of cardiac arrest may be related to the effects of the sars-cov-2 virus, as abovementioned, or the virus may simply be a bystander. in all circumstances, as community transmission of covid-19 increases, it will become difficult to differentiate patients at presentation with respect to infectious status and the default will be a presumption of positivity. irrespective of their infectious status and the aetiology of the cardiac arrest, the resource constraints imposed by the pandemic may limit usual processes of care. delays in ccpr initiation due to the reluctance of members of the public and healthcare workers to initiate out-of-hospital resuscitation attempts, fig. 1 current models for ecpr provision in ohca. in all comers with ohca, the vast majority will be pronounced dead at scene or on arrival to hospital. a in select patients with refractory cardiac arrest, ecpr may be advocated; this demands consideration of the predominant arrest rhythm (shockable preferable), the presence of bystander cpr, and the logistics of cannulation, icu capacity, and availability of services such as pci to determine and treat potential aetiologies. b expedient cannulation and establishment of extracorporeal perfusion is a requisite of an effective ecpr; for ohca, this may occur: (i) on-scene cannulation by mobile ecmo practitioners and (ii) rapid retrieval to ecpr hospital recognising those patients who might benefit from ecpr, requirements for donning personal protective equipment (ppe), impaired ambulance response times, and lack of critical care resources, may preclude the use of ecpr even in those who would otherwise be eligible. hypoxaemic respiratory failure leading to cardiac arrest appears to be common in covid-19 patients. in a retrospective cohort study of 136 patients suffering ihca in wuhan, china, 87.5% of arrests were due to a respiratory aetiology. the vast majority occurred outside of an icu setting, and shockable rhythms were observed in only 5.9% of this cohort. survival outcomes were dismal in this cohort with only one patient surviving to 30 days with a favourable neurologic outcome (cerebral performance category (cpc) [1, 2, 21] ). it is also reported that the interplay between patient comorbidities, in particular cardiovascular risk factors, and the aetiologic virus may give rise to a range of cardiovascular pathological insults [22] . acute myocardial infarction, myocarditis, and coronary spasm fuelled by hyperinflammation, multiorgan dysfunction, thrombotic phenomena, and severe hypoxaemia resulting in cardiac arrest have been described [23] . cardiac arrhythmias are also frequently reported and may reflect direct effects of the disease or cardiotoxicity from agents [24] repurposed to treat covid-19. in a true surge crisis, critical care demand outstrips capacity, and it becomes untenable to provide ecpr and post-resuscitative support. establishing even basic ccpr may be hindered by delayed response times, time to allow ppe donning, and system pressures diverting the resuscitation team. exceptions would include patients who arrest during coronary angiography, for instance, in which case rapid cannulation is possible, the aetiology may be more amenable to reversal, and there is the added benefit of advanced imaging available to confirm cannula placement should ecpr be initiated. continuing access to ecpr during the coivd-19 pandemic requires adherence to surge-specific protocols and prompt involvement of senior decision-makers at the time of an arrest in order to promote acceptable outcomes. local tools could be developed to aid with rapid assessment of ecpr candidacy and feasibility [3] . as with ccpr, ad hoc decision-making regarding ecpr should be discouraged. goals of care and resuscitation status should be addressed transparently with patients and surrogate decision-makers, so that any limitations dictated by patient or system factors are explicit. the nature of ecpr often precludes such discussions from happening in real-time, only adding to the burden of responsibility on clinicians. the ecpr team response in covid-19 (fig. 2) is complicated by the need for ppe arising from the heightened risk of healthcare worker infection and contamination of clinical areas and equipment by aerosolised fomites [25] and blood [26] . provision of ecpr should ideally be an interdisciplinary decision and is best prepared for via high-fidelity simulation and streamlined cannulation teams [4, 20] . for example, situations such as ecpr in the covid-19 patient who is in the prone position would need to be anticipated and rehearsed, if such a scenario is to be considered. there also needs to be an appreciation for wider system demands. for example, there are critical blood product shortages (due in part to a shrinking pool of healthy donors), and so conservation strategies such as percutaneous over surgical cannulation are important [27] . patient transfer after ecpr necessitates predesignated egress routes from the place of cannulation to other destinations, to mitigate the risks of crosscontamination of "clean" areas. ideally, in already experienced ecmo centres, patients treated for covid-19 disease and related complications should have a clearly declared escalation status, including candidacy for ecmo support and ecpr if the need were to arise. such decisions must take into account the local protocols, the equipment availability, and the readiness of the system to accommodate sudden and dramatically increased demands. a fundamental principle underpinning all pandemic responses is the maximisation of benefit from scarce resources [6] . resource scarcity and resource saturation are fluid judgements, relying on continual cycles of appraisal, integrating real-time data, and epidemiological projections [8] . maximising benefit refers not only to enhancing survival in individuals, but also to extending this opportunity to as many patients as possible or most appropriate candidates to benefit from. ecpr exacts a heavy toll on equipment (membrane oxygenator and ecmo circuit, blood products, ultrasound devices, and ppe among them) and staff (intensified nursing and other key supports, ecmo specialists, senior intensivist oversight, and others). personnel siphoned to support ecpr might be better deployed caring for several other less critical patients with a better chance of helping a greater number; similarly, the ecmo circuit may provide respiratory support for a patient with single organ dysfunction. beyond the immediate intervention, there are ongoing costs to convalescence. although survivors of ecpr may demonstrate favourable neurologic outcome, the covid-19 cohort cannot be assumed to be typical. the potential for generating dependent survivors is a burden ecpr may impose, and the benefits of ecpr may be overestimated in the covid-19 cohort. there may be fig. 2 possible management of the confirmed or suspected covid-19-positive patient with oohca. a bystander ccpr, with risk of aerosolisation and viral transmission: in many cases, this may not be performed on patients with known infectious status. b ambulance service provides defibrillation and early airway securement to minimise aerosol generation. time to don ppe and elevated system demands may delay attendance. in sustained non-shockable cardiac arrest, it may be appropriate to curtail resuscitation and avoid hospital transfer. c e-cpr if appropriate, in an isolated negative pressure environment with mechanical compressions. ecmo team should be in high-level ppe including papr. in non-ecpr centres, the patient may proceed to coronary angiography if appropriate intra-arrest or more typically post-rosc. inter-hospital transfer for ecpr or pci would not be routine. d icu admission is contingent upon patient prognosis and system capacity. it may be reasonable to admit only if rosc has been achieved. good neurological survival remains the desired outcome. patients may receive ttm/hypothermia and ongoing mechanical circulatory support for an agreed duration. outcomes include recovery, wlst, or brain death. organ donation may only be considered in patients confirmed to be covid-19 negative. ccpr, compression only cpr; ppe, personal protective equipment; ttm, targeted temperature management; wlst, withdrawal of life-sustaining therapy survivors with ecpr during the coivd-19 pandemic, but at what individual and health opportunity cost? if resources are committed to ecpr early during a surge, ongoing availability of icu resources may be further limited to other patients, infected or not [28] , who have a greater probability of benefit. whilst it is important to support the individuals' right to treatment, equity during a pandemic dictates a process of triage and prioritisation, ensuring that healthcare allocation is contingent on anticipated utility and maximum benefit. many scenarios may arise without a clear right answer. best judgement necessarily depends on dispassionate, open communication, triage, and frequent re-evaluation of the healthcare landscape. the right to withhold life-sustaining treatment varies globally [29] . in denmark, ccpr initiation by paramedics is a mandatory practice as the absence of a circulation defines a patient with cardiac arrest, not death [30] . in some jurisdictions, it is only when "inconsistent with good medical practice" that it is permissible to withdraw therapy without consent [31] . with respect to life-sustaining treatment, the concept of futility is illdefined, and often there is poor agreement between the physician and patient or surrogate decision-maker. furthermore, public perception of ccpr is skewed through media portrayals. the most appropriate argument for withholding or withdrawing ccpr and ecpr in covid-19 patients must be non-maleficence to the patient and others. it is accepted that extended resuscitation can be curtailed during crises, and since ecpr is not yet the standard of resuscitative care, whether access to ecpr may be refused is not nearly as contentious as reluctance to provide ccpr. a number of health systems are declining resuscitation of covid-19-positive patients as a rule [32] , discerning risks to the system and healthcare workers from potential aerosolisation to exceed individual benefit of attempted resuscitation. although resuscitation is sometimes performed to alleviate family suffering, by providing assurances that "everything was done", this practice should be questioned during a crisis. emotions should be tempered, and objectivity should dictate actions [30] . some centres routinely mandate ethicist consultations in the withdrawal of ecmo support [33] . the urgency of ecpr necessitates expediency, so limited opportunities exist to fully explore outcome scenarios with surrogate decision-makers at the time of cannulation; the decision to offer and subsequently limit ecpr rests heavily on the clinicians' shoulders. ecpr initiation is an organisational decision, requiring support from multiple specialties. this impacts on attendance to other clinical priorities, risks to other hospitalised patients, and to the hospital infrastructure; therefore, cannulation should be by consensus; equally, withdrawal should incorporate multiple stakeholders. fairness and equity dictate that objective criteria motivate both treatment escalation and withdrawal of life-sustaining therapies. where ecpr has been offered, evolving multiorgan dysfunction or signs of poor neurological recovery must prompt the treating team to approach the subject of withdrawal [2] , in systems where this is considered acceptable, not only to prevent burdensome treatment to the patient, but also to make available resources for those who may yet benefit. these hard truths would ideally be explicit before cannulation commences and will require empathy and transparency with families [33] . staff morale is an important but secondary consideration, and both moral and psychological injuries [34] to the workforce are significant risks when embarking upon interventions with limited potential for therapeutic benefit. observational data suggests that ecpr provides an improved opportunity for favourable neurological survival in highly selected patients experiencing cardiac arrest compared with ccpr. whilst there is a need for prospective study and high-quality randomised trials in this area [35] , the current covid-19 pandemic presents practical and ethical challenges to the ongoing provision and implementation ecpr programmes. at a time when critical care faces heavy constraints, it is important to work within ethical and legal frameworks to espouse equity and consistency in healthcare allocation, remembering not to inadvertently disadvantage non-covid-19 patients. the extracorporeal life support organization maastricht treaty for nomenclature in extracorporeal life support. a position paper of the extracorporeal life support organization ecpr or do not ecpr-who and how to choose position paper for the organization of ecmo programs for cardiac failure in adults planning and provision of ecmo services for severe ards during the covid-19 pandemic and other outbreaks of emerging infectious diseases ecpr for out-of-hospital cardiac arrest: more evidence is needed fair allocation of scarce medical resources in the time of covid-19 ethics in the time of coronavirus: recommendations in the covid-19 pandemic prioritisation of icu treatments for critically ill patients in a covid-19 pandemic with scarce resources association between duration of resuscitation and favorable outcome after out-of-hospital cardiac arrest: implications for prolonging or terminating resuscitation american heart association focused update on advanced cardiovascular life support: use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest: an update to the american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care international liaison committee on resuscitation's advanced life s, pediatric task f. extracorporeal cardiopulmonary resuscitation for cardiac arrest: a systematic review neurologic outcomes in patients who undergo extracorporeal cardiopulmonary resuscitation extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study a pre-hospital extracorporeal cardio pulmonary resuscitation (ecpr) strategy for treatment of refractory out hospital cardiac arrest: an observational study and propensity analysis should we emergently revascularize occluded coronaries for cardiac arrest?: rapid-response extracorporeal membrane oxygenation and intra-arrest percutaneous coronary intervention management of acute myocardial infarction during the covid-19 pandemic coronary angiography after cardiac arrest without st-segment elevation (coact) angiotensin-converting enzyme 2 (ace2) as a sars-cov-2 receptor: molecular mechanisms and potential therapeutic target critical care utilization for the covid-19 outbreak in lombardy, italy: early experience and forecast during an emergency response extracorporeal life support organization covid-19 interim guidelines a consensus document from an international group of interdisciplinary ecmo providers inhospital cardiac arrest outcomes among patients with covid-19 pneumonia in wuhan the variety of cardiovascular presentations of covid-19 covid-19 and cardiovascular disease chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (sars-cov-2) infection: preliminary safety results of a randomized, double-blinded, phase iib clinical trial (clorocovid-19 study) aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 covid-19 may transmit through aerosol. ireland: ir protecting health-care workers from subclinical coronavirus infection tackling covid-19: are the costs worth the benefits? considerations for ventilator triage during the covid-19 pandemic termination of prehospital resuscitative efforts: a study of documentation on ethical considerations at the scene the legal role of medical professionals in decisions to withhold or withdraw life-sustaining treatment: part 2 (queensland) covid-19: doctors are told not to perform cpr on patients in cardiac arrest understanding ethical decisions for patients on extracorporeal life support managing mental health challenges faced by healthcare workers during covid-19 pandemic early initiation of extracorporeal life support in refractory out-of-hospital cardiac arrest: design and rationale of the inception trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations ks acknowledges research support from the metro north hospital and health service. authors' contributions db, ks, and rl conceptualised the paper. ew wrote the first draft and coordinated the writing process. dg contributed substantially to the writing of the manuscript and designed the figures. db, ks, rl, and ac critically evaluated and made significant edits to the subsequent versions of the manuscript. all authors approved the final version of the manuscript prior to submission. not applicable. not applicable.availability of data and materials not applicable.ethics approval and consent to participate not applicable to this work. competing interests db is on the medical advisory boards for breethe, xenios, and hemovent and is a past medical advisory board member for baxter and alung technologies; he is currently on the trial steering committee for the vent-avoid trial sponsored by alung technologies; he is a member of the board of directors of elso and is chairman of the executive committee of ecm-onet. rl is a consultant for medtronic and livanova, and a member of the medical advisory board of eurosets and pulsecath. ac reports grants and personal fees from getinge and baxter; he was the president of euroelso and is a member of the executive and scientific committees of the international ecmo network (ecmonet). ks is a member of the ecmonet scientific committee and the asia-pacific elso steering and educational committees and is the research lead for the elso educational taskforce (ecmoed). key: cord-337485-nqcnd9py authors: buetti, niccolò; wicky, paul-henri; le hingrat, quentin; ruckly, stéphane; mazzuchelli, timothy; loiodice, ambre; trimboli, pierpaolo; forni ogna, valentina; de montmollin, etienne; bernasconi, enos; visseaux, benoit; timsit, jean-françois title: sars-cov-2 detection in the lower respiratory tract of invasively ventilated ards patients date: 2020-10-16 journal: crit care doi: 10.1186/s13054-020-03323-5 sha: doc_id: 337485 cord_uid: nqcnd9py background: data on sars-cov-2 load in lower respiratory tract (lrt) are scarce. our objectives were to describe the viral shedding and the viral load in lrt and to determine their association with mortality in critically ill covid-19 patients. methods: we conducted a binational study merging prospectively collected data from two covid-19 reference centers in france and switzerland. first, we described the viral shedding duration (i.e., time to negativity) in lrt samples. second, we analyzed viral load in lrt samples. third, we assessed the association between viral presence in lrt and mortality using mixed-effect logistic models for clustered data adjusting for the time between symptoms’ onset and date of sampling. results: from march to may 2020, 267 lrt samples were performed in 90 patients from both centers. the median time to negativity was 29 (iqr 23; 34) days. prolonged viral shedding was not associated with age, gender, cardiac comorbidities, diabetes, immunosuppression, corticosteroids use, or antiviral therapy. the lrt viral load tended to be higher in non-survivors. this difference was statistically significant after adjusting for the time interval between onset of symptoms and date of sampling (or 3.78, 95% ci 1.13–12.64, p = 0.03). conclusions: the viral shedding in lrt lasted almost 30 days in median in critically ill patients, and the viral load in the lrt was associated with the 6-week mortality. the sars-cov-2 disseminated in europe in late february 2020, causing the largest pandemic due to any respiratory viruses any respiratory viruses in recent history [1] . several authors suggested that viral shedding and severity of disease might be correlated [2] , but they mostly focused on viral presence in upper respiratory secretions [3, 4] . viral shedding from upper respiratory tract appeared to be higher soon after symptoms' onset, but during the course of disease, the shedding originates predominantly from the lower respiratory tract (lrt) [5] . to date, data on viral replication in distal airways are scarce. only one small study partly investigated the role of viral presence into lrt [6] . moreover, the association between sars-cov-2 viral load in lrt and mortality remains unevaluated [7] . our objectives were (1) to describe the viral shedding and the viral load in lrt and (2) to determine the association between viral presence and mortality in critically ill covid-19 patients. we conducted a binational study merging prospectively collected data from two covid-19 reference centers in france and switzerland. we included all covid-19 patients under mechanical ventilation who underwent regularly to lrt sampling for sars-cov-2. the bichat university hospital served as a reference center for the northern paris region, whereas the locarno regional hospital was an entirely covid-19-dedicated hospital for all (n = 7) public hospitals of southern switzerland (canton of ticino). all data of covid-19 patients were prospectively collected in two specific standardized institutional databases. we collected demographic characteristics, medical history, characteristics at hospital and intensive care unit (icu) admissions, organ support procedures, administration of antivirals and other agents, and biological and virological results. of note, prescription of antivirals and anti-inflammatory drugs varied among countries, availability, and choice of physician. all patients had a sars-cov-2 positive nasopharyngeal swab before icu admission. during the icu stay, all patients underwent a regularly monitoring of lrt samples (lrts) until the detection of two consecutive negative real-time polymerase chain reaction (rt-pcr) results [8] . all patients underwent regularly to lrt rt-pcr reevaluation until removal of the endotracheal tube or death. endotracheal aspirates, bronchoalveolar leakage fluid, and plugged telescoping catheter were all considered as lrts. the sampling was performed according to a predefined protocol. all specimens were sent to two accredited reference virology laboratories and used for rna extraction and amplification by rt-pcr techniques utilizing validated commercial kits that were previously described [9] . a cycle threshold (ct) value of < 40 was defined as positive for sars-cov-2 rna and ≥ 40 was defined as negative (see supplementary material). then, rt-pcr values were transformed in viral load as previously published [10] . the french and the regional swiss ethics committees approved this study. the primary objective was the description of viral shedding duration (i.e., time to negativity) in lrts and was defined as the time between onset of symptoms and viral clearance process (i.e., first negative detection of viral rna in lrt). of note, we previously showed that the association of the first negative rt-pcr with a second negative result was very high (i.e., 97%) in lrts [11] . secondary objectives were (1) the analysis of rt-pcr viral load in lrts and (2) the assessment of 6-week mortality. patients discharged before 6-weeks were considered alive. the statistical plan had three steps. first, we explored the duration of viral shedding in lrt using kaplan-meier curves for different clinical relevant patient populations (i.e., age, diabetes, cardiac comorbidities, immunosuppression, and corticosteroids during the icu stay) which are thought to influence viral shedding in upper respiratory tract samples [2, [12] [13] [14] [15] . a log rank test was performed; a specific subgroup had prolonged viral shedding if the log rank test between the two groups (e.g., diabetic versus non-diabetic) was statistically significant. second, we evaluated viral load in lrt during the icu stay (i.e., quantitative rt-pct) using graphical and descriptive statistics (i.e., wilcoxon test) between survivors and non-survivors. third, we determined the association between viral presence in lrt and mortality using mixed-effect logistic models for clustered data (proc glimmix of sas) and adjusting for the time between symptoms' onset and date of sampling. all collected samples were considered for this analysis. these models take into account the clustering effect of multiple sampling per patient and the center effect (i.e., random effect). we performed two sensitivity analyses: the first using only endotracheal aspirates and the second adjusting for sex and age. tests were twotailed, with p < 0.05 being considered significant. all analyses were performed using sas (version 9.4) and r (version 3.5.3). the current analysis complied with the strobe guidelines for observational studies [16] . prolonged viral shedding was not associated with age (p = 0.32), cardiac comorbidities (p = 0.93), diabetes (p = 0.16), immunosuppression (p = 0.14), nor corticosteroid use (p = 0.99, fig. 1) . however, using a graphical description, the lrt viral load tended to be higher in non-survivors (fig. 2) . this difference was statistically significant using mixed-effect models and after adjusting for the time interval between onset of symptoms and date of sampling, patient, and center random effect (or 3.78, 95% ci 1.13-12.64, p = 0.03). a sensitivity analysis using only endotracheal aspirates (i.e., without bronchoalveolar leakage fluid and plugged telescoping catheter) showed similar results (or 2.96, 95% ci 0.78-11.25, p = 0.10). after adjustment for age and gender, we observed again similar results (or 3.25, 95% ci 0.95-11.17, p = 0.06). our findings have several clinical, pathophysiological, and infection prevention implications. first, we showed that viral load in the lrt was associated with the 6week mortality. therefore, positive lrts may be used as a prognostic marker in covid-19 patients. second, covid-19 is characterized by an initial phase of viral replication in the upper respiratory tract, followed by a second pulmonary phase driven especially by the host inflammatory response [17] , and this latter phase probably determines the prognosis of disease. for this reason, some investigators administered immunomodulatory drugs in severe covid-19 patients [18] . however, our data may suggest a possible direct cytopathic role of virus in the lrt, supported by the significant association between viral load and mortality. third, we showed that the viral shedding in lrt lasted almost 30 days in median, and we did not identify specific risk factors for prolonged viral shedding in the lrt. several studies illustrated that viral shedding in the upper respiratory tract in non-critically ill patients varied from 8 to 24 days [2, 5, [12] [13] [14] [15] 19] . we observed that the viral shedding in critically ill patients may be longer, probably due to a prolonged replication in the lrt. interestingly, any of the well-known risk factors for upper respiratory tract appeared to be able to influence the viral shedding in lrt. critically ill patients may, therefore, require prolonged infection prevention measures during their hospitalization. our study has several limitations. first, we performed an observational study using surveillance data and we showed only an association between viral presence and mortality. second, viral cell cultures (i.e., the gold standard) were not routinely performed during the study: the results on viral shedding might have been different if this method would have been used and firm assumptions on infectivity cannot be made. third, all aspirates (endotracheal samples, bal, and telescope catheters) were categorized as lrts and a comparison between them may be debatable. however, a sensitivity analysis using only endotracheal samples showed similar results. moreover, the lrts dilution was not standardized between the two participating centers and a dilution marker was not used. finally, we did not routinely collect nasopharyngeal samples and the true viral excretion (e.g., from the upper respiratory tract) concomitantly with lrt replication remains unknown; therefore, assumptions on infectivity based on lrt analyses should be interpreted with caution. the viral shedding in lrt lasted almost 30 days in median in critically ill patients, and the sars-cov-2 viral presence in the lrt was associated with the 6week mortality. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03323-5. additional file 1. assessment of deaths from covid-19 and from seasonal influenza viral load dynamics and disease severity in patients infected with sars-cov-2 in zhejiang province, china quantitative detection and viral load analysis of sars-cov-2 in infected patients comparisons of viral shedding time of sars-cov-2 of different samples in icu and non-icu patients virological assessment of hospitalized patients with covid-2019 sars-cov-2 viral load in clinical samples from critically ill patients sars-cov-2 viral load predicts covid-19 mortality guidance for discharge and ending isolation in the context of widespread community transmission of covid-19 clinical and virological data of the first cases of covid-19 in europe: a case series viral load of sars-cov-2 in clinical samples diabetes mellitus is a risk factor for prolonged sars-cov-2 viral shedding in lower respiratory tract samples of critically ill patients risk factors for viral rna shedding in covid-19 patients factors associated with prolonged viral rna shedding in patients with covid-19 profile of rt-pcr for sars-cov-2: a preliminary study from 56 covid-19 patients factors associated with duration of viral shedding in adults with covid-19 outside of wuhan, china: a retrospective cohort study strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies covid-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal tocilizumab for the treatment of severe covid-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in factors associated with prolonged viral shedding and impact of lopinavir/ritonavir treatment in hospitalised non-critically ill patients with sars-cov-2 infection publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank céline féger, m.d. (emibiotech), for her editorial support. the authors thank the french covid-19 study group. the authors have disclosed that they do not have conflict of interest. jft received fees for lectures to 3m, msd, pfizer, and biomerieux. jft received research grants from astellas, 3m, msd, and pfizer. jft participated to advisory boards of 3m, msd, bayer pharma, nabriva, and pfizer. bv reports grants, personal fees for lectures, and travel accommodations from qiagen. bv received personal fees for lecture and travel accommodation support from biomérieux. bv received personal fees for lectures from hologic and gilead. authors' contributions nb, phw, al, and jft analyzed and interpreted the data. nb, phw, jft, eb, and ppt were responsible for the data collection. nb and phw were the major contributors in writing the manuscript. all authors read and approved the final manuscript.funding nb is currently receiving a mobility grant from the swiss national science foundation (grant number: p400pm_183865) and a grant from the bangerter-rhyner foundation. these grants support his fellowship in france. the french center (bichat university hospital) was part of the overall french covid-19 cohort assessing patients with covid-19 and registered in clinicaltrials.gov (nct04262921). the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.ethics approval and consent to participate all studies were approved by the national ethics committees. not applicable. key: cord-335172-5ig907on authors: busse, laurence w.; chow, jonathan h.; mccurdy, michael t.; khanna, ashish k. title: covid-19 and the raas—a potential role for angiotensin ii? date: 2020-04-07 journal: crit care doi: 10.1186/s13054-020-02862-1 sha: doc_id: 335172 cord_uid: 5ig907on nan the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and its associated coronavirus disease 2019 (covid-19) have wreaked havoc on healthcare systems globally. the potential for spread of this highly infectious virus, which is more transmissible and lethal than influenza, has reached pandemic proportions and has left many clinicians scrambling to provide care with scarce resources, all in the setting of no curative treatment, immunization, or effective therapy. some candidate therapies include antivirals (remdesivir), antimalarials (hydroxychloroquine), and vaccines (mrna-1273). moreover, as we learn more about this virus, we have begun to draw some noteworthy conclusions regarding currently available ancillary "therapies" which may affect the natural history of the covid-19 infection. some of these "therapies" may actually be the avoidance of certain medications, like ibuprofen. likewise, patients on angiotensin-converting enzyme (ace) inhibitors or angiotensin receptor blockers (arb) could be at a greater risk due to the mechanism by which sars-cov-2 enters the cell. it stands to reason that therapeutics that act counter to this mechanism may confer protection. angiotensin (ang) ii, the novel vasopressor agent recently approved in both the usa and europe, may do just this. while its role as a vasopressor in shock is well known, its role in conferring protection from covid-19, both to patients with shock and perhaps those without, is unknown and must be explored in this time of international crisis. the level of critical illness attributable to covid-19 has been recently described. in the recent outbreak in china, approximately 5% of patients with covid-19 required icu admission [1] . in italy, the prevalence of critical illness has surpassed rates seen in china, with icu admission required for 12% of positive cases and 16% of all hospitalized patients [2] . critically ill patients are typically described as older with comorbidities, but cases involving young and healthy patients challenge this generalization [2, 3] . patients are typically admitted to the icu after 9-10 days of illness, commonly as a result of respiratory failure and acute respiratory distress syndrome (ards) [3] . while less common than respiratory failure, septic shock may occur in a significant portion of patients with covid-19, and is associated with increased mortality [4] . a case series out of china described the incidence of shock in a cohort of hospitalized patients with covid-19 to be 1.1%, but, in those with severe disease, incidence rose to 6.4% [5] . the renin-angiotensin-aldosterone system (raas) may be tied into the pathogenesis of the covid-19 viral illness. the traditional raas pathway utilizes ace1, primarily a pulmonary capillary endothelial enzyme, to convert angi to angii. as such, significant lung injury decreases the activity of pulmonary capillary endothelialbound ace. initial reports from china demonstrate that approximately 40% of patients with severe illness have ards [5] , increasing the risk for very low ace1 function. notably, inadequate ace function is an independent predictor of mortality. specific to the sars-cov-2 virus, the sars-coronavirus receptor utilizes ace2 and the cellular protease tmprss2 to enter target cells (fig. 1 ) [6] . the spike protein on the viral surface of sars-cov-2 has been shown to bind to ace2 with 10-20 times the affinity of sars-cov-1, the coronavirus responsible for the sars outbreak in 2003 [7] . the higher ace2 affinity of sars-cov-2 may explain the ease of human-to-human transmission in the current pandemic [8] . preclinical studies of novel coronaviruses (e.g., sars-cov-1, sars-cov-2) highlight that the degree of ace2 expression directly correlates to the degree of infectivity [9, 10] . thus, strategies to decrease ace2 expression may attenuate the impact of sars-cov-2 infection. the endogenous mammalian peptide angii is hypothesized to prevent infection from sars-cov-2 in multiple ways. first, because it normally binds to ace2 during its degradation and hydrolysis into angiotensin-(1-7) [11] , it may compete with the sars-cov-2 for the ace2 receptor (fig. 1) . second, the binding of angii to the at1 receptor has been shown to cause internalization and downregulation of ace2 through an erk1/2 and p38 map kinase pathway in both in vitro animal and in vivo human models [12, 13] . third, angii has been shown to cause at1 receptor-dependent destruction of ace2 through ubiquitination and transport into lysosomes. the competitive inhibition, downregulation, internalization, and then degradation of ace2 may decrease the degree of viral infection by interfering with host cell entry of the virus. much has been made of the hypothetical risk of covid-19 in the setting ace inhibitors and arbs, which have been shown by multiple investigators to increase expression or activity of ace2 [14, 15] . in fact, severe covid-19 disease has been described in patients with conditions known to be associated with raas blockade therapy, such as hypertension and diabetes mellitus [5] . however, to date, the link between ace inhibitors and arbs and severity of illness of sars-cov-2 infection is purely speculative. both the american college of cardiology and the european society of cardiology have published statements advising against the discontinuation of ace inhibitors and arbs in sars-cov-2. fig. 1 effect of angiotensin ii on the raas and sars-cov-2 binding. angiotensin i is hydrolyzed by ace1 to form angiotensin ii, which binds to at 1 receptors. this causes release of aldosterone from the adrenal gland, vasopressin secretion from the hypothalamus, and vasoconstriction. vasopressin and aldosterone both lead to increased sodium and free water reabsorption in the kidney, leading to increased mean arterial pressure (map). angiotensin ii is then metabolized into ang-(1-7) by ace2. sars-cov-2 binds to ace2 to gain entry into the host cell. exogenous angiotensin ii can also bind to ace2, which can lead to competitive inhibition of the ace2 receptor. in addition, binding of angiotensin ii to at 1 receptors leads to internalization, downregulation, and degradation of ace2. these actions may potentially prevent sars-cov2 from entering the cell. figure created with motifolio toolkit. ang-2, angiotensin ii; sars-cov-2, severe acute respiratory syndrome coronavirus 2; ace1, angiotensinconverting-enzyme 1; ace2, angiotensin-converting-enzyme 2; h 2 o, water; na + , sodium the support of map with angii in the setting of sars-cov-2 infection seems physiologically rational, given the aforementioned hypotheses (table 1) . due to the large number of critically ill sars-cov-2 patients, angii has been made available in italy, germany and the united kingdom for compassionate use because, despite approval by the european medicines agency, it is not yet commercially available in europe. perhaps we will learn some important lessons from these patients, so as to inform our efforts going forward. for instance, should angii be used for all covid-19 patients in shock? should it be considered earlier in the course of disease, perhaps as a first-line vasopressor? finally, and more controversially, should we evaluate the modulating effects of angii on ace2 for the treatment of covid-19 in patients without shock? angii use has been described at sub-pressor doses, and multiple studies have shown that higher levels of map may not be harmful. as the sars-cov-2 pandemic evolves, we must consider any form of therapy that may "flatten" the curve (https://www.flattenthecurve.com). the physiologic relationship between ace2 and angiotensin ii is persuasive, and given the enormity of the situation, we are obligated to explore this therapy as a potential avenue of treatment. table 1 information supporting the use of angiotensin ii in covid-19 disease increased ace2 increases infectivity of sars [6, 10] decreased ace2 expression decreases infectivity of sars [6, 10] sars-cov-2 utilizes ace2 to enter cells like sars-cov-1 [6] patients taking ace inhibotors and arbs have increased ace2 expression [15] exogenous angiotensin ii decreases ace2 expression [12, 13] patient with hypertension are at high risk for severe covid infection and death [5] hypothesis: exogenous angiotensin ii via reduction ace2 expression in the vasculature and heart may decrease viral propagation and thus improve outcomes. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention critical care utilization for the covid-19 outbreak in lombardy, italy: early experience and forecast during an emergency response clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in care for critically ill patients with covid-19 clinical characteristics of coronavirus disease 2019 in china sars-cov-2 cellentry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor cryo-em structure of the 2019-ncov spike in the prefusion conformation a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster susceptibility to sars coronavirus s protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor angiotensin-converting enzyme 2 is a functional receptor for the sars coronavirus angiotensin converting enzyme defects in shock: implications for future therapy angiotensin ii up-regulates angiotensin i-converting enzyme (ace), but down-regulates ace2 via the at1-erk/p38 map kinase pathway aerobic exercise traininginduced left ventricular hypertrophy involves regulatory micrornas, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme 2 upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin ii receptors publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions all authors were major contributors in writing the manuscript. all authors read and approved the final manuscript. the authors received no funding related to this manuscript. not applicable ethics approval and consent to participate not applicable competing interests jhc serves on the speaker's bureau for la jolla pharmaceutical company. all other authors report no competing interests. 1 key: cord-314872-njlgggzq authors: kornilov, sergey a.; lucas, isabelle; jade, kathleen; dai, chengzhen l.; lovejoy, jennifer c.; magis, andrew t. title: plasma levels of soluble ace2are associated with sex, metabolic syndrome, and its biomarkers in a large cohort, pointing to a possible mechanism for increased severity in covid-19 date: 2020-07-22 journal: crit care doi: 10.1186/s13054-020-03141-9 sha: doc_id: 314872 cord_uid: njlgggzq nan plasma levels of soluble ace2are associated with sex, metabolic syndrome, and its biomarkers in a large cohort, pointing to a possible mechanism for increased severity in covid-19 patients at high risk for mortality from covid-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), are more likely to be older and male and have chronic diseases such as hypertension, diabetes, cardiovascular, and chronic lung disease [1, 2] . although the mechanisms behind these associations are poorly understood, this increased risk could be partly associated with increased expression of the cellular receptor of sars-cov-2, angiotensin-converting enzyme-2, found at elevated levels in older individuals, men, and in cardiovascular and inflammatory conditions [3, 4] . it maintains homeostasis of the renin-angiotensin system and converts angiotensin ii to angiotensin 1-7, which has vasodilatory and anti-inflammatory properties. the membrane-bound form (mace2) is highly expressed in the heart, airways, kidney, and liver tissue, and the enzymatically active soluble form (sace2) is generated in response to inflammatory signals and disease via mace2 shedding. we interrogated the associations between plasma concentrations of sace2 and biomarkers of metabolic syndrome (body mass index, bmi; blood pressure; glycemic markers; and lipid levels), adiposity (plasma leptin and serum adiponectin), inflammation (high-sensitivity creactive protein, hscrp, white blood cell count, and interleukin-8), and liver damage (alanine aminotransferase, aspartate transaminase, and gamma-glutamyltransferase, ggt) in a large cohort of participants in a commercial wellness program who had undergone comprehensive multi-omic profiling (n = 2051; 1238 women and 813 men, aged 22 to 87 years, m = 47.3, sd = 11.71) (see [5] for details). clinical laboratory tests were performed in clia-certified laboratories by quest diagnostics or labcorp. plasma sace2 and leptin levels were measured via proximity extension immunoassaying using olink® cardiovascular ii proteomics panel. analyses were performed using transformed and scaled biomarker values in a robust linear regression framework controlling for age, sex (where appropriate), 8 genetic principal components, smoking, vendor, season, use of diabetes, cholesterol-lowering, and ace-inhibitor medications. confirming results from recent studies [3, 4] , we found higher plasma sace2 levels in men compared to women (p = 2 × 10 −16 ), and in older individuals (p = 8.6 × 10 −11 ), with the age association more pronounced in women (for the interaction, p int = 0.02). we found higher levels of sace2 in post-menopausal women, compared to premenopausal women (p = 0.02; see fig. 1 ). fig. 1 the associations of plasma sace2 levels with sex, age, and metabolic syndrome (mets). a sex differences in plasma sace2 levels. b differences in sace2 levels between pre-(n = 272) and post-menopausal (n = 251) women over 35 years of age. c associations between sace2 and age. d differences in sace2 levels in individuals who do vs. who do not meet diagnostic criteria for mets and its subcomponents. the following diagnostic criteria, based on who guidelines, were used: obesity, bmi > 30 kg/m 2 ; hyperglycemia, fasting glucose > 100 mg/dl or other evidence of insulin resistance (e.g., prescription); hypertension, systolic/diastolic blood pressure ≥ 140/90 mm/hg; dyslipidemia, triglycerides > 150 or hdl-c < 35 for men and < 39 for women. overall status was determined as mets if the individual met criteria for insulin resistance and satisfied at least one other domain criterion for the syndrome. sace2, soluble ace2 (normalized protein expression, npx, values adjusted for covariates and scaled) fig. 2 associations between sace2 and biomarkers of metabolic syndrome, inflammation, and liver damage. a marginal effect size (b) estimates from robust linear regressions predicting sace2 from biomarkers estimated for men and women separately. biomarkers for which a significant interaction with sex was established are marked with an asterisk. b partial spearman correlations between study biomarkers and sace2 levels. c scatterplot of associations between ggt and sace2. bmi, body mass index; map, mean arterial blood pressure; hba1c, glycohemoglobin a1c; homa-ir, homeostatic model assessment of insulin resistance; hdl-c, high-density lipoprotein cholesterol; ldl-c, low-density lipoprotein cholesterol; il-8, interleukin 8; hscrp, high-sensitivity c-reactive protein; alat, alanine aminotransferase; asat, aspartate transaminase; ggt, gamma-glutamyl-transferase individuals who met world health organization's diagnostic criteria for metabolic syndrome (mets) (n = 171) displayed elevated plasma sace2 levels compared to controls (n = 1880; p = 4.7 × 10 − 5 ); the effect was stronger in men (p int = 8.9 × 10 − 5 ). all of mets component biomarkers were positively associated with plasma sace2 (see fig. 2 ). the associations were significantly stronger in men for biomarkers of obesity and adiposity (bmi, p int = 0.0123; leptin, p int = 0.0342) and insulin resistance and hyperglycemia (hba1c, p int = 0.0368; homa-ir, p int = 0.042), as well as triglycerides (p int = 0.0134) and serum hscrp (p int = 0.041). the strongest association was observed between sace2 and ggt (p = 3.44 × 10 −90 ), an important indicator of oxidative stress, liver, and bile duct damage. this association was also stronger in men (pint = 0.01). the robust pattern of associations between increased plasma sace and mets points to the possible shared pathways in cardiometabolic disease and covid-19, implicating insulin resistance, chronic inflammation, and liver damage. this is intriguing given that both sace2 and mace2 have been shown to be upregulated in a rat model of chronic liver disease [6] and that sace2 levels are higher in patients with heart failure [4] . the upregulation may be related to the tissue-specific patterns of increased sars-cov-2 infectivity in patients with cardiometabolic disease and/or liver damage and warrants further research on sace2 as a potential biomarker for covid-19 severity. abbreviations sace2/mace2: soluble/membrane-bound angiotensin-converting enzyme-2; mets: metabolic syndrome; ggt: gamma-glutamyl-transferase; bmi: body mass index; hba1c: glycohemoglobin a1c; homa-ir: homeostatic model assessment of insulin resistance; hscrp: high-sensitivity c-reactive protein predictors of mortality in hospitalized covid-19 patients: a systematic review and meta-analysis diabetes is a risk factor for the progression and prognosis of covid-19 age and sex differences in soluble ace2 may give insights for covid-19 circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors genetic predisposition impacts clinical changes in a lifestyle coaching program upregulation of hepatic upregulation of hepatic angiotensin-converting enzyme 2 (ace2) and angiotensin-(1-7) levels in experimental biliary fibrosis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors express their gratitude to the members of the arivale program for granting the permission to use their deidentified data for research and to mr. brett smith at the institute for systems biology for his contribution to the study. authors' contributions sk, ilb, kj, jl, cd, and am conceptualized the study and drafted the manuscript. sk, cd, and am performed data quality control and assurance, transformation, and data analysis. all authors critically revised the manuscript. the authors read and approved the final manuscript. no external funding was received to complete this study. the dataset supporting the conclusions of this article is available from the authors upon request.ethics approval and consent to participate all research was conducted in accordance to regulations and guidelines for observational research in human subjects. the study was reviewed and approved by the western irb (study number 1178906). the research was performed entirely using deidentified and aggregated data of individuals who had signed a research authorization allowing the use of their anonymized data in research. per current us regulations for use of deidentified data, informed consent was not required. not applicable. the authors were previously employed by arivale, inc. and held stock options in the company. arivale is now closed.received: 15 june 2020 accepted: 1 july 2020 key: cord-340205-cwn0gx7h authors: chen, yih-ting; shao, shih-chieh; lai, edward chia-cheng; hung, ming-jui; chen, yung-chang title: mortality rate of acute kidney injury in sars, mers, and covid-19 infection: a systematic review and meta-analysis date: 2020-07-16 journal: crit care doi: 10.1186/s13054-020-03134-8 sha: doc_id: 340205 cord_uid: cwn0gx7h nan and independently assessed the full texts of selected results. the final list of included studies was derived by discussion and unanimous agreement from both authors. statistical analyses were performed using medcalc for windows, version 15.0 (medcalc software, ostend, belgium). we report the mortality rate from aki in sars, mers, and covid-19 infections as proportions with 95% confidence interval (ci) based on random effects model, represented by forest plot. we detected heterogeneity among studies using the cochran q test, with p value < 0.10 indicating significant heterogeneity, and calculated i 2 statistic to determine the proportion of total variation in study estimates attributable to heterogeneity. after screening 97 records in total, we excluded 74 articles (15 duplicates, 11 irrelevant to study question, 1 conference abstract, 5 review articles and 42 lacking data on aki mortality). our final analysis included 23 articles comprising 4, 3 and 16 on sars, mers and covid-19 infection, respectively. demographic data for included articles are presented in table 1 . overall, mortality in patients with sars, mers and covid-19 infection, and developing aki, was 77.4% (95%ci: 64.7-88.0). we found the mortality rate of aki was highest in sars (86.6%; 95%ci: 77.7-93.5), followed by covid-19 (76.5%; 95%ci: 61.0-89.0) and mers (68.5%; 95%ci: 53.8-81.5). there was no evidence of statistical heterogeneity among studies reporting aki mortality in sars (i2: 0.0%, p = 0.589) and mers (i2: 0.0%, p =v0.758), but there was for covid-19 infection (i2: 97.0%, p < 0.001) (fig. 1 ). the present analyses indicate aki as a poor prognosis factor in coronavirus infections, whereby aki mortality in covid-19 is higher than mers but lower than sars infections. possible mechanisms of higher aki mortality following coronavirus infections are multifactorial (e.g., severe sepsis-related multiorgan failure, direct kidney involvement, and acute respiratory distress syndrome) [26] [27] [28] , although comparative pathogenesis of kidney involvement among the three infections remains unclear. to our best knowledge, this is the first systematic review exploring aki mortality of different coronavirus infections. however, we should be cautious about interpreting causal relationships between coronavirus infections and aki, given the nature of observational data. also, clinical heterogeneity between studies should be noted; for example, various healthcare systems of included studies may produce different aki mortality rates. coronaviruses are unlikely to be eliminated in the near future, and our synthesis indicates that aki secondary to coronavirus infection may contribute to higher mortality. hence, in the current exceptional pandemic, first-line healthcare providers should recognize the importance of timely detection of aki and consider all available treatment options for maintenance of kidney functions to prevent death in covid-19 patients [29] . authors' contributions ycy and scs contributed equally to this work. ycy and scs contributed to the critical analysis, interpretation of the data, and drafting of the incidence of acute kidney injury in covid-19 infection: a systematic review and metaanalysis the novel coronavirus 2019 epidemic and kidneys acute renal failure in patients with severe acute respiratory syndrome hospital: acute renal failure in sars patients: more than rhabdomyolysis acute renal impairment in coronavirus-associated severe acute respiratory syndrome outcomes and prognostic factors in 267 patients with severe acute respiratory syndrome in hong kong clinical aspects and outcomes of 70 patients with middle east respiratory syndrome coronavirus infection: a single-center experience in saudi arabia histopathology of middle east respiratory syndrome coronovirus (mers-cov) infection -clinicopathological and ultrastructural study critical care team of national medical center: renal complications and their prognosis in korean patients with middle east respiratory syndrome-coronavirus from the central mers-cov designated hospital a single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for sars-cov2 pneumonia acute kidney injury in patients hospitalized with covid-19 clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of covid-19 infection clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in wuhan, china: a retrospective study clinical course and outcome of 107 patients infected with the novel coronavirus, sars-cov-2, discharged from two hospitals in wuhan clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study fulminant acute kidney injury in a young patient with novel coronavirus ):e7561.suwanwongse k, shabarek n: rhabdomyolysis as a presentation of covid-19 infection in kidney transplant recipients clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study coronavirus disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the clinical course and outcomes of 344 intensive care patients with covid-19 correction to: clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china clinical features and shortterm outcomes of 102 patients with corona virus disease in-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during middle east respiratory syndrome (mers) coronavirus infection multiorgan and renal tropism of sars-cov-2 the role of mitochondrial dysfunction in sepsis-induced multiorgan failure management of acute kidney injury in patients with covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-034948-w59wxu8i authors: kuriyama, akira; jackson, jeffrey l.; kamei, jun title: performance of the cuff leak test in adults in predicting post-extubation airway complications: a systematic review and meta-analysis date: 2020-11-07 journal: crit care doi: 10.1186/s13054-020-03358-8 sha: doc_id: 34948 cord_uid: w59wxu8i background: clinical practice guidelines recommend performing a cuff leak test in mechanically ventilated adults who meet extubation criteria to screen those at high risk for post-extubation stridor. previous systematic reviews demonstrated excellent specificity of the cuff leak test but disagreed with respect to sensitivity. we conducted a systematic review and meta-analysis to assess the diagnostic accuracy of the cuff leak test for predicting post-extubation airway complications in intubated adult patients in critical care settings. methods: we searched medline, embase, scopus, isi web of science, the cochrane library for eligible studies from inception to march 16, 2020, without language restrictions. we included studies that examined the diagnostic accuracy of cuff leak test if post-extubation airway obstruction after extubation or reintubation was explicitly reported as the reference standard. two authors in duplicate and independently assessed the risk of bias using the quality assessment for diagnostic accuracy studies-2 tool. we pooled sensitivities and specificities using generalized linear mixed model approach to bivariate random-effects meta-analysis. our primary outcomes were post-extubation airway obstruction and reintubation. results: we included 28 studies involving 4493 extubations. three studies were at low risk for all quadas-2 risk of bias domains. the pooled sensitivity and specificity of cuff leak test for post-extubation airway obstruction were 0.62 (95% ci 0.49–0.73; i(2) = 81.6%) and 0.87 (95% ci 0.82–0.90; i(2) = 97.8%), respectively. the pooled sensitivity and specificity of the cuff leak test for reintubation were 0.66 (95% ci 0.46–0.81; i(2) = 48.9%) and 0.88 (95% ci 0.83–0.92; i(2) = 87.4%), respectively. subgroup analyses suggested that the type of cuff leak test and length of intubation might be the cause of statistical heterogeneity of sensitivity and specificity, respectively, for post-extubation airway obstruction. conclusions: the cuff leak test has excellent specificity but moderate sensitivity for post-extubation airway obstruction. the high specificity suggests that clinicians should consider intervening in patients with a positive test, but the low sensitivity suggests that patients still need to be closely monitored post-extubation. morbidity, duration of mechanical ventilation, and icu stay [2] [3] [4] [5] [6] [7] [8] . in select cases, systemic corticosteroids before extubation can be used to prevent post-extubation airway complications [9] . therefore, it is important to estimate the risk of laryngeal edema before extubation. since the endotracheal tube precludes direct visualization of the upper airway, the cuff leak test was proposed to predict the presence of laryngeal edema and post-extubation airway obstruction [10, 11] . theoretically, when there is no laryngeal edema, there is an air leak around the tube after deflating the balloon cuff of the endotracheal tube [12, 13] . in contrast, a failed cuff leak test suggests little or no air leak around the tube, suggesting potential airway obstruction from laryngeal edema [12, 13] . the clinical practice guideline published by the american thoracic society and american college of chest physicians in 2017 recommends performing a cuff leak test in mechanically ventilated adults who meet extubation criteria to screen those at high risk for post-extubation stridor [14] . this guideline referenced two systematic reviews on the diagnostic accuracy of cuff leak test [15, 16] , published in 2009 and 2011. both reviews demonstrated excellent specificity of the cuff leak test but disagreed with respect to sensitivity. in addition, there have been several studies of the diagnostic accuracy of cuff leak test published after these reviews were completed. consequently, we conducted a systematic review and meta-analysis to assess the diagnostic accuracy of the cuff leak test for predicting post-extubation airway obstruction and subsequent reintubation. the conduct and reporting of this systematic review followed the prisma-dta statement [17] . our review protocol was registered at prospero (crd42018084357). we searched medline, embase, scopus, isi web of science, and the cochrane library for eligible studies from inception to march 16, 2020 , without language restrictions [18] . our search strategy was developed with the help of a medical librarian (additional file 3: table s1 ). we hand-searched the references of included articles for potentially relevant studies. we examined the diagnostic accuracy of cuff leak test in intubated adult patients awaiting extubation in critical care settings. the index test was cuff leak test regardless of the type of cuff leak test (quantitative or qualitative) and threshold used. the reference standards included post-extubation airway obstruction determined by the original authors and subsequent reintubation. we included observational studies (cross-sectional and cohort studies) that examined the diagnostic accuracy of cuff leak test in critical care settings if: (1) the data were extractable into a 2 × 2 table from the reported data, (2) post-extubation airway obstruction after extubation or reintubation was explicitly reported as the reference standard. we considered both published studies and conference proceedings; however, we included the abstracts from conference proceedings only when they provided data in enough detail to be extractable. we considered interventional studies in critical care settings that examined the efficacy of systemic corticosteroids to prevent post-extubation airway complications; however, we excluded patients to whom systemic corticosteroids were administered after they were judged at high risk of postextubation airway complications. two authors (ak and jk) independently screened titles and abstracts obtained from the search and selected potentially relevant articles. disagreement was resolved through discussion. the first author (ak) and one of the other authors (jlj and jk) in duplicate and independently extracted the following data from each study: (1) patient demographics (age, sex); (2) study characteristics (country, study population; duration of mechanical ventilation; mode of ventilation; observation period after extubation); (3) the type of cuff leak test (quantitative or qualitative); (4) numbers of true-positive, false-positive, true-negative, and falsenegative; and (5) the reference standards used. quantitative cuff leak test measures the air leak volume with a cuff deflated and judges the post-extubation airway obstruction based on its absolute volume or proportion in comparison with the expiratory tidal volume against a certain threshold [19] . qualitative cuff leak test examines the presence or absence of audible expired air around an endotracheal tube, which indicates the pass or failure of the test [19] . in this study, a lack of a cuff leak, having a risk of post-extubation complications, was considered a positive test, while having a leak, suggesting low risk of post-extubation complications was a negative test [19] . two authors (ak and jlj) independently assessed the risk of bias using the quality assessment for diagnostic accuracy studies-2 (quadas-2) tool [20] . inconsistency was resolved through consensus. we had two primary outcomes: (1) post-extubation airway obstruction and (2) reintubation due to post-extubation airway obstruction. the reference standards for post-extubation airway obstruction included stridor (audible high-pitched inspiratory wheeze) [21] , or laryngeal edema defined by the study authors (including confirmation with bronchoscopy [22] or laryngoscope [23] ). we pooled the data using a generalized linear mixed model approach to bivariate random-effects meta-analysis to calculate summary estimates of sensitivity, specificity, and likelihood ratios as well as the associated 95% confidence intervals (cis) [24] . we pooled prevalence using a random-effects model, with exact binomial estimates of standard deviation and the freeman-tukey transformation for zero cells [25] . to examine the sources of heterogeneity, we examined the receiver operating characteristic (roc) curves, assessed the correlation between sensitivity and specificity, and analyzed whether sensitivity and specificity of cuff leak changed with the type of cuff leak test (qualitative or quantitative), the proportion of women, inclusion or exclusion of reintubated patients in a study, and the length of intubation, using subgroup or meta-regression analysis [14, 19] . we also calculated the sensitivity and specificity of cuff leak test using a cutoff of 110 ml, a value that is frequently used in clinical practice [21] . we tested for publication bias using deeks' method [26] . we created a fagan's nomogram, which determines the posttest probability according to the pretest probability and the calculated positive and negative likelihood ratios [27] . we followed standard diagnostic meta-analytic approaches in focusing on the sensitivity, specificity, and likelihood ratios instead of positive and negative predictive values because predictive values are dependent on the population prevalence of post-extubation complications, which can vary considerably. the threshold of statistical significance was set at p < 0.05. all analyses were performed with stata se, version 15.1 (stata corp; college station, tx). our literature search produced 2236 studies. after application of inclusion and exclusion criteria, 28 studies involving 4493 extubations were included in the analysis ( fig. 1) [12, 13, [21] [22] [23] . among the 28 included studies, 27 were published in english and one in korean [35] . twenty-seven studies (96%) were prospective [12, 13, 21-23, 28-37, 39-50] . nine studies and ten were conducted in medical [21, 22, 31, 32, 35-37, 43, 49] and mixed intensive care units [12, 13, 23, 28, 33, 34, 40, 41, 44, 45] , respectively ( table 1 ). the included studies were published between 1992 and 2019. all but one were published studies and the remaining one an abstract in a conference proceeding. eight studies were conducted in the usa, four each in france and taiwan, three in thailand, two in egypt, one each in australia, belgium, india, iran, italy, south korea, and turkey. the median sample size was 101, ranging 34-543 (interquartile range 51-236). the reported mean/median duration of mechanical ventilation ranged from 2 to 28.1 days. five studies used a qualitative cuff leak test (auscultation of airflow) [23, 28, 31, 39, 45] , and 21 used a quantitative measurement of the cuff leak [12, 13, 21, 22, 29, 30, 32-37, 40-44, 46, 47, 49, 50] (table 2 ). one study reported the results from both qualitative and quantitative cuff leak tests examined in a single cohort [48] . the remaining study reported on the data of patients who underwent either qualitative or quantitative cuff leak test [38] . the most frequent cutoff values for quantitative cuff leak tests ranged from 50 to 283 ml (median, 110 ml) in volume and from 10 to 57% in proportion. twenty studies used assist control ventilation [12, 13, 21, 22, 29, 30, 32-38, 41-44, 46, 47, 49] , and four used spontaneous breathing including pressure support ventilation [23, 31, 40, 45] . another study examined either of these two ventilation modes [28] . one study applied the ambu bag, while the cuff leak was tested [39] . one study performed a qualitative cuff leak test during spontaneous breathing via t-tube and during cough while still intubated [48] . the remaining one did not report the mode of ventilation used [50] . twenty-four studies used stridor [12, 13, 21, 28-39, 41-43, 45-50] and three used direct visualization of the airway following extubation as reference standards [22, 23, 40] for airway obstruction. one study used either of these reference standards [44] . three of the 28 studies were at low risk of bias for all quadas-2 risk of bias domains (table 3) . seventeen studies (60.7%) were deemed at low risk of bias for the domain of patient selection. eight out of 22 studies that assessed quantitative cuff leak prespecified the cutoff of cuff leak; fourteen studies (50%) were deemed to have adequately assessed the index test. a reference standard was adequately assessed in 18 studies (64.3%). study participants were adequately followed up in 19 studies (67.9%). the prevalence of post-extubation airway obstruction ranged from 4 to 37% (pooled estimate 9%; 95% ci 7-11; i 2 = 86.3%). the pooled sensitivity and specificity of cuff leak test for post-extubation airway obstruction were 0.62 (95% ci 0.49-0.73; i 2 = 81.6%) and 0.87 (95% ci 0.82-0.90; i 2 = 97.8%), respectively. the forest plots are shown in additional file 1: figure s1 . the pooled positive and negative likelihood ratios were 4.63 (95% ci 3.44-6.22) and 0.44 (95% ci 0.32-0.60), respectively. the area under the summary receiver operating characteristic (sroc) curve was 0.85 (95% ci 0.82-0.88) (fig. 2) , and the pooled diagnostic odds ratio (dor) was 10.54 (95% ci 6.26-17.76) (additional file 4: table s2 ). there was no evidence of publication bias (p = 0.189). subgroup analysis suggested that the specificity was similar between the qualitative and quantitative cuff leak tests ( a nomogram based on the pretest probability of 9% (the incidence of stridor in the studies included in our study) is provided (fig. 3) . the prevalence of reintubation varied from 0 to 11% (pooled estimate: 3%; 95% ci 1-5; i 2 = 79%). the pooled sensitivity and specificity of the cuff leak test for reintubation were 0.66 (95% ci 0.46-0.81; i 2 = 48.9%) and 0.88 (95% ci 0.83-0.92; i 2 = 87.4%), respectively. the forest plots of the sensitivity and specificity of the cuff leak table s2 ). there was no evidence of publication bias (p = 0.52). our study found that the cuff leak test has excellent specificity but moderate sensitivity for post-extubation airway obstruction. the cuff leak test thus works better to rule in than to rule out potential post-extubation airway obstruction. however, the false-negative rate of nr not reported 38% suggests that the cuff leak test may fail to identify some patients with post-extubation airway obstruction. our study found that the specificity of the cuff leak test for post-extubation airway obstruction was excellent, which is consistent with two previous systematic reviews [15, 16] . in contrast, ochoa et al. and zhou et al. concluded that the sensitivity of cuff leak testing for postextubation airway obstruction was 56% and 80%, respectively [15, 16] : our pooled sensitivity was 62%, which fell between those two findings. we included nearly double the number of studies that their reviews did. furthermore, the additional studies we included were higher quality, potentially making our findings more reliable. our analysis found that the qualitative cuff leak test had low sensitivity (35%) in predicting post-extubation airway obstruction. this has been consistently found in recent studies. the most likely explanation is the subjective nature of this test. in addition, since schnell et al. provided data from three different methods of qualitative cuff leak testing [48] , the sensitivity of which were all around 30%; this study may have been overweighed, although repeat analysis limiting schnell's study to a single data contribution did not change the sensitivity of the qualitative test. in contrast, the specificity of both qualitative and quantitative cuff leak tests was high, nearly 90%, while there was a statistically significant difference between two methods, clinically both performed equally well. a cutoff of 110 ml also had a low sensitivity (44%) and high specificity for predicting post-extubation airway obstruction. we thus conclude that the cuff leak test has high specificity and can be used to select patients to consider treating with systemic corticosteroids, but its low sensitivity suggests that the traditional practice of closely observing all patients in the immediate post-extubation period should be continued. consistent with these findings, the nomogram suggested that while a negative cuff leak test represents low possibility of post-extubation airway obstruction, a positive test still provides a relatively low posttest probability. the guideline by ats/accp provided a conditional recommendation regarding cuff leak test [14] , because failing the cuff leak test might lead a delay in extubation and an increase in complications such as barotrauma and ventilator-associated pneumonia. the guideline weakly recommended that the cuff leak test be reserved for highrisk patients, who experienced a traumatic intubation, were intubated more than 6 days, have a large endotracheal tube, are female, or were reintubated after an unplanned extubation [14] . our analysis found that the length of intubation had a small impact on the specificity of cuff leak test. female sex and reintubation had no impact of the accuracy of cuff leak test. since the original studies included in our review examined non-selected patients with respect to the risk of post-extubation airway obstruction and the sensitivity of cuff leak test is moderate, we support the idea of the ats/accp guideline to reserve cuff leak test for high-risk patients. our study suggested that the cuff leak test has moderate sensitivity and excellent specificity for reintubation. although the sensitivity in our study was similar to those of previous meta-analyses, the specificity in our study was slightly higher [15, 16] . the area under the sroc curve and dor were also greater than previously reported [16] . thus, a failed cuff leak test may serve as a good marker for those at risk of reintubation, if postextubation airway obstruction is not treated adequately. the limitation of cuff leak test has been repeatedly discussed. cuff leak test can be susceptible to relationship of tube size to laryngeal diameter [41] , respiratory system compliance and resistance, inspiratory flow, expiatory flow and time, and airway collapse [51] , and clinicians should bear in mind that the ability of cuff leak test may vary according to the condition or type of patients [52] . additionally, coughing during cuff deflation test hinders accurate measurement of the leak volume and lowers the reproducibility. a previous physiological study suggested that while patients were sedated and paralyzed, the cuff leak volume was reliably measurable [53] . an adequate amount of sedatives and opioids can suppress coughing during the airway suctioning before cuff leak test or cuff deflation during the test. further, cuff leak testing is recommended several hours before extubation, which allows the arousal of patients from sedation by the time of extubation. thus, we may be able to at least attempt to increase the reliability of cuff leak measurement. few tests are available to estimate the risk of postextubation airway complications. a case series of three patients suggested that video laryngoscopy enabled visualization of laryngeal edema prior to extubation [54] , but its clinical efficacy in estimating post-extubation airway complications is yet to be determined. several studies have examined the role of laryngeal ultrasonography in adult patients. laryngeal air column width difference is the difference between width of airway at the level of the vocal cord with cuff inflated and deflated. its reported sensitivity and specificity varied across studies, ranging from 50 to 91% and 54 to 72%, respectively [44, 46, 49] . laryngeal air column width ratio is the ratio of air column width before extubation over that after intubation. it has been examined in only one study [55] and needs further validations. thus, no single available options can correctly estimate the risk of post-extubation airway complications. clinicians should not overly rely on one single test in predicting the success or failure of extubation. our study had several strengths and limitations. strengths included a comprehensive search in five databases without language restrictions. this allowed us to conduct relevant subgroup analyses with a larger number of studies. further, inclusion of non-english studies facilitates the generalizability of our findings in various clinical settings [56] . our study had some limitations. first, the definition of post-extubation airway obstruction differed across studies. stridor was more frequently used as the reference standards than laryngeal edema (as assessed with endoscopy). laryngeal edema may be more frequent than stridor, because stridor and respiratory distress occur when laryngeal edema narrows the airway by ≥ 50% [57] . however, laryngeal edema is not always screened for in extubated patients, and the presence of stridor is an accepted sign of respiratory distress that triggers a concern for airway obstruction. thus, the finding of our study is generalizable to the clinical practice. second, although we attempted to include in the analysis the incidence of stridor due to post-extubation airway events, some patients might have had a concurrent clinical state that necessitated high minute ventilation or tachypnea through an edematous airway, which manifested as 'stridor. ' therefore, we might not have been able to completely separate stridor due to post-extubation airway events from stridor due to other etiologies, such as respiratory insufficiency. this limitation also applies to reintubation. third, whether to reintubate patients is subject to treating physicians' discretion and the effect of treatment to abort post-extubation stridor. therefore, the value of cuff leak test in predicting the need for reintubation in clinical practice may be limited along with the third limitation. however, prevention of post-extubation airway obstruction is more important than reintubation per se. once the cuff leak test identifies patients at high risk of postextubation airway obstruction, prophylactic systemic corticosteroids are indicated [9, 14, 58] . fourth, 15 out of 23 studies that assessed the quantitative cuff leak test determined the cutoff with the knowledge of the results of the reference standards. it is known that data-driven optimization of the cutoff can lead to overestimation of test performance [59] . thus, the pooled accuracy of quantitative cuff leak test in our study can be an overestimation; the optimal cutoff is still unknown. fifth, the quantitative cutoff for a positive test varied between the studies. since we had aggregate data from each included study, we failed to determine the optimal cutoff of cuff leak test. finally, there was substantial statistical heterogeneity in the pooled sensitivity and specificity for both outcomes. the presence of statistical heterogeneity is a common issue intrinsic to the the prediction region illustrates the extent of statistical heterogeneity by depicting a region within there is 95% confidence that the true sensitivity and specificity of a future study should lie meta-analysis of diagnostic accuracy of a test, given the clinical and methodological diversity in original studies as well as the possible relationship between sensitivity and specificity, as exemplified in roc curves in which more sensitive cut points have lower specificity (and vice versa). our subgroup analyses suggested that the type of cuff leak test (quantitative versus qualitative) and length of intubation might have been the cause of statistical heterogeneity of sensitivity and specificity, respectively, for post-extubation airway obstruction. the cuff leak test has excellent specificity but moderate sensitivity for post-extubation airway obstruction. the cuff leak test is a useful tool in the decision-making about extubation, but the low sensitivity suggests that a negative test cannot completely exclude post-extubation airway obstruction and that patients still need to be closely monitored post-extubation. the higher specificity suggests that clinicians should consider intervening in patients with systemic corticosteroids in response to a positive test. continued research to find better modalities to rule out post-extubation airway obstruction is needed. postextubation laryngeal edema and stridor resulting in respiratory failure in critically ill adult patients: updated review re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation outcome of reintubated patients after scheduled extubation independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation effect of failed extubation on the outcome of mechanical ventilation the outcome of extubation failure in a community hospital intensive care unit: a cohort study the effect of extubation failure on outcome in a multidisciplinary australian intensive care unit outcomes of extubation failure in medical intensive care unit patients prophylactic corticosteroids for prevention of postextubation stridor and reintubation in adults: a systematic review and meta-analysis when to extubate the croup patient: the 'leak' test cuff" test for safe extubation following laryngeal edema the cuff leak test to predict failure of tracheal extubation for laryngeal edema post-extubation stridor in intensive care unit patients. risk factors evaluation and importance of the cuff-leak test practice guideline: liberation from mechanical ventilation in critically ill adults. rehabilitation protocols, ventilator liberation protocols, and cuff leak tests cuff-leak test for the diagnosis of upper airway obstruction in adults: a systematic review and meta-analysis cuffleak test for predicting postextubation airway complications: a systematic review preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: the prisma-dta statement the accuracy of google translate for abstracting data from non-english-language trials for systematic reviews the cuff leak test: does it "leak" any information? respir care group q-: quadas-2: a revised tool for the quality assessment of diagnostic accuracy studies association between reduced cuff leak volume and postextubation stridor the cuff-leak test is a simple tool to verify severe laryngeal edema in patients undergoing long-term mechanical ventilation the "cuff-leak" test for extubation bivariate meta-analysis of sensitivity and specificity with sparse data: a generalized linear mixed model approach transformations related to the angular and the square root the performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed diagnostic tests 4: likelihood ratios the cuff-leak test as a predictor of postextubation stridor: a prospective study evaluation of the cuff-leak test in a cardiac surgery population measurement of endotracheal tube cuff leak to predict postextubation stridor and need for reintubation how to identify patients with no risk for postextubation stridor? high body mass index and long duration of intubation increase post-extubation stridor in patients with mechanical ventilation the endotracheal tube cuff-leak test as a predictor for postextubation stridor intravenous injection of methylprednisolone reduces the incidence of postextubation stridor in intensive care unit patients risk factors of extubation failure and analysis of cuff leak test as a predictor for postextubation stridor dexamethasone to prevent postextubation airway obstruction in adults: a prospective, randomized, double-blind, placebo-controlled study the role of the cuff leak test in predicting the effects of corticosteroid treatment on postextubation stridor the cuff leak test is not predictive of successful extubation risk factors evaluation and the cuff leak test as predictors for postextubation stridor cuff-leak test predicts the severity of postextubation acute laryngeal lesions: a preliminary study intra-individual variation of the cuff-leak test as a predictor of post-extubation stridor cuff leak volume as a clinical predictor for identifying post-extubation stridor cuff leak tests at the time of extubation correlate with voice quality assessment predicting laryngeal edema in intubated patients by portable intensive care unit ultrasound cuff leak test and laryngeal survey for predicting post-extubation stridor ultrasound-guided laryngeal air column width difference and the cuff leak volume in predicting the effectiveness of steroid therapy on postextubation stridor in adult. are they useful? laryngeal ultrasound versus cuff leak test in prediction of post-extubation stridor cuff leak test for the diagnosis of post-extubation stridor laryngeal ultrasonography versus cuff leak test in predicting postextubation stridor clinical risk, cuff leak test and laryngeal ultrasound based scoring system to predict postextubation stridor in intensive care unit patients determinants of the cuff-leak test: a physiological study the cuff-leak test: what are we measuring? is the leak test reproducible? use of video laryngoscopy and camera phones to communicate progression of laryngeal edema in assessing for extubation: a case series laryngeal air column width ratio in predicting post extubation stridor how often do systematic reviews exclude articles not published in english? tracheoesophageal compression associated with substernal goitre. correlation of symptoms with cross-sectional imaging findings adverse events associated with prophylactic corticosteroid use before extubation: a cohort study bias in sensitivity and specificity caused by data-driven selection of optimal cutoff values: mechanisms, magnitude, and solutions publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to sincerely thank ms. elizabeth suelzer, mlis, ahip for her help with literature search. supplementary information accompanies this paper at https ://doi. org/10.1186/s1305 4-020-03358 -8.additional file 1: figure s1 . forest plot of the sensitivity and specificity of the cuff leak test for predicting post-extubation upper airway obstruction.additional file 2: figure s2 . forest plot of the sensitivity and specificity of the cuff leak test for predicting reintubation.additional file 3: table s1 . search strategy. table s2 . the pooled diagnostic accuracy of cuff leak test for post-extubation airway obstruction and reintubation. authors' contributions ak and jlj substantially contributed to conception of the study design, data acquisition, data analysis, interpretation, and the writing and critical revision of the manuscript. jk substantially contributed to data acquisition, interpretation, and critical revision of the manuscript. all authors read and approved the submission of the final manuscript. there was no funding source for this study. all data generated or analyzed during this study are included in this published article and its supplementary information files. this study is a systematic review and an ethics approval was not necessary. not applicable. the authors declare that they have no competing interests. received: 27 july 2020 accepted: 23 october 2020 key: cord-343940-fdnmeuh8 authors: tzotzos, susan j.; fischer, bernhard; fischer, hendrik; zeitlinger, markus title: incidence of ards and outcomes in hospitalized patients with covid-19: a global literature survey date: 2020-08-21 journal: crit care doi: 10.1186/s13054-020-03240-7 sha: doc_id: 343940 cord_uid: fdnmeuh8 nan systems and to inform critical care clinicians. this information should enable the prediction of requirements for hospital resources and thereby facilitate planning an appropriate and timely response in the future. we carried out regular searches of pubmed using combinations of the search terms "ards," "covid-19," "clinical characteristics," "clinical features," "clinical findings," "icu," "incidence," "outcome," and "prevalence" (last search july 31, 2020). over 1000 publications were retrieved from which only studies reporting consecutively hospitalized patients, and giving numbers for ards patients and outcomes, were selected. meta-analyses were excluded. seventeen studies reporting results from 2486 hospitalized covid-19 patients in five countries fitted the inclusion criteria (tables 1 and 2 ). limitations are that seven studies did not define ards and only one study classified patients as mild, moderate, and/or severe; the patient sample is comparatively small: twelve of the studies had less than 200 patients. furthermore, there was heterogeneity in types of data gathered by each research group, hence for many of the studies, patient numbers did not permit calculation of all parameters (tables 1 and 2) . there is variability between individual studies with respect to frequency of ards, rates of icu admission, and mortality among patients. calculation of weighted averages for these parameters incorporating data from individual studies for which data is available indicate that among hospitalized covid-19 patients, approximately 1/3 (33%) develop ards, 1/4 (26%) require transfer to patient numbers for chen t study not included an icu, 1/6 (16%) receive imv, and 1/6 (16%) die (table 1 ). for covid-19 patients transferred to an icu, nearly 2/3 (63%) receive imv and 3/4 (75%) have ards ( table 2 ). the mortality rate of icu covid-19 patients is 40% and of those who receive imv 59%; the mortality rate in covid-19-associated ards is 45%, and the incidence of ards among non-survivors of covid-19 is 90% ( table 2 ). the high incidence of ards among covid-19 patients revealed in our survey is consistent with the results of postmortem examinations of patients with covid-19, in which the predominant finding is diffuse alveolar damage, the most frequent histopathologic correlate of ards. for as long as there is neither a safe and efficacious vaccine nor therapy for severely affected covid-19 patients, standard supportive care with lung-protective mechanical ventilation will be the cornerstone of treatment for these patients [5, 6] . the implications of these survey results are important and demonstrate the considerable challenges posed by the "covid-19 crisis" to icu practitioners, hospital administrators, and health policy makers. susan data generated or analyzed during this study are included in this published article. ethics approval and consent to participate not applicable all authors have approved the manuscript for submission. for study reference see table 1 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention mechanical ventilation in covid-19: interpreting the current epidemiology risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china acute respiratory distress syndrome: the berlin definition covid-19-associated acute respiratory distress syndrome: is a different approach to management warranted? treatment for severe acute respiratory distress syndrome from covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions sjt conducted the literature search and survey. sjt, bf, and hf evaluated and contributed to the interpretation and presentation of the data. sjt drafted the manuscript; bf, hf, and mz revised the final version of the manuscript. the authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord-322726-obnil3b7 authors: nakamura, kensuke; nakano, hidehiko; naraba, hiromu; mochizuki, masaki; hashimoto, hideki title: early rehabilitation with dedicated use of belt-type electrical muscle stimulation for severe covid-19 patients date: 2020-06-15 journal: crit care doi: 10.1186/s13054-020-03080-5 sha: doc_id: 322726 cord_uid: obnil3b7 nan coronavirus disease 2019 (covid-19), caused by severe acute respiratory syndrome coronavirus 2, has produced a global pandemic. many patients, mainly those with plural risk factors, have developed to critically ill status and have required intensive care including mechanical ventilation and extracorporeal membrane oxygenation. although evidence remains limited about how long mechanical ventilation is generally necessary, 1 to 2 weeks of ventilation usage are typically prepared to treat severe cases of covid-19 [1] . because intensive care unit (icu) acquired weakness (icu-aw) often accompanies acute respiratory distress syndrome, treatment of icu-aw is fundamentally important for clinical practice for covid-19. early mobilization and exercise are vitally necessary to treat severe covid-19. in an international expert team's guide to physiotherapy management for covid-19, early exercise is recommended, with active involvement by a physiotherapist, after icu treatment [2] . however, in actual practice, active early rehabilitation can frequently not be performed for various reasons such as exhaustion of medical resources, especially of personal protective equipment. moreover, chinese recommendations for respiratory rehabilitation have suggested avoidance of early rehabilitation in the acute phase of severe covid-19 [3] . to reduce exposure and to conserve medical resources, service automation is also desired in early mobilization. electrical muscle stimulation (ems) is an exclusive automated method of physiotherapy used in current critical care. as discussed for ems efficacy, its use in early acute phase can contribute to the countering of icu-aw if combined with optimal nutrition therapy including adequate protein delivery [4] . automated ems is expected to be an ideal mobilization for severe covid-19 patients. moreover, among the various modes of ems, belt-type ems is expected to be effective for critical care because it can induce whole lower extremity exercise through whole muscle contraction between wrapped belts [5] . exposure to medical staff can be minimized while realizing frequent actuation with a longer duration for each bout of stimulation by assigning each covid-19 patient a dedicated belt-type ems, for which no belt change would be necessary (fig. 1) . at hitachi general hospital, we assigned each ventilated covid-19 patients a dedicated belt-type ems: a measure which achieved better outcomes by administration of 50 min bouts, with three bouts per day, requiring only switching on by a nurse. in conclusion, we propose the use of dedicated belttype ems for early rehabilitation in severe covid-19. ultimately, a ventilator with an installed ems would be ideal, not only for covid-19 patients, but also for all future ventilated patients. fig. 1 belt-type electrical muscle stimulation for severe covid-19 patients. belt-type electrical muscle stimulation ems for intensive care unit patient with extracorporeal membrane oxygenation. the ems machine is dedicated to this patient and is not brought out of the patient's bedroom. the ems belt is worn continuously during daytime. this figure was provided after informed consent and permission were received from the patient baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region physiotherapy management for covid-19 in the acute hospital setting: clinical practice recommendations rehabilitation crgocsopma. recommendations for respiratory rehabilitation of coronavirus disease 2019 in adult exploring the potential effectiveness of combining optimal nutrition with electrical stimulation to maintain muscle health in critical illness: a narrative review efficacy of belt electrode skeletal muscle electrical stimulation on reducing the rate of muscle volume loss in critically ill patients: a randomized controlled trial the authors thank all the nursing specialists in hitachi general hospital for their support. authors' contributions kn: conception and drafting the manuscript. hn, hn, mm: conducting the clinical practice described in this manuscript. hh: revisions of the manuscript and supervised the study. all authors have read and approved the manuscript. the authors affirm that they were given no funding related to this paper.availability of data and materials not applicable. ethics approval is not applicable. we obtained the consent from the patients to use the figure in the manuscript. we gained the consent from the patient. all authors have no competing interest.received: 18 may 2020 accepted: 9 june 2020 key: cord-312484-epbhdx55 authors: wang, hongliang; wang, sicong; yu, kaijiang title: covid-19 infection epidemic: the medical management strategies in heilongjiang province, china date: 2020-03-18 journal: crit care doi: 10.1186/s13054-020-2832-8 sha: doc_id: 312484 cord_uid: epbhdx55 nan education and training of staffs as soon as the outbreak of covid-19 began in wuhan, the heilongjiang provincial health administration department started to launch training protocols for all the medical staffs. the content of training included personal protection such as hand hygiene, wearing personal protective equipment (ppe), safe waste disposal, and emergency handling protocols. the means of training included presentations, videos, and wechat. first, the infection control experts from various hospitals trained their own staffs both theoretically and practically. the training emphasized the importance of standardized protection. second, the infection control experts conducted standardized pre-job training. the infection control experts supervised the whole process to ensure that all the staffs had followed the correct procedures. third, the infection control experts monitored the entire process before and after the medical staff entering the isolation wards. they also supervised the procedures of medical staffs in the isolation wards by wireless communication equipment. the mental stress of the medical staffs increased significantly since they had to work in a relatively confined space, wearing thick isolation clothes, and care for a large number of anxious patients. the high-intensity work further deteriorated the mental health of the medical staffs, especially for those who came from all over the country to support wuhan. it is crucial to ensure the stable psychological state of the medical staffs. therefore, early professional intervention is necessary. at the same time, active communication with family members and initiative support from a local hospital can also be very helpful. it is particularly important to ensure the physical health of the medical staffs. all of them should undergo medical examinations, including blood routine tests and chest ct before managing covid-19 patients. daily self-examinations of respiratory symptoms and body temperature were also conducted. once the medical staff had any uncomfortable symptoms, they should report to the team leader immediately. a specialized screening for covid-19 would be performed. the medical staffs who treated covid-19 patients lived in special and isolated areas. adequate protective equipment was prepared for all the medical staffs who participated in the management of covid-19. the protective equipment included medical masks, goggles, face shields, and waterproof isolation clothes. the protective equipment was supplied by the government and hospitals, as well as donated by the public. the equipment such as goggles and face shields that was reused would be disinfected strictly. heilongjiang province set up a multidisciplinary team (mdt) soon after the outbreak of covid-19, including intensive care unit (icu), emergency department, infectious disease department, respiratory department, psychological department, infection control department, administrative department, and nursing department. meanwhile, the medical resources of the whole province were redistributed to meet medical needs. medical staffs in heilongjiang province were divided into 4 groups (fig. 1 ). wuhan, as the most serious epidemic area, needs a national support. the first set of medical teams arrived in wuhan on january 27, 2020, and soon started medical work. as of february 23, heilongjiang province had dispatched eight medical teams consisting of 1533 medical staffs to hubei province. the majority of the medical staffs worked in the fever clinics, which involved the largest number of patients to be screened. fever clinics were essential for the proper triage of fever patients: diagnosis of covid-19 patients, isolation of suspected cases, and exclusion of non-covid-19 patients. heilongjiang province appointed four designated hospitals in harbin to treat all the covid-19 patients. medical staffs of the whole province, especially intensivist, respiratory physician, emergency physician, and infectious disease physician, were assigned to work in the designated hospitals. the group members included provincial health authorities, medical experts, and infection control experts. during inspection, the team summarized, discussed, and handled any problems timely, thus ensuring that the infection rate of the medical staffs was zero. during the outbreak of covid-19, all the patients with fever in our province were screened according to the procedure, as detailed in fig. 2 . in all isolation wards, a three-level round system was adopted, both in heilongjiang and hubei. the morning and evening medical care shifts were adopted to achieve the standardized management of covid-19. the medical resources were reassigned accordingly: physicians from general wards who specialized in respiratory or infectious disease treated mild patients, while critical cases were handled by a team led by intensivists. medical treatment and nursing were managed in the same way as mentioned above. to prevent the spread of covid-19, our province suspended outpatient services and non-emergency surgeries of all levels of hospitals. health commission of heilongjiang province launched online free consultations. more than 12,000 medical staffs provided free online consultation, initial screening, popularizing the in conclusion, the covid-19 outbreak is a significant threat to international health and a big challenge for all of us. we need to understand more and more about the disease to overcome it. clinical features of patients infected with 2019 novel coronavirus in wuhan epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china coronavirus covid-19 global cases by johns hopkins csse publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank all the medical staffs and local authorities of heilongjiang province for their efforts in combating the outbreak of covid-19. all authors were major contributors in writing the manuscript and approved the final manuscript. availability of data and materials all data generated or analyzed during this study are included in this published article.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord-346394-rk8jkf19 authors: pinkham, maximilian; tatkov, stanislav title: effect of flow and cannula size on generated pressure during nasal high flow date: 2020-05-24 journal: crit care doi: 10.1186/s13054-020-02980-w sha: doc_id: 346394 cord_uid: rk8jkf19 nan nasal high flow (nhf) with supplemental oxygen has been proposed to treat covid-19 patients with acute respiratory failure (arf) [1] . nhf gained its popularity due to the high oxygenation efficiency and success in treating patients with hypoxemic arf [2] . apart from the delivery of oxygen, nhf reduces the rebreathing from anatomical dead space and generates positive airway pressure; however, the delivered pressure is difficult to quantify due to the unsealed cannula interface. the purpose of this research is to provide clinicians with the indicative data of the generated pressure using different flow settings and cannula sizes. a chamber with two adjacent orifices to fit the cannula served as a model of the nasal cavity with nares, which has been described in detail previously [3] . briefly, two "nare" sizes of 9-mm and 10-mm diameter were included to replicate similar pressures observed previously in patients [4] . nhf was delivered via a smaller-sized cannula, o.d. 6.1 mm/i.d. 5.1 mm, and a larger-sized cannula, o.d. 7.2 mm/i.d. 6.0 mm (optiflow™ opt944 "medium" and opt946 "large", fisher & paykel healthcare, nz). measurements were made during the static condition to replicate pressure at the end of expiration in a mouth-closed position. as shown in fig. 1 , nhf generates greater pressure when delivered using a larger cannula and with higher flow rate. for example, nhf of 60 l/min generated pressure of 12.1 cmh 2 o using the larger cannula compared to 4.8 cmh2o using the smaller cannula, in the 9-mm diameter "nare". the same cannula size will generate greater pressure when used in a smaller nare. therefore, using higher flow rates as well as increasing the prong/nare area ratio will generate greater positive airway pressure. the data show that in order to deliver higher pressure during nhf, then the flow rate and/or cannula size need to be increased. the results are taken from a bench experiment with inelastic orifices, and patients rarely have a closed system; however, the bench data demonstrate that a small reduction of the leak around the cannula, by occluding a larger area of the nare, may lead to a substantial increase of delivered pressure, particularly in the upper range of nhf rates. the relationship between the occlusion and flow rate in generating positive airway pressure is non-linear; as the occlusion is increased, then pressure will increase significantly due to the increased resistance to flow leaving the nare [3] . using a very small internal diameter of cannula may also affect relationship between flow and pressure through the jetting effect; however, this was outside the scope of the study [5] . the increase of pressure may reduce comfort and encourage a patient to open their mouth, which may lead to an increase of leak and reduction of pressure [4] ; there is no data on the clinical effects of opening the mouth in patients with arf. also, the opening of the mouth may enhance the dead space clearance [6] . larger-sized cannula may potentially reduce the clearance due to the lower leak if the mouth is not opened. however, at the highest flow rate, the dead space clearance is likely to be maximized regardless of the cannula size. therefore, at 60 l/min, which is 1000 ml/s, the nasal cavity will be filled with fresh gas within a fraction of a second leading to rapid dilution and purging of the expired air. the experimental data demonstrates the rise in pressure with the increase of the cannula size and flow rate. the findings can be of practical value in the management of patients with severe arf who need higher levels of positive airway pressure. fig. 1 the graph shows the positive airway pressure, cmh2o, that is generated by nasal high flow (nhf) using a smaller cannula (o.d. 6.1 mm) and larger cannula (o.d. 7.2 mm) in "nares" with two different diameters: 10 mm (left panel) and 9 mm (right panel) in the bench top model. pressure generated by nhf can be increased by higher flow and by occluding a larger area of the nare, which can be achieved by increasing the cannula size management of critically ill adults with covid-19 high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure mechanisms of nasal high flow therapy in newborns the effects of flow on airway pressure during nasal high-flow oxygen therapy correlation of high flow nasal cannula outlet area with gas clearance and pressure in adult upper airway replicas effectiveness of nasal highflow in hypercapnic copd patients is flow and leakage dependent publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.authors' contributions s.t. conceived the study. m.p. performed the data collection and analysis. both authors contributed in the interpretation and writing and approved the final manuscript. availability of data and materials all data generated or analyzed during this study are included in this published article.ethics approval and consent to participate not applicable. not applicable. key: cord-326315-ncfxlnpj authors: cillóniz, catia; ewig, santiago; ferrer, miquel; polverino, eva; gabarrús, albert; puig de la bellacasa, jorge; mensa, josep; torres, antoni title: community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis date: 2011-09-14 journal: crit care doi: 10.1186/cc10444 sha: doc_id: 326315 cord_uid: ncfxlnpj introduction: the frequency and clinical significance of polymicrobial aetiology in community-acquired pneumonia (cap) patients admitted to the icu have been poorly studied. the aim of the present study was to describe the prevalence, clinical characteristics and outcomes of severe cap of polymicrobial aetiology in patients admitted to the icu. methods: the prospective observational study included 362 consecutive adult patients with cap admitted to the icu within 24 hours of presentation; 196 (54%) patients had an established aetiology. results: polymicrobial infection was present in 39 (11%) cases (20% of those with defined aetiology): 33 cases with two pathogens, and six cases with three pathogens. the most frequently identified pathogens in polymicrobial infections were streptococcus pneumoniae (n = 28, 72%), respiratory viruses (n = 15, 39%) and pseudomonas aeruginosa (n = 8, 21%). chronic respiratory disease and acute respiratory distress syndrome criteria were independent predictors of polymicrobial aetiology. inappropriate initial antimicrobial treatment was more frequent in the polymicrobial aetiology group compared with the monomicrobial aetiology group (39% vs. 10%, p < 0.001), and was an independent predictor of hospital mortality (adjusted odds ratio = 10.79, 95% confidence interval = 3.97 to 29.30; p < 0.001). the trend for higher hospital mortality of the polymicrobial aetiology group compared with the monomicrobial aetiology group (n = 8, 21% versus n = 17, 11%), however, was not significantly different (p = 0.10). conclusions: polymicrobial pneumonia occurs frequently in patients admitted to the icu. this is a risk factor for inappropriate initial antimicrobial treatment, which in turn independently predicts hospital mortality. community-acquired pneumonia (cap) remains a common and potentially life-threatening condition. among patients hospitalised by cap, the rates of severe cap range from 6.6 to 16.7% [1] . the pathogens causing cap may vary according to geographic area and underlying risk factors. appropriate initial antimicrobial treatment has been repeatedly shown to be crucial for the outcome in severe infections. the knowledge of pathogen patterns causing cap as the basis for the selection of such treatment is therefore crucial. some studies have revealed that more than one causative microorganism was present in a considerable amount of cases. one of main problems for the studies on microbial aetiology in cap is that not all microbiological tests are applied systematically for all patients. this limitation could possibly imply that the real frequency of polymicrobial aetiologies in main series is often underestimated. the reported rates for polymicrobial aetiology, however, differ considerably between 5.7 and 38.4% [2] [3] [4] [5] [6] [7] . the clinical significance of polymicrobial aetiology in cap patients admitted to the icu has not been specifically addressed. we therefore studied the prevalence, clinical characteristics and outcomes of severe cap of polymicrobial aetiology in icu patients. the study was approved by the ethics committee of our institution, but written informed consent was waived due to the non-interventional design. the present cohort included 362 consecutive adult patients with cap admitted to the icu within 24 hours of admission to the emergency department in an 850bed tertiary care university hospital (hospital clinic of barcelona, spain) between january 2003 and december 2010. the decision for admission to an icu was made by the attending physician in all cases. pneumonia was defined as a new pulmonary infiltrate found on the hospital admission chest radiograph with symptoms and signs of lower respiratory tract infection. we excluded patients with immunosuppression (for example, patients with neutropaenia after chemotherapy or bone marrow transplantation, patients with druginduced immunosuppression as a result of solid-organ transplantation or corticosteroid (> 10 mg/day) or cytotoxic therapy, and all hiv-infected patients) and healthcare-associated pneumonia patients. the following parameters were recorded at admission: age, sex, tobacco use, alcohol and drug consumption, co-morbidities (chronic respiratory disease, including chronic obstructive pulmonary disease, asthma and bronchiectasis among others, diabetes mellitus, chronic cardiovascular disease, neurological disease, chronic renal disease and chronic liver disease), antibiotic treatment in the previous 30 days before hospital admission, treatment with corticosteroids, clinical symptoms and features (fever, cough, pleuritic chest pain, dyspnoea, mental confusion and aspiration), clinical signs (blood pressure, body temperature, respiratory rate and heart rate), arterial blood gas measurements, chest radiograph findings (number of lobes affected, pleural effusion and atelectasis), laboratory parameters (haemoglobin level, white blood cell count, platelet count, serum creatinine level, c-reactive protein level and other biochemical parameters), diagnostic procedures, empiric antibiotic therapy, ventilatory support, pulmonary complications (empyema, acute respiratory distress syndrome (ards) criteria, pleural effusion and surgical pleural draining) and other clinical events (cardiac arrhythmias, septic shock, and acute renal failure). the duration of treatment, length of hospital stay and 30-day in-hospital mortality were noted. we also calculated the pneumonia severity index (psi) at admission [8] . microbiological examination was performed in sputum, urine, two samples of blood and nasopharyngeal swabs. pleural puncture, tracheobronchial aspirates and bronchoalveolar lavage (bal) fluid, when available, were collected. conventional tests were used to evaluate the presence of bacterial, parasitic and fungal agents, and of respiratory viruses. sputum, bronchial aspirate sample (bas) and bal specimens were stained using the gram and ziehl-neelsen methods for bacterial and mycobacteria detection, respectively. in bal samples, the following additional stains were used: may-grünwald giemsa for fungal detection and cellular differential count, and gomori methenamine silver for pneumocystis jirovecii. sputum and pleural fluid samples were qualitatively cultured for bacterial pathogens, fungi and mycobacteria. bronchial aspirate sample (bas) and bal samples were homogenised and processed for quantitative culture by serial dilutions for bacterial pathogens; undiluted cultures for legionella spp., fungi and mycobacteria were also carried out. nasopharyngeal swabs and bal specimens were processed for antigen detection by immunofluorescence assay and for isolation of viruses in cell culture (influenza virus a, influenza virus b, human parainfluenza viruses 1 to 3, adenovirus and respiratory syncytial virus). in addition, two independent multiplex-nested rt-pcr assays able to detect from 1 to 10 copies of viral genomes were performed for the diagnostics of respiratory viruses. one rt-pcr assay detected influenza virus types a, b and c, respiratory syncytial viruses a and b, and adenovirus. another rt-pcr assay studied parainfluenza viruses 1, 2, 3 and 4, coronaviruses 229e and oc43, rhinoviruses and enteroviruses. all positive results were subsequently confirmed by a second independent assay. sputum and blood samples were obtained for bacterial culture before the start of antibiotic therapy in the emergency department. nasopharyngeal swab for respiratory virus detection and urine samples for streptococcus pneumoniae and legionella pneumophila antigen detection were obtained within 24 hours after hospital admission. blood samples for serology of atypical pathogens and respiratory virus were taken at admission and within the third and sixth week thereafter. the aetiology was considered definite if one of the following criteria was met: blood culture positive (in the absence of an apparent extrapulmonary focus); positive bacterial culture of pleural fluid or transthoracic needle aspiration samples; elevated serum levels of igm against chlamydophila pneumoniae (≥ 1:64), coxiella burnetii (≥ 1:80) and mycoplasma pneumoniae (any positive titre); seroconversion (that is, a fourfold increase in igg titres) for c. pneumoniae and l. pneumophila > 1:128, c. burnetii > 1:80 and respiratory viruses (influenza viruses a and b, parainfluenza viruses 1 to 3, respiratory syncytial virus and adenovirus); positive urinary antigen for l. pneumophila (binax now l. pneumophila urinary antigen test; trinity biotech, bray, ireland); positive urinary antigen for s. pneumoniae (binax now s. pneumoniae urinary antigen test; emergo europe, the hague, the netherlands); bacterial growth in cultures of tracheobronchial aspirates (≥ 10 5 cfu/ml), in a protected specimen brush (≥ 10 3 cfu/ ml) and in bal (≥ 10 4 cfu/ml); and detection of antigens by immunofluorescence assay plus virus isolation or detection by rt-pcr testing for respiratory virus (influenza viruses a and b, parainfluenza viruses 1 to 3, respiratory syncytial virus, rhinovirus and adenovirus). the aetiology of pneumonia was classified as presumptive when a predominant microorganism was isolated from a purulent sample (leukocytes > 25 per high-power microscopic field and few epithelial cells < 10 per highpower microscopic field) and the findings of gram staining were compatible. for the purpose of the present study, presumptive and definitive diagnostics were analysed together. polymicrobial pneumonia was defined as pneumonia due to more than one pathogen. severe cap was defined when at least one major criterion or three minor criteria of the infectious disease society of america/american thoracic society (idsa/ats) guidelines were present [9] . appropriateness of empiric antibiotic treatment was defined when the isolated pathogens were susceptible in vitro to one of the antimicrobials administrated according to current european guidelines for microbiological susceptibility testing [10] . for pseudomonas aeruginosa infection, adequate treatment needed a combination of two active antibiotics against the isolated strain. categorical variables are described as frequencies and percentages, while continuous variables are presented as means and standard deviations, or as the median and interquartile range for data not normally distributed (kolmogorov-smirnov test). categorical variables were compared with the chi-square test or fisher's exact test where appropriate. continuous variables were compared using the student t test once normality was demonstrated; otherwise, the nonparametric mann-whitney u test was performed. univariate and multivariate logistic regression analyses were performed to identify variables predictive of patients with polymicrobial pneumonia (dependent variable). the independent variables analysed were: age, gender, smoking, alcohol consumption, previous antibiotic, influenza vaccine, pneumococcal vaccine, inhaled corticosteroids, systemic corticosteroids, chronic cardiovascular disease, chronic renal failure, diabetes mellitus, chronic liver disease, neurological disease, chronic pulmonary disease, fever, c-reactive protein level, white blood cell count, creatinine, psi, multilobar infiltration, ards criteria, shock and mechanical ventilation. univariate and multivariate logistic regression analyses were performed to predict 30day mortality (dependent variable). the independent variables were the previous plus the number of aetiologies and adequacy of empirical treatment, with the exception of ards, shock and mechanical ventilation. variables that showed a significant result univariately (p < 0.1) were included in the multivariate logistic regression backward stepwise model. the hosmer-lemeshow goodness-of-fit test was performed to assess the overall fit of the model [11] . all tests were two-tailed and significance was set at 5%. all analyses were performed with spss version 16.0 for windows (spss inc., chicago, il, usa). during the study period, 2,200 patients were hospitalised with a diagnosis of cap. of these, 362 (16%) patients were admitted to the icu. the main characteristics of patients and the outcome variables are shown in table 1 . among the 67 patients who had received antimicrobial treatment prior to hospital admission, the median duration of treatment was 2.8 days. the types of antibiotics received were: 25 (8%) β-lactams, 20 (6%) fluoroquinolones, six (2%) macrolides and 16 (5%) unknown. the specimens obtained included blood cultures from 330 (91%) patients, urine from 345 (95%) patients, acute and follow-up sera from 150 (41%) patients, sputum from 285 (79%) patients, bronchoscopically obtained lower respiratory secretions from 84 (23%) patients, pleural fluid in 62 (17%) patients, and nasopharyngeal and oropharyngeal swabs from 180 (50%) patients. the aetiology of cap could be established in 196 (54%) icu patients. the proportion of patients with defined aetiology was higher in those with available lower respiratory tract samples, which included sputum and bronchoscopically obtained secretions (table 2) . patients with lower respiratory tract samples were more severe, assessed by higher psi risk classes, more frequent septic shock, ards criteria and the need for mechanical ventilation. monomicrobial infection was detected in 157 cases and polymicrobial infection in 39 cases (11% of the overall population and 20% of those with defined aetiology only), with two pathogens isolated in 33 cases and three pathogens in six cases. as shown in table 3 , the most frequently identified pathogens were s. pneumoniae, respiratory viruses, p. aeruginosa, methicillin-resistant staphylococcus aureus (mrsa), gram-negative enteric bacilli (gneb) and l. pneumophila. patients with polymicrobial aetiology had previously received antibiotics less frequently, had a higher proportion of chronic respiratory and neurological diseases, less frequently presented fever at admission, had higher rates of psi risk class v, had severe cap according to the idsa/ats definition, and fulfilled ards criteria. the length of hospital stay and hospital mortality tended to be higher in these patients ( table 4) . as regards the aetiologic pathogens, the proportion of respiratory viruses-particularly influenza a, mrsa, p. aeruginosa, gneb, haemophilus influenzae and moraxella catarrhalis -were more frequently isolated in patients with polymicrobial pneumonia, without differences in the remaining pathogens (table 3) . data on antibiotic treatment were available in 347 (96%) patients. the most frequent regimens were fluoroquinolones plus β-lactam (n = 217, 63%), β-lactam plus macrolide (n = 73, 21%), fluoroquinolone monotherapy (n = 39, 11%) and β-lactam monotherapy (n = 18, 5%). these regimens were similarly administered in patients with monomicrobial or polymicrobial aetiology. the empirical antibiotic treatment was more frequently inappropriate in patients from the polymicrobial aetiology group (table 4 ). when respiratory viruses were not taken into account, the pathogens most frequently associated with inadequate treatment were mrsa in 10 cases, and s. pneumoniae, p. aeruginosa and gneb in nine cases each. none of our patients received antiviral therapy. several variables were significantly associated with polymicrobial pneumonia in the univariate logistic regression analyses (table 5) . among these variables, chronic respiratory disease and ards criteria at hospital admission were independent predictors of polymicrobial aetiology in the multivariate analysis. the univariate logistic regression analyses revealed several variables significantly associated with hospital mortality (table 6 ). although polymicrobial pneumonia (that is, two or more pathogens identified) was associated with increased mortality compared with the absence of defined aetiology, the differences between monomicrobial and polymicrobial aetiology were not significant, as shown in table 4 . among these variables, age ≥ 65 years, neurological disease, chronic liver disease and inappropriate antimicrobial treatment were independently associated with increased hospital mortality in the multivariate analysis. polymicrobial aetiology was found in 11% of all patients with cap admitted to the icu, 20% considering those with defined aetiology only. although s. pneumoniae was the most frequent pathogen in both groups, we found mrsa, p. aeruginosa, gneb, h. influenzae, m. catarrhalis and respiratory viruses more frequently identified in polymicrobial pneumonia than in monomicrobial pneumonia. chronic respiratory disease and ards criteria were independent predictors of polymicrobial aetiology. although an independent predictor of hospital mortality such as inappropriate treatment was more frequent in the polymicrobial aetiology group, the trend for higher hospital mortality in patients from this group was not statistically significant. in general populations of hospitalised patients with cap, we have previously reported lower rates of polymicrobial pneumonia (5%) [3, 12] than in this series of icu patients. other studies on patients with cap found 5.7% and 38.4% rates of polymicrobial aetiology in their series [4, 5] . these wide variations might be explained by differences in the populations studied, epidemiological settings, rate of antimicrobial pretreatment, microbiological workup and definitions of aetiology. a typical limitation of many studies dealing with microbial aetiology in cap is that not all microbiological tests are applied systematically for all patients. this issue means that the real frequency of polymicrobial aetiologies could possibly be higher if a complete microbiological investigation was performed in all cases. in view of these methodological problems, it seems difficult to indicate precisely the extent of the problem of polymicrobial aetiology. analysing the potential impact of polymicrobial aetiology is therefore more important, particularly in the most severely ill patients and in those at highest risk of death. s. pneumoniae was not only the most frequent pathogen but also by far the most frequent co-pathogen in polymicrobial infections. this finding underlines the importance of pneumococcal coverage in any initial antimicrobial treatment regimen. the most frequent polymicrobial pattern was s. pneumoniae and viral infection, particularly influenza virus. pneumococci have been identified as the most frequent bacterial superinfection in both seasonal [13] and novel h1n1 [14, 15] influenza virus-associated pneumonia. interestingly, whereas s. pneumoniae was by far the most frequent single pathogen, the rate of this pathogen was similar among patients with monomicrobial aetiology and those with polymicrobial aetiology. among the pathogens more frequently identified in polymicrobial pneumonia, respiratory viruses were the most frequent. we did not find that polymicrobial aetiology was associated with higher mortality. viruses were the most frequent microorganisms associated with polymicrobial aetiology. except for influenza a h1n1, viruses are not a cause of excess mortality-as recently pointed out by two recent studies [13, 16] . the role of viruses in the aetiology of pneumonia is unclear, since they may be regarded either as primary infection or, with bacteria, as representing superinfection [17] . none of our patients received antiviral treatment. we feel that at least during the influenza season, however, patients could benefit from antiviral treatment. the role of mrsa in cap is limited in europe, even if patients meeting criteria for healthcare-associated pneumonia remain included [18] . although for our series we excluded patients with healthcare-associated pneumonia, the frequent association of this pathogen with severe underlying illness [19] may explain the higher rate of this pathogen in the polymicrobial aetiology group, since these patients were more severe at admission than those with monomicrobial aetiology. the exact role of mrsa in polymicrobial cap is difficult to assess, however, because even a high bacterial load of mrsa may still represent colonisation rather than infection [20] . the higher rate of p. aeruginosa and gneb in polymicrobial pneumonia may also be related to the higher rate of chronic respiratory diseases in this group, since identification of these pathogens occurs more frequently in those with chronic lung disease [21] . as for mrsa, the identification of p. aeruginosa does not necessarily mean this is the causative pathogen of acute exacerbation in all chronic obstructive pulmonary disease patients colonised by the pathogen [22] , and similarly mrsa eventually may represent colonisation rather than infection in patients with pneumonia. we identified chronic respiratory disease and ards criteria as independent predictors of polymicrobial aetiology. in chronic obstructive pulmonary disease, this finding can be explained by the previous colonisation of different bacteria these patients may have in their lower airways. on the contrary, ards may be the consequence of a mixed infection with higher pulmonary insult. in both chronic obstructive pulmonary disease and ards with severe cap, our recommendation is to give a broad empirical antibiotic treatment from the beginning of therapy because mixed infections are more frequent [23, 24] . a relevant issue in polymicrobial aetiology of severe cap refers to its potential prognostic implications. we found a strong association between polymicrobial aetiology and initial inappropriate antimicrobial treatment, which in turn was an independent predictor of increased hospital mortality. inappropriate empiric treatment has already been associated with poor outcome in patients with severe infections [25, 26] . although crude mortality was near double in patients with polymicrobial aetiology, this difference did not reach statistical significanceprobably due to the insufficient number of patients included. these results indicate that the impact of initial inappropriate antimicrobial treatment is crucial for survival, and that polymicrobial aetiology is an important determinant for such inappropriateness. to the best of our knowledge, this is the first study addressing the issue of multiple aetiologies of cap in a large population of icu patients. we decided to include all patients admitted to the icu regardless of whether they met idsa/ats severity criteria. we think that clinical decisions for icu admission may be valid, while the idsa/ats severity criteria have proven to be overly sensitive [1, 12] . several limitations have to be addressed. first, the complete diagnostic workup and microbiological sampling could not be applied in every patient. second, the true incidence of polymicrobial aetiology may be underestimated since 21% patients had received prior antimicrobial treatment. finally, viral infections may have been missed since paired serology is frequently not available in nonsurvivors. we did not include molecular techniques such as pcr for bacterial detection. we believe that the systematic use of qualitative and quantitative pcr for the diagnosis of respiratory infections may increase substantially the hosmer-lemeshow goodness-of-fit test, p = 0.81. b the p value corresponds to differences between the three groups (none, one or more than one pathogen). the odds ratio and 95% confidence interval (ci) of monomicrobial and polymicrobial pneumonia are related to cases with no pathogen identified. number of identified bacterial pathogens [7, 27] . moreover, these new techniques could play a crucial role in the determination of the clinical impact of polymicrobial aetiology in cap. unfortunately, the use of molecular techniques is not yet part of the routine diagnostic workup in cap. polymicrobial aetiology is a frequent finding in patients with cap admitted to the icu. our data support the potential implication of polymicrobial pneumonia in the outcome of patients related to an increased risk of inappropriate antimicrobial treatment, and suggests the importance of an extensive microbiological testing in very severe cap patients since the cap may be caused by more than one aetiology. the most important clinical implication of the identified predictors of polymicrobial aetiology is to emphasise the use of broad-spectrum antimicrobial treatment in these groups of patients. • polymicrobial aetiology is frequent among patients with cap admitted to the icu and may result in inappropriate empiric antimicrobial treatment. • polymicrobial aetiology of cap should be suspected in the presence of chronic respiratory disease or criteria for ards. • if antimicrobial treatment is appropriate, polymicrobial aetiology does not result in increased hospital mortality from severe cap. abbreviations ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage; cap: community-acquired pneumonia; gneb: gram-negative enteric bacilli; idsa/ ats: infectious disease society of america/american thoracic society; mrsa: methicillin-resistant staphylococcus aureus; pcr: polymerase chain reaction; psi: pneumonia severity index; rt: reverse transcriptase. towards a sensible comprehension of severe community-acquired pneumonia community-acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome mixed community-acquired pneumonia in hospitalised patients multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of 346 consecutive patients study of community acquired pneumonia aetiology (scapa) in adults admitted to hospital: implications for management guidelines microbial aetiology of community-acquired pneumonia and its relation to severity value of the polymerase chain reaction assay in noninvasive respiratory samples for diagnosis of community-acquired pneumonia a prediction rule to identify low-risk patients with community-acquired pneumonia infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults applied logistic regression severe community-acquired pneumonia: validation of the infectious diseases society of america/american thoracic society guidelines to predict an intensive care unit admission ewig s: how deadly is seasonal influenza associated pneumonia? the german competence network for community-acquired pneumonia (capnetz) centres for disease control and prevention: bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza a (h1n1)-united states community-acquired respiratory cillóniz et al. critical care coinfection in critically ill patients with pandemic 2009 influenza a (h1n1) virus influenza pneumonia: a comparison between seasonal influenza virus and the h1n1 pandemic insights into the interaction between influenza virus and pneumococcus health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes bts guidelines for the management of community acquired pneumonia in adults: update ventilator-associated tracheobronchitis in a mixed surgical and medical icu population community-acquired pneumonia in chronic obstructive pulmonary disease. spanish multicenter study pseudomonas aeruginosa in adults with chronic obstructive pulmonary disease airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock appropriate use of antimicrobial agents: challenges and strategies for improvement streptococcus pneumoniae coinfection is correlated with the severity of h1n1 pandemic influenza community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis the authors are indebted to the nursing staff and the attending physicians of the two icus for their cooperation in this trial. financial support was provided by 2009-sgr-911, ciber de enfermedades respiratorias (ciberes cb06/06/0028). authors' contributions cc is the main author of the paper; she reviewed the study data and realised the statistical analysis, edited the main body of the manuscript, and contributed to supervising the collection of clinical, radiological and microbiological data. se contributed to conception of the project and database design. mf contributed to results analysis and interpretation, and to editing the final manuscript. ep contributed to data analysis and drafting the original manuscript, and to supervising the collection of clinical, radiological and microbiological data. ag realised the statistical analysis of the study. jpdlb supervised the microbiological studies. jm supervised the collection of epidemiologic and microbiological data. at led the study group, contributed to conception of the project design and contributed to the final study, being the guarantor of the entire manuscript. all authors read and approved the manuscript for publication. the authors declare that they have no competing interests. key: cord-315685-ute3dxwu authors: ehaideb, salleh n.; abdullah, mashan l.; abuyassin, bisher; bouchama, abderrezak title: evidence of a wide gap between covid-19 in humans and animal models: a systematic review date: 2020-10-06 journal: crit care doi: 10.1186/s13054-020-03304-8 sha: doc_id: 315685 cord_uid: ute3dxwu background: animal models of covid-19 have been rapidly reported after the start of the pandemic. we aimed to assess whether the newly created models reproduce the full spectrum of human covid-19. methods: we searched the medline, as well as biorxiv and medrxiv preprint servers for original research published in english from january 1 to may 20, 2020. we used the search terms (covid-19) or (sars-cov-2) and (animal models), (hamsters), (nonhuman primates), (macaques), (rodent), (mice), (rats), (ferrets), (rabbits), (cats), and (dogs). inclusion criteria were the establishment of animal models of covid-19 as an endpoint. other inclusion criteria were assessment of prophylaxis, therapies, or vaccines, using animal models of covid-19. result: thirteen peer-reviewed studies and 14 preprints met the inclusion criteria. the animals used were nonhuman primates (n = 13), mice (n = 7), ferrets (n = 4), hamsters (n = 4), and cats (n = 1). all animals supported high viral replication in the upper and lower respiratory tract associated with mild clinical manifestations, lung pathology, and full recovery. older animals displayed relatively more severe illness than the younger ones. no animal models developed hypoxemic respiratory failure, multiple organ dysfunction, culminating in death. all species elicited a specific igg antibodies response to the spike proteins, which were protective against a second exposure. transient systemic inflammation was observed occasionally in nonhuman primates, hamsters, and mice. notably, none of the animals unveiled a cytokine storm or coagulopathy. conclusions: most of the animal models of covid-19 recapitulated mild pattern of human covid-19 with full recovery phenotype. no severe illness associated with mortality was observed, suggesting a wide gap between covid-19 in humans and animal models. in part the easy transmission from person-to-person, and its dissemination within the body in severe and fatal cases [11] [12] [13] [14] [15] [16] [17] [18] . accordingly, sars-cov-2-induced covid-19 has led to a pandemic that overwhelmed the capacity of most national health systems, resulting in a global health crisis [19] . so far, an estimated 11,280 million persons in 188 countries were infected, of which 531,000 died [20] . the clinical spectrum of covid-19 is complex and has been categorized as mild, severe, and critical, representing 81, 14, and 5% [2, 3] . the mild pattern comprises patients with either no signs and symptoms or fever and radiological evidence of pneumonia [3] . the severe pattern manifests as rapidly progressive hypoxemic pneumonia involving more than half of the lung with a full recovery phenotype [2, 3] . the critical pattern consists of ards requiring respiratory assistance and mosd that result in death in approximately half of the patients [2, 3, 7, 21] . mortality was associated with host factors such as old age, comorbidities, and immune response [4] . viral and immunopathological studies revealed distinct patterns between mild and severe or critical forms of covid-19 [4, 5, 9, [21] [22] [23] [24] [25] [26] [27] . both severe and critically ill patients displayed higher viral load in the upper respiratory tract than mild cases, together with delayed clearance overtime [21, 22] . likewise, they presented with lymphopenia due to a decrease in cd4+ and cd8+ t cells, as well as t cell exhaustion accompanied by a marked inflammatory response [5, 9, [24] [25] [26] [27] . pro-and anti-inflammatory cytokines and chemokine concentrations were increased systemically and locally in the lung and correlated with severity [5, 9, 24] . in contrast, in the mild illness, the lymphocyte count was normal, with no or minimal inflammatory response [5, 23] . together, these suggest that the viral load and dynamic together with the host inflammatory response may play a pathogenic role. clinical and post-mortem studies of fatal cases of covid-19 demonstrated major alteration of coagulation and fibrinolysis [17, 18] . this was associated with widespread thrombosis of small and large vessels, particularly of the pulmonary circulation contributing to death in a third of patients [8, [28] [29] [30] [31] [32] [33] . these observations suggest that dysregulated coagulation may be an important mechanism of covid-19 morbidity and mortality [34] . in this context, animal models appear crucial to a better understanding of the complex biology of covid-19. animal models of sars-cov-2-induced covid19 have been rapidly reported since the start of the pandemic [35] . however, whether they express the full phenotype of covid-19, particularly the severe and critical patterns associated with lethality, remains to be determined. in this systematic review, we examined whether the newly created animal models reproduce the phenotype of human covid-19. moreover, we examined the knowledge generated by these models of covid-19 including viral dynamic and transmission, pathogenesis, and testing of therapy and vaccines. we conducted a systematic review according to the preferred reporting items for systematic reviews and meta-analysis (prisma) statement [36] to identify studies describing the creation of an animal model of covid-19 as an endpoint (table 1 and additional file 1). additional file 1 shows the data extraction and appraisal approach as well as the selected outcome. the systematic search identified 101 studies and 326 preprints, of which 400 articles were excluded because they were reviews, non-original articles, unrelated to the covid-19 infection, or experimental animals that do not support sars-cov-2 replication such as pigs, ducks, and chickens ( fig. 1 and additional file 2). additional file 2 displays all the excluded studies and the rationale for their exclusion. thirteen peer-reviewed studies and 14 preprints were included in the analysis. the studies used nonhuman primates (n = 13) [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] , mice (n = 7) [50] [51] [52] [53] [54] [55] [56] , hamsters (n = 4) [56] [57] [58] [59] , ferrets (n = 4) [60] [61] [62] [63] , cats, and dogs (n = 1) [63] (tables 2, 3 , 4, and 5). male and female, as well as young and old, were included but with no associated comorbidities. the aims were to investigate the pathogenesis of covid-19 (n = 15), testing drugs and vaccines (n = 14), the host table 1 search strategy and selection criteria we searched the medline, as well as biorxiv and medrxiv preprint servers for original research describing or using an animal model of sars-cov-2 induced covid published in english from january 1, 2020, to may 20, 2020. we used the search terms (covid-19) or (sars-cov-2) and, (animal models), (hamsters), (nonhuman primates), (macaques), (rodent), (mice), (rats), (ferrets), (rabbits), (cats), and (dogs). the preprint servers were included in the search as the field of covid-19 is developing quickly. inclusion criteria were the establishment of animal models of covid-19 as an endpoint. other inclusion criteria were assessment of prophylaxis, therapies, or vaccines, using animal models of covid-19. exclusion criteria consisted of reviews, non-original articles, and unrelated to the covid-19 infection or experimental animals that do not support sars-cov-2 replication. 101 studies and 326 preprints were screened of which 13 peer-reviewed studies and 14 preprints were included in the final analysis (fig. 1) . the variables extracted were the population type, study aim, the virus strain used, clinical response, pathology, viral replication, and host response as well as the effects of prophylaxis, drugs, or vaccines. the outcomes were organized according to species and categorized into phenotype (signs or symptoms; histopathology, timecourse of the illness and outcome), viral (titer in each tissue organ, detection methods, duration of positivity), and host response (dynamic of seroconversion, inflammatory, and hemostatic markers), therapy, and vaccine (efficacy and safety) immune response (n = 6), and the virus dynamic and transmission (n = 4) (tables 2, 3, 4, and 5). all the experimental animals were inoculated with sars-cov-2 with various strains, doses, and route of administration that differed across studies (tables 2, 3 , 4, and 5). likewise, the time-point for tissue collection and pathological assessment were variables. these together precluded any comparisons between the animal models either intra-species or inter-species. nonhuman primate models viral model rhesus macaques (n = 10) [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] , cynomolgus (n = 3) [46] [47] [48] , and african green model (n = 1) [49] and common marmoset (n = 1) [46] were assessed as models for covid-19 (table 2) . sars-cov-2 strains, dose, and route of inoculation were different across studies. different doses of virus inoculum were compared in a single study and showed that viral load in the upper and lower respiratory tract, fever, weight loss, respiratory distress, and mortality were comparable regardless of the doses except for mild transient neutropenia and lymphopenia in the high dose group [43] . in contrast, the route of administration resulted in different pathological response as the intratracheal route elicited severe interstitial pneumonia, as compared with mild interstitial pneumonia and no pneumonia from the intraconjunctival and intragastric routes, respectively [45] . the animals were euthanized at different time-points post-inoculation ranging from 3 to 33 days. the animals displayed variable clinical manifestations from none to fever, altered respiratory patterns, and igg antibody anti-sars-cov-2 spike s1 subunit evaluation of medical interventions reticulonodular opacities pet scan: fdg uptake lung and regional lymph nodes (2), mediastinal lymph nodes and . § dpi day post-inoculation, ¶ crp c-reactive protein, || na not available. **vaccine encoding spike protein variants: full-length sars-cov-2 s protein, s.dct deletion of the cytoplasmic tail of sars-cov-2 s protein, s.dtm deletion of the transmembrane domain and cytoplasmic tail reflecting the soluble ectodomain, s1 s1 domain with a fold on trimerization tag, rbd receptor-binding domain with a fold on trimerization tag, s.dtm.pp a prefusion stabilized soluble ectodomain with deletion of the furin cleavage site, two proline mutations, and a fold on trimerization tag, im intramuscular other general signs ( table 2 ). the clinical manifestations were not different between old and young macaques [46] [47] [48] . structural and ultrastructural examination of the respiratory tract were also variables including mild to moderate interstitial pneumonitis, edema, foci of diffuse alveolar damage with occasional hyaline membrane formation, and pneumocytes type ii hyperplasia ( table 2) . old rhesus macaques exhibited more diffuse and severe interstitial pneumonia than young ones [47] . the extrapulmonary injury was investigated in five studies [40, 42, 43, 46, 49] . these revealed pathological changes in two studies [46, 49] including distention and flaccidity of the intestine, inflammatory cells infiltrating the jejunum, and colon, steatosis of the liver, and alteration of myocardial fiber architecture with increased mitochondrial density [46, 49] . no mortality was observed in any of the nonhuman primate models. comparisons between species of nonhuman primates were not possible except in one study, which suggested that rhesus macaques were superior to cynomolgus and common marmoset as models of human covid-19 [46] . other comparisons suggested that sars-cov elicited more severe lung pathology than sars-cov-2 and middle east respiratory syndrome (mers-cov) [48] ( table 2) . the virus replicated rapidly and at higher titers in the upper airway and lung in all four species [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] . the virus was detected in pneumocytes type i and ii and ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosa [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] . this differs from mers-cov where the virus was mainly present in type ii pneumocytes [46] ( table 2 ). replication of the virus was also demonstrated in jejunum, duodenum, colon, and rectum [37, 38, [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] . viral genome was detected in the blood of rhesus macaques, cynomolgus, and marmoset in one study [46] . viral replication of nasopharyngeal as well as anal swabs, and the lung in old macaques was higher than in young ones [47, 48] . sars-cov-2 infection-induced igg antibodies response against the sars-cov-2 spike was noted in all species [37, 46, 48, 49] except in marmoset [46] . the antibodies were protective against a second exposure to the virus [43, 44] . there was no difference between males and females [37, 39-43, 46, 47] ; however, young rhesus macaques had lower antibody titers than the old macaques [46] . the innate immune response to sars-cov-2 infection was variable with normal, high, or low leucocytes and lymphocyte counts [37, 46] . occasional reduction of cd4 + and cd8 + t cell concentrations was documented [37] as well as the transitory release of various cytokines and chemokines at different days postinoculation [37, 46, 49] . dna and inactivated virus-based vaccines were evaluated and showed protection in these nonhuman primates. however, the dna vaccine did not reduce the virus presence in the upper airway, while there was a residual small interstitial pneumonitis in the macaques that received the inactivated virus [40, 41] . this suggests that none of the virus tested so far displayed a comprehensive protection against sars-cov-2 infection. several candidate dna vaccines based in various forms of the sars-cov-2 spike (s) protein were also tested in rhesus macaques [39] . the findings revealed that only the vaccine encoding the full-length (s) offered optimal protection against sars-cov-2 [64] . nonhuman primates served also for the evaluation of antiviral therapies and medical interventions such as ct-and petscanners [47] . wild type mice (balb/c, c57bl/6), immunodeficient mice (scid), chimeric mouse expressing human angiotensinconverting enzyme 2 (hace2), and the rna-dependent rna polymerase (sars1/sars2-rdrp) were evaluated as models of covid-19 (table 3) . moreover, knockout (ko) mice were generated to test specific immunological pathways or therapy, including ablation of type i (ifnar1−/−), iii interferon (ifn) receptors, (il28r−/−), signal transducer and activator of transcription 2 (stat2−/−), and serum esterase (ces1c−/−). patient isolates of sars-cov-2 from different sources and variable times of passaging on various cell cultures or balb/c mice were employed (table 3) . mouseadapted sars-cov-2 was developed using two methods. the first by serial passaging (up to 6) through the lungs of balb/c mice until the virus spike receptor-binding domain (rbd) adapted to the murine ace-2 [54] . in the second, using genetic engineering, the sars-cov-2 rbd was remodeled to enhance its binding efficiency to murine ace2 [52] . the clinical signs and symptoms varied from none to mild weight loss, arched back, and slight bristles. whole-body plethysmography was used to measure the respiratory function of the animals and showed a mild to moderate reduction in old more than in young (table 3) . likewise, the pathological changes varied according to the experimental models and included peribronchiolar inflammation, lung edema, moderate multifocal interstitial pneumonia, lymphocyte infiltration, and intraalveolar hemorrhage. survival of hace2 mice was decreased at 5-day post-inoculation and was attributed to high viral replication in the brain, while it was weight and minimal in the lung, suggesting a different pathogenic mechanism of death from human covid-19 [52] . wild type mice showed no pathology as compared to hace2 mice, indicating that the lack of human ace2 receptor cannot be infected or inefficiently with sars-cov-2 [50, 56] . on the other hand, mouse-adapted sars-cov-2 exhibited more severe pathology, particularly in the aged mouse than hace2 transgenic mouse, suggesting that these models may be more relevant for the study of human covid-19 [52, 54] . however, whether the pathogenesis induced by the mouse-adapted sars-cov-2 is translatable to humans warrants further studies [52, 54] . the virus replicated to high titers in the upper and lower respiratory tract in most of the genetically modified mice models but not in wild type. viral replication was detected outside the respiratory tract in the intestine of hace2 mice [50] as well as in the liver, and heart in mouse modified sars-cov-2 rbd [52] . increased viral replication in ko mice ifnar1−/− suggested that interferon limited the viral replication [56] . specific igg antibodies against sars-cov-2 were documented in two studies ( table 3 ). the igg antibodies were found to cross-react in their binding to the spike protein of sars-cov, however, with no crossneutralization, hence suggesting the conservation of the same spike protein epitopes among coronaviruses [53] . proinflammatory cytokines and chemokines were demonstrated in mouse-adapted sars-cov-2 and ko mouse ( table 3 ). the inflammatory response was significantly higher in the old than young mice. antiviral therapies, including remdesivir [55] , ifn lambda [52] , and human monoclonal igg1 antibody against rbd [50] , were tested in these mouse models and produced a protective effect. likewise, vaccines using viral particles expressing sars-2-s protein [52] or an rbd-based vaccine were tested and showed protection [55] . wild type syrian hamsters and knockout hamsters for signal transducer and activator of transcription 2 (stat2−/− lacking type i and iii interferon signaling) and interleukin 28 receptors (il28r−/− lacking ifn type iii signaling) were reported as models for covid-19. patient isolate of sars-cov-2 from different sources and different passages on various cell cultures was used (table 4) . sars-cov-2 was administered intranasally at different titers to anesthetized hamsters. viral transmission between hamsters was demonstrated either through direct contact or indirectly via airborne transmission. the clinical manifestations included weight loss, which was consistently observed. other clinical signs and symptoms such as rapid breathing, lethargy, ruffled furs, and hunched back posture were reported in one study [57] . the histopathological findings were variables according to the experimental models and ranged from lung consolidation to multifocal necrotizing bronchiolitis, leukocyte infiltration, and edema. stat2−/− hamsters exhibited attenuated lung pathology as compared with il28r-a−/− hamsters [56] . the virus replicated to high titer in the upper and lower respiratory tract in most of the hamsters' models. viral replication was detected in the blood and kidney with a low concentration (table 4 ). stat2−/− hamsters had higher titers of infectious virus in the lung, viremia, and high levels of viral rna in the spleen, liver, and upper and lower gastrointestinal tract in comparison with wild type and il28r-a−/− hamsters. specific igg antibodies against sars-cov-2 were documented in the sera of hamsters at different time-points from virus inoculation ranging from 7 to 21 days. increased expression of proinflammatory and chemokine genes was demonstrated in the lungs of the sars-cov-2 infected animals, however with no increase in circulating levels of proteins such as tnf, interferon-γ, and il-6. immunoprophylaxis with early convalescent serum achieved a significant decrease in viral lung load but not in lung pathology [57] . ferrets, cats, and dogs were administered intranasally or intratracheally with various doses and strains of sars-cov-2 (table 5 ). ferrets displayed elevated body temperature for several days associated with signs that differed according to the studies. these include decreased activity and appetite, sporadic cough, and no body weight loss [60] [61] [62] [63] . no clinical signs were reported either in cats or in dogs. ferrets exhibited acute bronchiolitis [61, 63] , with perivasculitis and vasculitis [63] , but with no discernible pneumonia. cats disclosed lesions in epithelial nasal, tracheal, and lung mucosa (table 5 ). the virus replication and shedding were demonstrated in the upper airways and rectal swabs in ferrets and cats, but the extent to other tissues varied in ferrets from none to multiple organs, including the lung, blood, and urine. no viral rna was detected in cats' lungs. dogs showed rna-positive rectal swab but none in the upper or lower airways. viral transmission between ferrets and cats was demonstrated either through direct contact [55] or indirectly via airborne route [62] . ferrets, cats, and dogs exhibited specific antibody response against sars-cov-2 [60, 62, 63] . a study of the ferret immune response to sars-cov-2 revealed a subdued low interferon type i and type iii response that contrasts with increased chemokines and proinflammatory cytokine il6, which is reminiscent of the human response [61] . this systematic review of experimental animal models of sars-cov-2 induced-covid-19 identified 13 peerreviewed studies and 14 preprints that reported data on nonhuman primates [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] , mice [50] [51] [52] [53] [54] [55] [56] , hamsters [56] [57] [58] [59] , ferrets [60] [61] [62] [63] , cats, and dog [63] models of covid-19. the main findings indicate that most of the animal models could mimic many features of mild human covid-19 with a full recovery phenotype [3] . they also revealed that older animals display relatively more severe illness than the younger ones [38, 46, 48, 52, 54] , which evokes human covid-19 [3, 6] . however, none of the animal models replicated the severe or critical patterns associated with mortality as observed in humans with covid-19 [3] . the results of this systematic review are consistent with studies of animal models of sars-cov and mers-cov, which failed to replicate the full spectrum of humans' illness [65, 66] . nonetheless, several features of mild covid-19 in humans could be mirrored. high viral titers in the upper and lower respiratory tract and lung pathology were demonstrated in both large and small animal models. the pathology encompassed mild interstitial pneumonia, consolidation, and diffuse alveolar damage, albeit localized to a small lung area, edema, hyaline membrane formation, and inflammation. sars-cov-2 elicited specific antibody response against various viral proteins in the sera of most of the animal models. this systematic review revealed that none of these newly established animal models replicated the common complications of human covid-19 such as ards and coagulopathy [6, 8, 28-33, 67, 68] . ards can be particularly severe and results in refractory hypoxemia requiring maximum respiratory supportive measures in the intensive care unit [6, 67, 68] . the coagulopathy can lead to severe complications such as massive pulmonary embolism, cerebrovascular stroke, and mesenteric infarction, including in younger people [8, 28, 32, 33] . the pathology underlying these two complications were recently revealed by post-mortem studies disclosing diffuse alveolar damage involving the whole lung, hyaline membrane formation, and infiltration with inflammatory cells, thus leaving no air space open for ventilation [17, 18, 64, 69, 70] . it also detected the presence of diffuse and widespread thrombosis in the micro-and macro-circulation, including the pulmonary circulation compromising the lung perfusion [17, 18] . this double hit affecting the ventilation and perfusion simultaneously underlies the intractable hypoxemia that contributed to the high mortality. none of the animal models replicated the respiratory failure, thromboembolic manifestations, and their the mechanisms of the lung injury and coagulopathy are not well understood, although several known pathways were postulated including cytokine storm leading to upregulation of tissue factor [5, 9, 24] , activation/injury of the endothelium infected by the virus [30, 67, 71] , complement activation [72] , alveolar hypoxia promoting thrombosis [73] , and autoantibodies against phospholipid and lupus anticoagulant [74, 75] modulating the hemostasis and coagulation cascade directly. hence, the development of animal models that replicate the dysregulation of the inflammation and coagulation could be important, as these would allow the deciphering of the intimate mechanisms at play. this, in turn, may aid in identifying therapeutic targets and the testing of immunotherapy, anticoagulation, and thrombolytic interventions and thereby may improve the outcome. both antiviral and vaccine therapies were tested in rhesus macaques and mice infected with sars-cov-2 [40] [41] [42] . the antiviral drug stopped the viral replication and improved the pneumonitis [42, 55] . the vaccines induced an increase in titers of neutralizing antibodies in the sera that correlated with the decrease of viral replication and prevented the lung pathology [39] [40] [41] . these results represent a substantial proof of the concept of antiviral or vaccine efficacy against sars-cov-2 in animal models. however, because of the lack of overt clinical illness, the rapid clearance of the virus, and spontaneous improvement of the pneumonitis without lethality, the models do not permit the full assessment of the duration of the protection of the vaccines, or the effect of antiviral therapy on survival. since the emergence of sars-cov infection in 2003 [76] , followed by the mers-cov in 2012 [77] , and now with covid-19, researchers have not been able to develop a model of coronavirus infection that reproduces the severity and lethality seen in humans [65, 66] . one of the well-known reasons lies in the difference of ace-2 receptor binding domain structure across species [78] . human and primates have conserved a comparable structure that allows binding with high affinity to the sars-cov-2 [78] . the hamsters, ferrets, and cats maintained an intermediate affinity, while mice exhibit very low affinity [78] . the latter explains why wild-type mouse does not support sars-cov-2 replication, and hence, the necessity to create a chimera that expresses human ace-2, to enable the use of this species as a model of covid-19 [50] . more recently, a study applying single-cell rna sequencing to nonhuman primate uncovered another explanation that may underlie the difference between nonhuman primates and humans in expressing the complex phenotype of covid-19 [79] . the study reveals that the cellular expression and distribution of ace2 and tmprss2 which are essential for virus entry in the cells and its spread inside the body differ in the lung, liver, and kidney between the two species. ace2 expression was found lower in pneumocytes type ii and higher in ciliated cells in nonhuman primate lung as compared to humans [40] . this is particularly significant as type ii pneumocytes are critical targets of sars-cov-2 in humans and the pathogenesis of lung injury/damage. finally, the innate immune response including the defense system against viruses diverged during evolution both at the transcriptional levels and cellular levels, which may also explain why the sars-cov-2 hardly progresses in these animals outside the respiratory system [80] . taken together, these fundamental differences represent a real challenge to the successful development of an animal model that reproduces human covid-19. this systematic review has a few limitations. first, it is the high number of preprints included in this study that have not been peer-reviewed. second, the animal models from the same species were difficult to compare across studies, as they used different viral strain, inoculum size, route of administration, and timing of tissue collection. this systematic review revealed that animal models of covid19 mimic mild human covid-19, but not the severe form covid-19 associated with mortality. it also disclosed the knowledge generated by these models of covid-19 including viral dynamic and transmission, pathogenesis, and testing of therapy and vaccines. likewise, the study underlines the distinct advantages and limitations of each model, which should be considered when designing studies, interpreting pathogenic mechanisms, or extrapolating therapy or vaccines results to humans. finally, harmonization of animal research protocols to generate results that are consistent, reproducible, and comparable across studies is needed. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03304-8. additional file 1. data extraction, appraisal, and outcome. a pneumonia outbreak associated with a new coronavirus of probable bat origin a novel coronavirus from patients with pneumonia in china characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention viral and host factors related to the clinical outcome of covid-19 clinical and immunological features of 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transmission of sars-cov-2 in golden hamsters infection and rapid transmission of sars-cov-2 in ferrets imbalanced host response to sars-cov-2 drives development of covid-19 sars-cov-2 is transmitted via contact and via the air between ferrets susceptibility of ferrets, cats, dogs, and other domesticated animals to sars-coronavirus 2 autopsy in suspected covid-19 cases is there an ideal animal model for sars? development of animal models against emerging coronaviruses: from sars to mers coronavirus pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19 management of covid-19 respiratory distress pathological findings of covid-19 associated with acute respiratory distress syndrome lung pathology of fatal severe acute respiratory syndrome endothelial cell infection and endotheliitis in covid-19 analysis of complement deposition and viral rna in placentas of covid-19 patients the stimulation of thrombosis by hypoxia coagulopathy and antiphospholipid antibodies in patients with covid-19 lupus anticoagulant and abnormal coagulation tests in patients with covid-19 a major outbreak of severe acute respiratory syndrome in hong kong isolation of a novel coronavirus from a man with pneumonia in saudi arabia broad host range of sars-cov-2 predicted by comparative and structural analysis of ace2 in vertebrates single-cell atlas of a non-human primate reveals new pathogenic mechanisms of covid-19 gene expression variability across cells and species shapes innate immunity publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable authors' contributions a.b. designed the study, analysis of the data, and writing the manuscript. s.e., m.a., and b.a. acquisition of the data, selection of studies, appraisal of the literature, and contributed to the writing of the manuscript. the authors read and approved the final manuscript. there was no funding source for this study.availability of data and materials all data generated or analyzed during this study are included in this published article [and its supplementary information files]. the authors declare that they have no competing interests.received: 13 july 2020 accepted: 21 september 2020 key: cord-334391-0172afa1 authors: gupta, rahul title: the double edged interferon riddle in covid-19 pathogenesis date: 2020-11-01 journal: crit care doi: 10.1186/s13054-020-03337-z sha: doc_id: 334391 cord_uid: 0172afa1 nan in their recent article [1] , jalkanen et al. discuss about the prospective usage of interferon beta 1 in managing covid-19 and substantiating usage of intravenous route of administration over subcutaneous route. i would like to humbly add some views to it: there has been two varying reported type i interferon responses in covid-19 pathogenesis [2] : one stating the suppression of host antiviral type i interferons (ifns) and interferon stimulated genes (isgs) and other stating increased expression of different isgs, with further inductions of chemokines and cytokines [2] . the viral nsps (particularly nsp1) and the orfs (particularly orf 6) are known to antagonise the host antiviral ifns initially by suppressing/delaying their expressions, leading to viral persistence and propagating inflammations. hence, neither type i ifn nor type iii ifn, which are known hard-wired for providing antiviral immunity, was activated in early stages of covid-19. however, sars-cov-2 at 2 days post-infection (dpi), induced isgs having antiviral action (rsad2, ifit, mx2, oas3, etc.) and at 7dpi, isgs having potentiating ifn mediated inflammatory signalling (ifihi,irf7,stat1,ifnar1/ 2,tyk2,etc.) [3] . as the disease progresses towards severity, the ifns exacerbate the pathophysiology with specific inflammatory signatures [2] . hence, cellular response to type 1 ifn (thru isgs) towards later stages of infection is immunopathogenic. neutrophils provide the first line of innate immune defence. neutrophil attracting chemokines (cxcl1, cxcl2, cxcl8, s100a9) and cognate receptor (cxcr2) were found to be activated in early stages (1-3 dpi) [3] . covid-19 is manifested with necrophilia having high neutrophil-to-lymphocyte ratio. type 1 ifns are known to inhibit neutrophil migration by downregulating neutrophil chemoattractants production (cxcl1/2) [4] . other than phagocytosis, neutrophils have another capacity to contain pathogens, by forming neutrophil extracellular traps (nets). nets are mesh-like structures of dna and proteins from degrading neutrophils (by neutrophil elastase) which entrap pathogens. interestingly against leishmania, ifnar −/− mice showed enhanced neutrophil elastase activity, with better infiltrations. aberrant production of nets have been known to cause severe covid-like pathophysiologies-thrombosis, lung damage, ards, multiorgan damage, etc. [5] . indeed, severe covid-19 patients reported of higher amount of netosis remnants like cell-free dna, myeloperoxidase-dna and citrullinated histone h3 [5] . these molecules further propagate inflammation by inducing il-1β production thru inflammasome activation. the initial type 1ifn suppression could lead to enhanced infiltration of neutrophils, net formation and ensuing pathophysiologies. early administration of ifnβ has proved beneficial [1, 2] ; hence, the "double edged sword" be tried prudently with respect to time and dosage. interferon beta-1a for covid-19: critical importance of the administration route. crit care the type i interferon response in covid-19: implications for treatment heightened innate immune responses in the respiratory tract of covid-19 patients type i ifns mediate development of postinfluenza bacterial pneumonia in mice neutrophil extracellular traps in covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations rahul is very grateful to dr kate fitzgerald and dr douglas golenbock (umassmed) for the initial insightful discussion. rahul did the literature survey and wrote the manuscript. the study has not received any funding as yet. *correspondence: rbiochem@gmail.com kolkata, india ready to submit your research ready to submit your research ? choose bmc and benefit from:? choose bmc and benefit from: literature survey. not applicable. yes.competing interests i do not have any competing interests.received: 5 october 2020 accepted: 8 october 2020 key: cord-329381-uwae8738 authors: evrard, bruno; goudelin, marine; montmagnon, noelie; fedou, anne-laure; lafon, thomas; vignon, philippe title: cardiovascular phenotypes in ventilated patients with covid-19 acute respiratory distress syndrome date: 2020-05-18 journal: crit care doi: 10.1186/s13054-020-02958-8 sha: doc_id: 329381 cord_uid: uwae8738 nan ). the higher prevalence of lv failure and lower cardiac index in patients with flu-related ards is presumably related to septic cardiomyopathy since they sustained associated septic shock more frequently than covid-19 patients. depressed indices of rv systolic function and elevated central venous pressure reflecting systemic venous congestion reflect the higher prevalence of rv failure in flu ards patients (table 1 ). this presumably results from the lower p/f, higher driving pressure, and lower respiratory-system compliance observed in this group. covid-19 patients with acp tended to have lower respiratory-system compliance than their counterparts, presumably due to distinct ards phenotypes [6] . this pilot study is limited by its small sample size and the retrospective comparison with historical flu-related ards patients. this first study assessing hemodynamically ventilated covid-19 patients with tee shows a lower **calculated as the tidal volume divided by the driving pressure (difference between the inspiratory plateau pressure and positive end-expiratory pressure) ***one patient was diagnosed with a tako-tsubo syndrome during transesophageal echocardiography examination performed shortly after tracheal intubation, after 6 days of high-flow nasal cannula; full recovery of left ventricular systolic function was documented under mechanical ventilation 10 days later ****measured using the doppler method applied at the left ventricular outflow tract *****as per april 24, with still 6 patients hospitalized in the intensive care unit, 5 of them being invasively ventilated prevalence of lv and rv failure than in flu-related ards patients. whether herein reported cardiovascular phenotypes are influenced by the type of covid-19 ards remains to be determined [6] . these preliminary data warrant confirmation in large-scale multicenter cohorts. funding none ethics approval and consent to participate local ethical committee approval #368-2020-24, which waived the need for informed consent. all patients agreed on the use of anonymized information as per the french law on the general data protection regulation (gdpr). author details abbreviations: rr respiratory rate, peep positive end-expiratory pressure, cvp central venous pressure, rveda right ventricular end-diastolic area, lveda left ventricular end-diastolic area, rvfac right ventricular fractional area change, tapse tricuspid annular plane systolic excursion, tr tricuspid regurgitation, ivc inferior vena cava, lvef left ventricular ejection fraction *calculated as the tidal volume divided by the driving pressure (difference between the inspiratory plateau pressure and positive end-expiratory pressure) **measured using the doppler method applied at the left ventricular outflow tract clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a singlecentered, retrospective, observational study description of the acute covid-19 cardiovascular syndrome the impact of 2019 novel coronavirus on heart injury: a systematic review and meta-analysis. prog cardiovasc dis cardiovascular clusters in septic shock combining clinical and echocardiographic parameters: a post hoc analysis acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: prevalence, predictors, and clinical impact covid-19 pneumonia: ards or not? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-355847-1ru15s5a authors: convertino, irma; tuccori, marco; ferraro, sara; valdiserra, giulia; cappello, emiliano; focosi, daniele; blandizzi, corrado title: exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in covid-19 patients date: 2020-06-11 journal: crit care doi: 10.1186/s13054-020-03020-3 sha: doc_id: 355847 cord_uid: 1ru15s5a sars-cov-2 complications include pneumonia and acute respiratory distress syndrome (ards), which require intensive care unit admission. these conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. particularly, since pneumonia and ards are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-il-6, anti-tnf, and jak inhibitors are currently studied. in this article, we discuss the potential advantages of the most promising pharmacological approaches. lymphocytopenia. in patients requiring icu admission, an increase in neutrophil count, d-dimer, blood urea, and creatinine levels have been detected as well as more severe lymphocytopenia. this condition is defined as a "cytokine storm" and is associated with high circulating levels of interleukins (il)-2, il-6, il-7, il-10, granulocyte colonystimulating factor (g-csf), 10 kda interferon-gammainduced protein (ip-10), monocyte chemo-attractant protein-1 (mcp-1), macrophage inflammatory protein 1α (mip-1α), and tumor necrosis factor (tnf) [4, 5] . in particular, in ards patients, a strong depletion of peripheral blood t cells, along with a decreased recruitment of lymphocytes and neutralizing antibodies and an increased production of cytokines, was detected in the lungs [6] . this network of pathogenic factors is thought to drive a severe immune-mediated interstitial pneumonia and a delayed pulmonary clearance of covid-19 [3] . current evidence supports a close relationship between cytokine storm and disease severity. indeed, icu patients displayed higher serum levels of cytokines (g-csf, ip-10, mcp-1, mip-1α, and tnf-α) than those not requiring icu. for instance, il-6 and tnf-α levels in icu patients were significantly higher when compared with non-icu ones [7] . patients with fatal outcome had higher serum concentrations of il-6 than those survived: the il-6 median levels reported by zou et al. were 11.00 pg/ml (iqr 7.50-14.40) and 6.30 pg/ml (iqr 5.00-7.90), respectively, p < 0.0001. similar findings were showed by ruan et al. 11 .4 pg/ml (iqr 8.5) in dead patients versus 6.8 pg/ml (iqr 3.61) in discharged ones [8, 9] . furthermore, a significantly close relationship between il-6 levels in critical covid-19 patients with fatal outcome (64.0 pg/ml, iqr 25.6-111.9) and rnaemia was found, in particular, the 83.3% of patients with il-6 > 100 pg/ml had positive levels of rnaemia, r 0.902. this suggests that high serum il-6 along with rnaemia could be predictors of mortality [10] . additionally, not only critically ill patients with ards have been associated with high cytokine serum levels but also non-severe patients with covid-19. indeed, il-6 median serum levels were 36.10 pg/ml (iqr 23.00-59. 20) in severe patients compared with 10.60 pg/ml (iqr 5. 13-24.18) in those with mild disease, p 0.002 [11] , and 6.69 pg/ml (iqr 4. 44-12.43) in patients with spo 2 ≥ 90% in comparison with 51.69 pg/ml (iqr 34.31-161.65) in those with spo 2 < 90%, p < 0.001, as well as the tnf-α levels (2.08 pg/ml, iqr 1.93-2.35 even in the conditions with spo 2 ≥ 90%) [12] . these data were confirmed by qin et al.; il-6 median serum levels in severe and non-severe patients were 25.2 pg/ml (iqr 9.5-54.5) and 13.3 pg/ml (iqr 3.9-41.1), respectively; and tnf-α median serum levels were 8.7 pg/ml (iqr 7.1-11.6) in severe patients and 8.4 pg/ml (iqr 6.9-10.4) in non-severe ones [6] . based on this knowledge, it has been proposed that the modulation of the above cytokines could represent an interesting approach to improve the prognosis of patients with covid-19 pulmonary complications, both pneumonia and ards. recently, the food and drug administration has allowed the emergency use of a device aiming at purifying blood of icu patients from the cytokine storm [13] . several drugs, endowed with modulating activity on cytokine pathways, including anti-il-6, anti-tnf, and janus kinase (jak) inhibitors, currently approved for the treatment of immune-mediated inflammatory diseases, have been suggested or could be yet taken into account for experimental use in covid-19 patients with ards and/or pneumonia ( fig. 1 ). tocilizumab is a humanized, immunoglobulin g1κ (igg1κ) anti-human il-6 receptor (il-6r) monoclonal antibody approved for some immune-mediated inflammatory rheumatic diseases. clinical evidence supports the view that this drug is an effective therapeutic option, with a good risk-benefit profile, in cytokine storm syndromes [14] . in china, its off label use has been tested in 21 icu ards patients with favorable results after 24-48 h in 20/21 patients [15] . moreover, a multicenter randomized clinical trial in covid-19 patients with ards, treated with tocilizumab at a dose of 4~8 mg/kg once, and an additional same dose when fever persists within 24 h after the first administration, has been approved in china [16] . the italian medicine agency has recently authorized a trial on the use of tocilizumab in covid-19 patients with ards [17] . this initiative was pushed on also by promising results published on italian newspapers. particularly, some patients treated with tocilizumab at the "pascale" cancer institute in naples showed disease improvements within 24 h and one of them did not require mechanical ventilation 2 days after starting tocilizumab [15] . another monoclonal antibody belonging to anti-il-6 drug class, siltuximab, currently approved in multicentric castleman disease with hiv-negative and human herpesvirus-8 negative, is under investigation for ards in covid-19 patients. in particular, an observational case-control study evaluating siltuximab in icu patients with ards-related covid-19 is performing at papa giovanni xxiii hospital in bergamo, italy [18] . preliminary results have shown promising outcomes as the clinical improvement in the 33% of treated icu patients [19] . in addition, a multicenter open-label randomized clinical trial is studying the benefit risk profile of siltuximab, as a single therapeutic option or in combination with anakinra, at a single dose of 11 mg/kg, in comparison with tocilizumab or anakinra, alone or in combination, in ards patients with covid-19 [20] . evidence suggested a higher binding affinity to il-6 involving siltuximab than tocilizumab but less insights are currently available on the effects of siltuximab in cytokine storm [21] . based on the results expected with tocilizumab and siltuximab, other anti-il-6 drugs, currently approved for rheumatoid arthritis, namely sarilumab and sirukumab, could be studied in ards and pneumonia patients with covid-19. notably, sarilumab has higher affinity for its target and a longer half-life than tocilizumab; thus, a sustained therapeutic effect could be achieved by administration of only one single dose [22, 23] . on march 19 th , 2020, a clinical trial evaluating the efficacy and safety of high dose and low dose of sarilumab in covid-19 patients was started [24] . subsequently, further clinical trials have followed, investigating the benefit risk profile of sarilumab in patients with covid-19related ards, at a dose of 200 mg or 400 mg, as single or repeated administration, subcutaneously or intravenously [25] [26] [27] [28] . sirukumab neutralizes il-6 specifically and directly by preventing its binding to its membrane receptor [29] , and thus, it leads to a subsequent suppression of il-6 biological actions. in a phase i trial, sirukumab showed linear pharmacokinetics with long half-life, low immunogenicity, and a good safety profile [30] . accordingly, it could represent a promising pharmacological option for counteracting the high il-6 levels occurring in ards patients. anti-tnf drugs, including infliximab, adalimumab, etanercept, golimumab, and certolizumab, could be tested also for covid-19-related ards and pneumonia. in china, a clinical trial on adalimumab in covid-19 patients was recently approved [31] . infliximab, adalimumab, and golimumab are igg 1 monoclonal antibodies, while etanercept is a fusion protein of two human tnf type 2 receptor moieties linked with the fc region of a human immunoglobulin, and certolizumab is the pegylated fab domain obtained from a humanized anti-tnf igg monoclonal antibody [32] . differences in the inhibitory mechanism were shown among these drugs, due to their different molecular binding patterns with tnf sites [33] . all anti-tnf drugs display higher binding affinity to soluble tnf than its membrane-bound form, with golimumab and etanercept showing the highest level [34] . greater binding avidity to soluble tnf was reported for etanercept than infliximab and adalimumab [35] . heterogeneity was also found in the neutralizing activity of anti-tnf drugs to soluble tnf, while that to transmembrane tnf was comparable [34] . infliximab and adalimumab displayed a greater binding activity for fcγrii and fcγriii than etanercept, but the latter was able to bind fcγri with higher affinity [36] . fcγrs play important roles in the modulation of immune responses, which rely on cytokines and vasoactive mediators [37] . in addition, a review showed that the proteins coded by the virus alter the complement system control and thus contribute to lung viral damages [3] . out of the anti-tnf drugs, the igg 1 monoclonal antibodies have a complement-dependent cytotoxicity activity [38] that could be explored in the covid-19 infection. the known differences in pharmacokinetics and pharmacodynamics among anti-tnf drugs support the need for testing these agents in covid-19-related ards and pneumonia patients without particular priorities, in order to identify the best option. other selection criteria, including the administration route, the possible positive or negative interactions resulting from combination with other drugs (i.e., hydroxychloroquine) and the costs (i.e., the use of biosimilar anti-tnf available) should be considered. anti-jak drugs (such as ruxolitinib, tofacitinib, baricitinib, oclacitinib, fedratinib, upadacitinib, and peficitinib) [39] should be considered also among the options for clinical investigations in covid-19-related ards and pneumonia patients. jaks are involved in jak/stat signaling associated with the receptors of a large variety of cytokines. in particular, stat-1 and stat-3 pathways are activated by binding of il-6 to its receptor (il-6r) [40] . tofacitinib acts as a non-selective inhibitor of all known jaks (jak1, jak2, jak3, tyk2) with moderate specificity for jak1 and jak3. baricitinib inhibits selectively jak1 and jak2 [41] . both are approved by the european medicines agency (ema); baricitinib for rheumatoid arthritis and tofacitinib for both rheumatic disorders and ulcerative colitis. ruxolitinib is a jak1/ jak2 inhibitor approved by the food and drug administration (fda) for psoriasis, myelofibrosis, and rheumatoid arthritis. upadacitinib (anti-jak1), fedratinib (anti-jak2), and oclacitinib (anti-jak1) were approved by fda for rheumatoid arthritis, myelofibrosis, and dermatitis, respectively [42] . peficitinib (anti-jak3) was approved for rheumatoid arthritis only in japan [43] . tofacitinib and upadacitinib showed potent inhibitory activities on jak1/3-dependent cytokines, both pathways being involved in lymphocyte activation. tofacitinib, baricitinib, and upadacitinib displayed also inhibitory actions on the jak2/tyk2-dependent signaling of il-3, gm-csf, and g-csf. tofacitinib was shown to act as the most potent inhibitor of g-csf (jak2/tyk2). moreover, tofacitinib, baricitinib, and upadacitinib inhibited il-6 and interferon (ifn) γ (jak1/2), as well as il-10 and ifn-α (jak1/tyk2), with tofacitinib appearing as the strongest inhibitor of il-6, ifn-γ, and il-10 signals [44] . evidence suggests that baricitinib, fedratinib, and ruxolitinib are also inhibitors of numb-associated kinases (nak), involved in viral endocytosis and replication. baricitinib showed the highest affinity for aak1 than ruxolitinib and fedratinib. thus, besides exerting putative anti-inflammatory effects in ards patients, it is expected also to reduce viral infectivity [45, 46] . of note, a clinical trial on such antiviral effect is going to start with ruxolitinib [47] , and an open-label trial is evaluating its efficacy and safety at a dose of 10 mg twice a day in covid-19 patients with ards [48] . furthermore, an expanded access program of the 5 mg ruxolitinib formulation is ongoing in severe covid-19 patients with ≥ 6 years old [49] . finally, an open label clinical trial is evaluating the benefit risk profile of baricitinib at a dose of 2 mg a day for 10 days in moderate and severe adult covid-19 patients [27] . whenever jak inhibitors could be identified as an effective pharmacological option in covid-19-related ards and pneumonia, their cost and safety issues, particularly the risk of thromboembolic events for some of them, should be taken into account [50] . several drugs 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redaction of the manuscript and ic, mt, sf, gv, ec, df, and cb reviewed the final version. the authors read and approved the final manuscript. no funding has been received to perform this article.availability of data and materials not applicable. key: cord-354355-i6ot4ef8 authors: decavele, maxens; trosini-désert, valery; boussouar, samia; duceau, baptiste; dres, martin; demoule, alexandre title: endobronchial ultrasound is feasible and safe to diagnose pulmonary embolism in non-transportable sars-cov-2 ards patients requiring extracorporeal lung support date: 2020-09-21 journal: crit care doi: 10.1186/s13054-020-03292-9 sha: doc_id: 354355 cord_uid: i6ot4ef8 nan the sars-cov-2 (severe acute respiratory syndrome coronavirus 2)-related acute respiratory distress syndrome (ards) is associated with an elevated coagulation activation pattern [1] and a high incidence of pulmonary embolism [2] . the diagnosis of pulmonary embolism (pe) may be challenging in these patients because computed tomography pulmonary angiogram (ctpa) requires an intrahospital transport with potential adverse effects and also may increase the risk of acute kidney failure (contrast-induced nephropathy). this is even more the case in up to 10% of sars-cov-2 ards patients who require venovenous extracorporeal membrane oxygenation (vv-ecmo) as an extracorporeal lung support [1] . in addition to the inherent risks of hospital transport, which are particularly high in these patients [3] , extracorporeal circulation is likely to alter the quality of the contrast agent distribution and may reduce the diagnostic performance of the ctpa [4] . finally, systematic curative antithrombotic therapy is not a safe option as it exposes to a serious risk of bleeding, especially when prolonged vv-ecmo is expected [5] . for all the abovementioned reasons, alternative techniques allowing the diagnosis of pe in these vv-ecmo patients would be of the highest interest. here, we describe the feasibility, safety, and diagnostic accuracy of endobronchial ultrasound (ebus) to detect pe in patients with severe sars-cov-2 ards requiring vv-ecmo. between april 15 and may 1, 2020, eleven patients were included. the procedure was performed using a 6.7-mm-outer-diameter, real-time, bronchoscope (eb-530us; fujifilm medical corporation, tokyo, japan) with a 7.5-mhz linear ultrasound transducer (su-1 h; fujifilm medical corporation, tokyo, japan) equipped with color-doppler. for each patient, ebus procedure followed the same roadmap [6] . all ebus images and videos were reviewed by two independent experts in thoracic radiology (s.b. and d.t.) blind from the ctpa interpretation. the study was approved by the research ethics committee of sorbonne university (cer-su n°2020-48) and information was given to the patients or their relatives. patients were mostly men (n = 10), 52 [49-55] years old, with a body mass index of 29 [28-31] kg/m 2 ( table 1) . the time between intubation, vv-ecmo and ebus was 21 [11-27] and 13 [7-18] days, respectively. at the time of ebus procedure, three patients were not receiving antithrombotic therapy, two were receiving effective curative unfractionated heparin, and six were receiving prophylactic unfractionated heparin (dose was 18,000 [14,000-20,000] ui/day). pulmonary embolism was observed on ebus in five of the eleven patients (45%) (fig. 1) . the duration of the procedure was 15 [13-17] min and no major adverse effect of ebus (e.g., serious bleeding, arterial oxygen saturation < 85%) was reported. ebus could explore part of segmental arteries in five (45%) patients. diagnostic correspondence between ebus and ctpa is depicted in table 1 . excluding patient 4, in which pe may have developed during the 7 days that separated ebus and ctpa, overall agreement was obtained in 9/ 10 (90%) patients. the patient (patient 2) without pe on the ebus had left segmental pulmonary embolism on ctpa, which was not accessible to the ebus. this case series of ebus to diagnose pe in severe sars-cov-2 ards patients requiring vv-ecmo suggests that the ebus procedure is safe and reliable to detect lobar and even segmental pe at bedside. given the high risk of pulmonary embolism in patients with severe ards due to covid-19, this minimally invasive diagnostic approach seems to be a useful and appropriate diagnostic tool to avoid the multiple adverse effects of ctpa in these severe and often unstable patients. the diagnostic performance of this innovative and promising technique needs now to be confronted to ctpa in larger prospective study and other clinical situations, especially for the analysis of segmental arteries. clinical research in intensive care and sepsis trial group for global evaluation and research in sepsis). high risk of thrombosis in patients with severe sars-cov-2 infection: a multicenter prospective cohort study acute pulmonary embolism associated with covid-19 pneumonia detected by pulmonary ct angiography extracorporeal membrane oxygenation in transport part 2: complications and troubleshooting hemodynamic changes in patients with extracorporeal membrane oxygenation (ecmo) demonstrated by contrast-enhanced ct examinations -implications for image acquisition technique bleeding, transfusion, and mortality on extracorporeal life support: ecls working group on thrombosis and hemostasis pathway and application value of exploration of the pulmonary artery by endobronchial ultrasound publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank mrs. pia chevalier for her help in the production of fig. 1 . received: 31 august 2020 accepted: 14 september 2020 dr. similowski reports personal fees from adep assistance, astrazeneca france, boerhinger ingelheim france, chiesi france, gsk france, lungpacer inc., novartis france, and teva france, outside the submitted work. in addition, dr. similowski has a patent titled "brain-ventilator interface" licensed to air liquide medical systems and mybraintechnology, a patent for a "protection device for intubation" pending, and a patent for a "non-contact thoracic movement imaging system" pending. alexandre demoule reports personal fees from medtronic, grants, personal fees and non-financial support from philips, personal fees from baxter, personal fees from hamilton, personal fees and non-financial support from fisher & paykel, grants from french ministry of health, personal fees from getinge, grants and personal fees from respinor, and grants and nonfinancial support from lungpacer, outside the submitted work. martin dres received personal fees and travel expenses from lungpacer outside the submitted work. the other authors had no conflict of interest to declare.author details key: cord-282571-ilf73g71 authors: ni, wentao; yang, xiuwen; yang, deqing; bao, jing; li, ran; xiao, yongjiu; hou, chang; wang, haibin; liu, jie; yang, donghong; xu, yu; cao, zhaolong; gao, zhancheng title: role of angiotensin-converting enzyme 2 (ace2) in covid-19 date: 2020-07-13 journal: crit care doi: 10.1186/s13054-020-03120-0 sha: doc_id: 282571 cord_uid: ilf73g71 abstract: an outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) that started in wuhan, china, at the end of 2019 has become a global pandemic. both sars-cov-2 and sars-cov enter host cells via the angiotensin-converting enzyme 2 (ace2) receptor, which is expressed in various human organs. we have reviewed previously published studies on sars and recent studies on sars-cov-2 infection, named coronavirus disease 2019 (covid-19) by the world health organization (who), confirming that many other organs besides the lungs are vulnerable to the virus. ace2 catalyzes angiotensin ii conversion to angiotensin-(1–7), and the ace2/angiotensin-(1–7)/mas axis counteracts the negative effects of the renin-angiotensin system (ras), which plays important roles in maintaining the physiological and pathophysiological balance of the body. in addition to the direct viral effects and inflammatory and immune factors associated with covid-19 pathogenesis, ace2 downregulation and the imbalance between the ras and ace2/angiotensin-(1–7)/mas after infection may also contribute to multiple organ injury in covid-19. the sars-cov-2 spike glycoprotein, which binds to ace2, is a potential target for developing specific drugs, antibodies, and vaccines. restoring the balance between the ras and ace2/angiotensin-(1–7)/mas may help attenuate organ injuries. graphical abstract: sars-cov-2 enters lung cells via the ace2 receptor. the cell-free and macrophage-phagocytosed virus can spread to other organs and infect ace2-expressing cells at local sites, causing multi-organ injury. [image: see text] many diseases [4] [5] [6] . considering that the spike protein of sars-cov-2 interacts with ace2, as does that of sars-cov, covid-19 may have a pathogenic mechanism similar to that of sars. in this review, we will discuss the role of ace2 in covid-19, and its potential therapeutic targets, aiming to provide more information on the management of the epidemic. the ras is a complex network that plays an important role in maintaining blood pressure as well as electrolyte and fluid homeostasis, affecting the function of many organs, such as the heart, blood vessels, and kidneys [6] . angiotensin ii (ang-ii), which is the most representative bioactive peptide in the ras, widely participates in the progression of cardiovascular diseases, such as hypertension, myocardial infarction, and heart failure [7] . in the classic ras, renin cleaves the substrate angiotensinogen to form the decapeptide angiotensin i (ang-i), and then, ace removes two amino acids at the carboxyl terminus of ang-i to yield ang-ii (fig. 1 ). to date, three ang-ii receptors have been identified, and the affinities of these receptors for ang-ii are similar, in the nanomolar range [7] . among these receptors, angiotensin type 1 receptor (at1r) binds to ang-ii, causing vasoconstriction, cell proliferation, inflammatory responses, blood coagulation, and extracellular matrix remodeling, whereas angiotensin type 2 receptor (at2r) counteracts the aforementioned effects mediated by at1r [8] . in 2000, two independent research groups discovered ace2, a homolog of ace, which can remove the carboxy-terminal phenylalanine in ang-ii to form the heptapeptide angiotensin-(1-7) [4, 9] . in addition, under the alternating effects of ace2 and ace, angiotensin-(1-7) can be formed without ang-ii (fig. 1 ). in this metabolic pathway, ang-i is first hydrolyzed by ace2 to form angiotensin(1) (2) (3) (4) (5) (6) (7) (8) (9) , and angiotensin-(1-9) is then hydrolyzed by ace to form angiotensin-(1-7). ang-i can also be directly converted to angiotensin-(1-7) by endopeptidases and oligopeptidases [6] . because of the higher affinity between ace and ang-i, the classical pathway of ang-ii to angiotensin-(1-7) is more common [6] . angiotensin-(1-7), as a ligand, binds to the gprotein-coupled receptor mas, which produces the opposite effect to that of ang-ii, and exerts a range of functions in multiple organs/systems [5, 6] . in addition to catalyzing the production of angiotensin-(1-7), ace2 is involved in the uptake of amino acids in intestinal epithelial cells [10] . entry into host cells is the first step of viral infection. a spike glycoprotein on the viral envelope of the coronavirus can bind to specific receptors on the membrane of host cells. previous studies have shown that ace2 is a specific functional receptor for sars-cov [11] . zhou et al. showed that sars-cov-2 can enter ace2expressing cells, but not cells without ace2 or cells expressing other coronavirus receptors, such as aminopeptidase n and dipeptidyl peptidase 4 (dpp4), confirming that ace2 is the cell receptor for sars-cov-2 [3] . further studies showed that the binding affinity of the sars-cov-2 spike glycoprotein to ace2 is 10-to 20fold higher than that of sars-cov to ace2 [12] . the probable mechanism of sars-cov-2 entry into host cells based on sars-cov studies is displayed in fig. 2 . briefly, the receptor-binding domain of the spike glycoprotein binds to the tip of subdomain i of ace2 [11] [12] [13] [14] . membrane fusion of the virus and the host cell is activated after binding, and viral rna is subsequently released into the cytoplasm, establishing infection. for sars-cov infection, intact ace2 or its transmembrane domain is internalized together with the virus [15] . the catalytically active site of ace2 is not occluded by the spike glycoprotein, and the binding process is independent of the peptidase activity of ace2 [14] . some transmembrane proteinases (such as a disintegrin and metallopeptidase domain 17 [adam17], transmembrane protease serine 2 [tmprss2], and tnf-converting enzyme) and proteins (such as vimentin and clathrin) may be involved in the binding and membrane fusion processes [16] [17] [18] [19] [20] [21] . for example, adam17 can cleave ace2 to cause ectodomain shedding, and tmprss2 can cleave ace2 to promote viral uptake [16, 17] . ace2 is expressed in nearly all human organs in varying degrees. in the respiratory system, the traditional immunohistochemical method and recently introduced single-cell rna-seq analysis revealed that ace2 is mainly expressed on type ii alveolar epithelial cells, but weakly expressed on the surface of epithelial cells in the oral and nasal mucosa and nasopharynx, indicating that the lungs are the primary target of sars-cov-2 [22, 23] . moreover, ace2 is highly expressed on myocardial cells, proximal tubule cells of the kidney, and bladder urothelial cells, and is abundantly expressed on the enterocytes of the small intestine, especially in the ileum [22] [23] [24] . the cell-free and macrophage phagocytosis-associated virus may spread from the lungs to other organs with high ace2 expression through blood circulation (fig. 2) . for example, up to 67% of patients who developed diarrhea during the course of sars and quite a number of patients with covid-19 showed enteric symptoms [25] [26] [27] . active viral replication in enterocytes of the small intestine has been reported, and sars-cov-2 has been successfully isolated from fecal specimens [28, 29] . ace2 is associated with multi-organ injury in covid-19 autopsies of sars patients showed that sars-cov infection can cause injury to multiple organs, such as the heart, kidney, liver, skeletal muscle, central nervous system, and adrenal and thyroid glands, besides the lungs [30, 31] . most critically ill patients with covid-19 also had multiple organ damage, including acute lung injury, acute kidney injury, cardiac injury, liver dysfunction, and pneumothorax [32] . as with sars and covid-19, organ injury is also frequently observed in mers, especially the gastrointestinal tract and kidneys, while the incidence of acute cardiac injury is less common [33] [34] [35] [36] . unlike sars-cov and sars-cov-2, mesr-cov uses dpp4 as its entry receptor, which is mainly expressed on pneumocytes, multinucleated epithelial cells, and bronchial submucosal gland cells of the lungs; epithelial cells of the kidney and small intestine; and activated leukocytes [37] [38] [39] . dpp4 is not abundantly expressed on myocardial cells [37] [38] [39] . therefore, this indicates that organ involvement and injury is strongly associated with receptor distribution in the body. according to the results of a series of studies on sars, the pathogenesis of covid-19 should be complex. the virus-induced inflammatory responses, including the excessive expression of cytokines and chemokines, excessive recruitment of inflammatory cells, insufficient interferon response, and possible production of autoantibodies are deemed to be vital factors in disease pathogenesis [30] . pro-inflammatory cytokines (pics) and chemokines in plasma, such as interleukin (il)-1, il-6, il-12, il-8, monocyte chemoattractant protein-1 (mcp-1), and interferon-gamma-inducible protein 10 (ip-10), are significantly elevated in the plasma of fig. 1 the renin-angiotensin system (ras) and ace2/angiotensin-(1-7)/mas axis. the protease renin converts angiotensinogen to ang-i, which is subsequently converted to ang-ii by angiotensin-converting enzyme (ace). ang-ii can bind to the angiotensin type 1 receptor (at1r) to exert actions, such as vasoconstriction, hypertrophy, fibrosis, proliferation, inflammation, and oxidative stress. ace2 can covert ang-i and ang-ii to angiotensin-(1-7). angiotensin-(1-7) binds to the mas receptor to exert actions of vasodilation, vascular protection, anti-fibrosis, anti-proliferation, and anti-inflammation. ang-ii can also bind to the angiotensin type 2 receptor (at2r) to counteract the aforementioned effects mediated by at1r patients with sars [40, 41] . significantly increased plasma concentrations of these pics were also found in severe patients with covid-19 [1] . autopsy studies of sars patients further found that pics and mcp-1 were highly expressed in sars-cov-infected ace2+ cells, but not in tissues without infected ace2+ cells, suggesting virus-induced local immune-mediated damage [42] . in addition to acting as the receptor for sars-cov and sars-cov-2, ace2 hydrolyzes ang-ii to angiotensin-(1-7), and the ace2/angiotensin-(1-7)/ mas counteracts the negative effects of the ras and exerts anti-inflammatory effects [6, 43] . several studies have shown that sars-cov infection can downregulate ace2 expression on cells, thereby disrupting the physiological balance between ace/ace2 and ang-ii/angiotensin-(1-7) and subsequently causing severe organ injury [44] [45] [46] [47] . given that sars-cov-2 is a species of sars-related coronaviruses and uses ace2 as its based on previous studies on sars and recent studies on sars-cov-2, the multiple organ injury in covid-19 (fig. 3 ) and the possible role of ace2 in organ injury are described below. although the mortality rate in covid-19 is lower than that in sars and mers, numerous patients have acute lung injury (ali) after infection [26, 32] . similar to the pathological features of sars and mers, severe diffuse alveolar damage, such as extensive edema, hyaline membrane formation, inflammatory infiltrates, microthrombi formation, organization, and fibrosis, was also observed in covid-19, but with more cellular fibromyxoid exudates in the alveoli and small airways [48, 49] . the role of the ras and ace2 in ards/ali has drawn great attention since the outbreak of sars in 2003. clinical studies have found that ace insertion/deletion polymorphism may be correlated with the severity of ards [50, 51] . high ang-ii levels in the lungs can increase vascular permeability and cause pulmonary edema [52, 53] . several studies have revealed the protective effects of the ace2/angiotensin-(1-7)/mas axis in the lungs. it alleviates lung inflammation, fibrosis, and pulmonary arterial hypertension, as well as inhibiting cancer cell growth, tumor angiogenesis, and tumor metastasis [6, [54] [55] [56] . in different animal models of ali, ace2-knockout mice exhibited enhanced vascular permeability, increased lung edema, neutrophil accumulation, and marked worsening of lung function compared with wildtype control mice [56] . injection of recombinant human ace2 protein or at1r blockers into ace2-knockout mice could decrease the degree of ali [56] . sars-cov infection considerably reduces ace2 expression in mouse lungs [46] . further experiments showed that mere binding of recombinant sars-cov spike-fc to human and mouse ace2 could result in the downregulation of cell-surface ace2 expression [46] . the spike-fc protein worsened acid-induced ali in wild-type mice, but did not affect the severity of lung failure in ace2-knockout mice, indicating that the effect of spike protein on ali is ace2-specific [46] . studies on influenza also found that ace2 was significantly downregulated after h1n1 infection [57] . ace2 deficiency significantly worsened the pathogenesis in infected mice, and inhibition of at1 alleviated the severity of influenza h7n9 virus-induced lung injury [58, 59] . moreover, ang-ii levels were elevated in h5n1-and h7n9infected patients, which was associated with the severity of lung injury and predicted fatal outcomes in h7n9-infected patients [59, 60] . in patients with covid-19, plasma ang-ii levels were markedly elevated and linearly associated with viral load and lung injury [61] . all these findings suggest that the ras and ace2 downregulation contribute to the pathogenesis of lung injury in covid-19. the heart abundantly expresses ace2, indicating that it is vulnerable to sars-cov-2 infection. autopsies of patients with sars revealed that 35% of them (7 of 20) were positive for the sars-cov genome in cardiac tissue, and patients with sars-cov cardiac infections had a more aggressive illness and earlier mortality than those without [47] . edema of the myocardial stroma, inflammatory cell infiltration, and atrophy of cardiac muscle fibers was observed in patients with sars and myocardial damage [30, 31, [62] [63] [64] . cardiac injury is quite common among severely ill patients with covid-19, and we found that early acute myocardial injury was associated with a higher risk of mortality [65] . the beneficial role of the ace2/angiotensin-(1-7)/ mas axis in the heart has been well demonstrated [6] . it can induce vasorelaxation of coronary vessels, inhibit oxidative stress, attenuate pathological cardiac remodeling, and improve postischemic heart function [66] . ace2 expression usually increases at the initial stage of heart injury, but decreases as the disease progresses [7] . ace2 knockout in mice results in myocardial hypertrophy and interstitial fibrosis and accelerates heart failure [67, 68] . in addition, ace2 knockout in mice aggravates cardiac dysfunction caused by diabetes [69] . in both sars-cov-infected mice and humans, ace2 expression in myocardial cells is markedly downregulated in the heart [47] . according to recent studies [26, 70] and our data [65] , a substantial number of patients with severe disease have hypertension as a comorbidity. over-activation of the ras may have already occurred in these individuals before infection. the significant downregulation of ace2 and upregulation of ang-ii in covid-19 results in ras over-activation, and loss of the protective effects of angiotensin-(1-7) may aggravate and perpetuate cardiac injuries. the gastrointestinal tract, especially the intestine, is vulnerable to sars-cov and sars-cov-2 infections. sars-cov particles have been detected in epithelial cells of the intestinal mucosa, but not in the esophagus and stomach [30, 42] . the main pathological finding in the intestines of patients with sars was the depletion of mucosal lymphoid tissue [71] . only mild focal inflammation was detected in the gastrointestinal tract [71] . these findings may explain why gastrointestinal manifestations in covid-19 are not severe and are transient. many patients with covid-19 show a slight to moderate increase in serum levels of alanine aminotransferase (alt) and/or aspartate aminotransferase (ast) during the course of infection [26, 72] . autopsies of sars patients revealed fatty degeneration, hepatocyte necrosis, and cellular infiltration in the liver [30] . however, sars-cov was not detected in the hepatic tissue of most patients autopsied [30] . both immunohistochemistry and single-cell rna-seq analyses showed that hepatocytes, kupffer cells, and the endothelial lining of the sinusoids were negative for ace2; only cholangiocytes were positive for ace2 [22, 23, 73] . gamma-glutamyl transpeptidase (ggt), which reflects cholangiocyte damage, was elevated in some covid-19 patients [74] . these findings indicate that most acute hepatic injury may not be due to virus infection, but is highly likely due to other causes, such as drug hepatotoxicity, hypoxia, and systemic inflammation. whether sars-cov-2 causes damage to the bile ducts by binding with ace2 on cholangiocytes requires further investigation. ace2 is highly expressed in the kidney, especially in the apical membranes of proximal tubular epithelial cells, suggesting that the kidney is another target of sars-cov-2 [22, 23, 75] . moreover, an imbalance between ang-ii and angiotensin-(1-7) caused by ace2 deficiency may aggravate the vulnerability of the kidney to other factors causing acute kidney injury (aki) [76] . sars-cov was detected in epithelial cells of the distal tubules, and viral sequences were identified in urinary samples from some patients [77, 78] . sars-cov-2 has also been isolated from urinary samples [79] . a retrospective analysis of 536 sars patients showed that 6.7% of patients developed acute renal impairment during the course of the disease [80] . a large cohort study from new york showed that the incidence of aki among patients with covid-19 could reach 36.6% [81] . pancreatic cells highly express ace2, indicating that covid-19 may affect the pancreas [82] . it has been reported that up to 16% of patients with severe covid-19 have elevated serum amylase and lipase levels, with 7% displaying accompanying significant pancreatic changes on ct scans [83] . clinical presentation of acute pancreatitis has been reported in patients with covid-19 [84] . ace2/angiotensin-(1-7) plays a protective role in diabetes by improving pancreatic β cell survival, stimulating insulin secretion, and reducing insulin resistance [6] . studies have shown that, compared to patients with non-sars pneumonia, many more sars patients who had no previous diabetes and had not received steroid treatment developed insulin-dependent acute diabetes during hospitalization [85, 86] . moreover, plasma glucose levels and diabetes are independent predictors of mortality in patients with sars [86] . autopsies of some sars patients found atrophy and amyloid degeneration in most pancreatic islets, suggesting the virus causes damage to the islets [64] . therefore, covid-19 may also influence pancreatic function, similar to sars, and glucose levels should be closely monitored, especially in patients with diabetes or glucocorticoid treatment. muscle weakness and elevated serum creatine kinase (ck) levels were observed in more than 30% of patients with sars [87] . mildly to moderately elevated ck levels were also observed in patients with covid-19 on admission [88] . myofiber necrosis and atrophy were observed in skeletal muscle tissues, but no sars-cov particles were detected by electron microscopy [30, 89] . recent studies revealed that the ras plays an important role in the pathogenesis of various skeletal muscle disorders, and the ace2/angiotensin-(1-7)/mas axis exerts protective effects against muscle atrophy [6] . nevertheless, whether sars-cov-2 attacks the muscles and whether the downregulation of ace2 is associated with myopathy is unclear. ace2 is widely present in the brain, predominantly in neurons, and participates in the neural regulation of broad physiological functions, such as cardiovascular and metabolic activities, stress response, and neurogenesis [6, 90, 91] . in a mouse model, sars-cov invaded the brain through the olfactory bulb and then spread transneuronally to other areas [92] . olfactory and gustatory dysfunctions have been reported in many patients with covid-19, suggesting the involvement of the olfactory bulb in sars-cov-2 infection [93, 94] . sars-cov was isolated from human brain tissue specimens [31, 95] . autopsies showed edema and focal degeneration of neurons in the brains of patients with sars [30, 31] . many patients (78/214) had neurologic manifestations in covid-19, and sars-cov-2 was detected in the cerebrospinal fluid of a patient with encephalitis [96, 97] . considering that sars-cov-2 has a much higher affinity for its receptor (ace2) than sars-cov, the former could be capable of infecting and damaging the central nervous system. ace2 is also expressed in the endothelial cells of small and large blood vessels, and the vascular endothelium can produce angiotensin-(1-7) [6, 22] . the ace2/angiotensin-(1-7)/mas axis induces vasodilatory, antiproliferative, and antithrombotic effects in the vasculature [6] . sars rna can be detected in the endothelia of the small veins in many tissues [98] . plasma d-dimer levels are significantly elevated in severely ill patients with covid-19 [1, 32, 72] , and the occurrence of disseminated intravascular coagulation (dic) at the early stage of the disease is not rare. viral infection and inflammatory responses damage the integrity of the vascular endothelium, causing increased permeability, coagulation activation, and microcirculation disturbances, which may contribute to organ injury in covid-19. as ace2 is the receptor for both sars-cov and sars-cov-2, and some transmembrane proteinases such as adam17 and tmprss are involved in binding and membrane fusion processes, these sites may be potential targets in the development of antiviral drugs for covid-19 treatment. for example, serum samples from patients with convalescent sars can neutralize spikedriven entry of sars-cov-2 into host cells, suggesting that vaccines targeting the spike protein will be promising [18] . studies have found that sars-cov-specific monoclonal antibodies and recombinant ace2-ig can potently neutralize sars-cov-2, and a hexapeptide of the receptor-binding domain of the spike protein binds to ace2, thus blocking sars-cov entry [18, [99] [100] [101] . the downregulation of ace2 in organs after virus infection disturbs the local balance between the ras and ace2/angiotensin-(1-7)/mas axis, which may be associated with organ injuries. animal studies have found that ace inhibitor (acei) therapy can increase plasma angiotensin-(1-7) levels, decrease plasma ang-ii levels, and increase cardiac ace2 expression, whereas angiotensin ii receptor blockers (arbs) can increase the plasma levels of both ang-ii and angiotensin-(1-7) as well as the cardiac expression and activity of ace2 [102] . thus, the use of aceis/arbs, renin inhibitors, and angiotensin-(1-7) analogs may attenuate organ injuries by blocking the renin-angiotensin pathway and/or increasing angiotensin-(1-7) levels [103] . other animal studies showed that ali mediated by sars-cov spike or the influenza virus in mice could be rescued by the use of arbs [46, 60, 104] . in a population-based study, the application of aceis and arbs significantly reduced the 30-day mortality rate of patients with pneumonia requiring hospitalization [105] . there are also concerns that treatment with aceis/arbs may facilitate infection and increase the risk of developing severe and fatal covid-19 by increasing ace2 expression levels in target organs [106] . however, two large cohort studies showed that aceis/arbs use was not associated with increased sars-cov-2 infection, but was associated with a lower risk of all-cause mortality in hospitalized patients [107, 108] . further studies are needed to test the protective effects of aceis/arbs in covid-19. the ras and ace2/angiotensin-(1-7)/mas axis play important roles in various physiological and pathophysiological contexts. both sars-cov-2 and sars-cov use ace2 as the receptor for entry into host cells. because ace2 is highly expressed in various organs and tissues, sars-cov-2 not only invades the lungs but also attacks other organs with high ace2 expression. the pathogenesis of covid-19 is highly complex, with multiple factors involved. in addition to the direct viral effects and inflammatory and immune factors, the downregulation of ace2 and imbalance 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infection in mouse population-based study of statins, angiotensin ii receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes are patients with hypertension and diabetes mellitus at increased risk for covid-19 infection? association of use of angiotensin-converting enzyme inhibitors and angiotensin iireceptor blockers with testing positive for coronavirus disease 2019 (covid-19) association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid-19 springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank editage (www.editage.cn) for english language editing. this study was supported by the national natural science foundation of key: cord-324598-z65p60z9 authors: he, huaiwu; chi, yi; long, yun; yuan, siyi; frerichs, inéz; möller, knut; fu, feng; zhao, zhanqi title: influence of overdistension/recruitment induced by high positive end-expiratory pressure on ventilation–perfusion matching assessed by electrical impedance tomography with saline bolus date: 2020-09-29 journal: crit care doi: 10.1186/s13054-020-03301-x sha: doc_id: 324598 cord_uid: z65p60z9 background: high positive end-expiratory pressures (peep) may induce overdistension/recruitment and affect ventilation–perfusion matching (vqmatch) in mechanically ventilated patients. this study aimed to investigate the association between peep-induced lung overdistension/recruitment and vqmatch by electrical impedance tomography (eit). methods: the study was conducted prospectively on 30 adult mechanically ventilated patients: 18/30 with ards and 12/30 with high risk for ards. eit measurements were performed at zero end-expiratory pressures (zeep) and subsequently at high (12–15 cmh(2)o) peep. the number of overdistended pixels over the number of recruited pixels (o/r ratio) was calculated, and the patients were divided into low o/r (o/r ratio < 15%) and high o/r groups (o/r ratio ≥ 15%). the global inhomogeneity (gi) index was calculated to evaluate the ventilation distribution. lung perfusion image was calculated from the eit impedance–time curves caused by 10 ml 10% nacl injection during a respiratory pause (> 8 s). deadspace(%), shunt(%), and vqmatch(%) were calculated based on lung eit perfusion and ventilation images. results: increasing peep resulted in recruitment mainly in dorsal regions and overdistension mainly in ventral regions. δvqmatch(%) (vqmatch(%) at high peep minus that at zeep) was significantly correlated with recruited pixels (r = 0.468, p = 0.009), overdistended pixels (r = − 0.666, p < 0.001), o/r ratio (r = − 0.686, p < 0.001), and δspo(2) (r = 0.440, p = 0.015). patients in the low o/r ratio group (14/30) had significantly higher shunt(%) and lower vqmatch(%) than those in the high o/r ratio group (16/30) at zeep but not at high peep. comparable deadspace(%) was found in both groups. a high peep caused a significant improvement of vqmatch(%), deadspace(%), shunt(%), and gi in the low o/r ratio group, but not in the high o/r ratio group. using o/r ratio of 15% resulted in a sensitivity of 81% and a specificity of 100% for an increase of vqmatch(%) > 20% in response to high peep. conclusions: change of ventilation–perfusion matching was associated with regional overdistention and recruitment induced by peep. a low o/r ratio induced by high peep might indicate a more homogeneous ventilation and improvement of vqmatch. trial registration: clinicaltrials.gov, nct04081155. registered on 9 september 2019—retrospectively registered. in the context of lung protective ventilation, positive end-expiratory pressure (peep) is applied to open collapsed lung regions and keep the lung open. peep setting is often based on the response of oxygenation and/ or respiratory compliance in patients with acute respiratory distress syndrome (ards) under mechanical ventilation. change of oxygenation, as a complex indicator of ventilation-perfusion matching, cannot directly reflect the change of shunt/dead space during the increase of peep. in fact, only a weak to moderate correlation was found between oxygenation and lung aeration during the peep changes [1, 2] . on the other hand, lung mechanics reflects merely ventilation and not perfusion. a recent clinical study found that peep selection based on best global respiratory compliance might result in poor outcomes in the ards patients [3] . because of the high degree of inhomogeneity in the respiratory system of ards patients, an increase of peep introduces regional lung overdistension and recruitment at the same time. this may subsequently alter shunt and dead space. little is known on how the regional lung overdistension and recruitment influence regional ventilation-perfusion (v-q) matching (shunt and dead space) in response to peep increase. karbing et al. recently found that improved lung aeration following an increase in peep and detected by ct scan was not always consistent with reduced shunt and v-q mismatch by modelbased method [4] . it remains a great challenge to assess the effect of peep on regional overdistension/recruitment and v-q matching directly at the bedside. electrical impedance tomography (eit) is a noninvasive, non-radiation, and real-time monitoring method to monitor regional ventilation distribution at the bedside [5] . in recent advance, eit was proposed to assess regional lung perfusion with saline bolus injection in icu patients [6] [7] [8] [9] . hence, eit would be the ideal bedside tool to evaluate the influence of peep on v-q matching. we hypothesized that eit may help to better explain the relationship between regional lung overdistension and recruitment, shunt and dead space, and v-q matching during a peep increase. the aim of the study was to investigate the association between lung overdistension/recruitment induced by peep and ventilation-perfusion matching in patients suffering from or being at high risk of developing ards. further, we explored a potential novel indicator of regional overdistension/recruitment ratio to assess the response of v-q matching after peep increase. the study was approved by the institutional research and ethics committee of the peking union medical college hospital. informed consent was obtained from all patients or next of kin before data were included into the study. the clinical trial registration number was nct04081155. when the research team was available from jan 2019 to may 2020, patients with ards or with high-risk ards admitted to the department of critical care medicine of peking union medical college hospital, who received mechanical ventilation, were screened for eligibility. diagnosis of ards was based on the berlin definition [10] . high-risk ards was defined as those mechanically ventilated patients who had some high risk factors of ards (major operation, massive transfusion and trauma, etc.) and lung collapse in the dependent region but with pao 2 /fio 2 > 300 mmhg at the enrollment. included patients should have been deeply sedated and a central venous catheter placed for treatment as per clinical decision at the time of enrollment. patients were excluded from the study in the presence of age < 18 years, pregnancy, ribcage malformation, baseline peep > 12 cmh 2 o and spo 2 < 88%, and any contraindication to the use of eit (e.g., automatic implantable cardioverter defibrillator, and implantable pumps). patient demographics and relevant clinical data were collected at the enrollment day, including age, sex, acute physiology and chronic health evaluation ii score (apache ii), heart rate, mean arterial pressure, fio 2 , spo 2, and as outcome the 28-day mortality. patients were ventilated under pressure control mode. ventilator settings were tidal volume 6-8 ml/kg of ideal body weight. peep, fio 2 was set to maintain spo 2 > 90%, and respiratory rate was set to obtain arterial ph of 7.30-7.45 based on the ards-net suggestions [11] . all patients were deeply sedated (richmond agitation-sedation scale at − 4) and kept in the supine position. the following peep adjustment was performed for each patient: 1. peep was switched to a zero end-expiratory pressure (zeep) for 10 min, and fio 2 was titrated to obtain peripheral oxygen saturation (spo 2 ) > 90%. 2. peep was increased to a high peep level (preferably 15 cmh 2 o) for another 10 min within a single step. if the patient was not able to tolerate 15 cmh 2 o as assessed by the physician (e.g., due to impaired circulation), peep of 12 cmh 2 o was used instead. eit measurements were performed with pulmovista 500 (dräger medical, lübeck, germany) throughout the peep adjustment. a silicone eit belt with 16 surface electrodes was placed around the patient's thorax at the 4th intercostal space level. all patients received standard care. eit measurements were continuously recorded at 20 hz. at the end of each peep level (i.e., zeep and high peep), a bolus of 10 ml 10% nacl was injected during a respiratory pause (at least for 8 s) through the central venous catheter. the eit data were digitally filtered using a low-pass filter with a cut-off frequency of 0.67 hz to eliminate periodic cardiac-related impedance changes (for evaluation of both ventilation and perfusion). perfusion evaluated via saline bolus injection corresponded to non-periodic impedance drop that was not influenced by the low-pass filtering. further, the data were analyzed offline using customized software programmed with matlab r2015 (the mathworks inc., natick, ma). ventilation map was equally divided into two nonoverlapping horizontal anterior-to-posterior regions of interest, which were denoted as the ventral and dorsal regions. regional ventilation map was calculated by subtracting the end-expiration from the end-inspiration image, which represents the variation during tidal breathing. the tidal images before the apnea period (2min period) were averaged to increase the signal-tonoise ratio. where v i is the pixel i in the ventilation image, n is the number of breaths within the analyzed period, and δz i,ins and δz i,exp are the pixel values in the raw eit image at the end-inspiration and end-expiration, respectively. the ventilation gain and loss via peep increase were assessed as follows: δv i > 0 is associated with ventilation gain whereas δv i < 0 with ventilation loss. to improve signal-to-noise ratio, we defined a threshold of 20% of maximum v i . recruited pixels were defined as pixels r that exhibited ventilation gains higher than the threshold: similarly, overdistended pixels were defined as pixels o with ventilation loss higher than the threshold: the number of overdistended pixels over the number of recruited pixels (o/r ratio) was subsequently calculated. with the o/r ratio, we tried to summarize the degrees of overdistension and recruitment with one single index. the patients were divided into low o/r (o/r ratio < 15%) and high o/r groups (o/r ratio > 15%). changes of end-expiratory lung impedance (δeeli) were determined relative to the reference time point during device calibration. the global inhomogeneity (gi) index [12] was calculated offline. due to its high conductivity, 10% nacl acts as an eit contrast agent, passes through the pulmonary circulation thereby producing a dilution curve after bolus injection during the apnea period based on the first pass kinetics theory [13, 14] . regional perfusion map was calculated as the slope of regional impedance-time curves after saline bolus injection [15, 16] . the detailed calculation was described in previous studies [6, 7] . in brief, the regional impedance-time curves during the descending phase were fitted with linear regression: where t is the time starting from one cardiac cycle after the initial descent in the global impedance curve caused by saline injection, and ending at the trough of the global curve during the apnea period. p i , the perfusion value of pixel i in the perfusion image, was equaled to -a i . further, ventilated and perfused regions were defined as follows: region k is ventilated if: similarly, region g was perfused if: subsequently, the following three regions were identified: the area that was only ventilated (a v ), the area that was only perfused (a p ), and the area that was both ventilated and perfused (a v+p ). to correlate with clinical events, the following eit-derived parameters were calculated according to their physiological definitions: figure 1 illustrates the analysis with patient data. the tidal impedance variation during normal tidal breathing before apnea was used for the calculation of ventilationrelated parameters. the impedance-time curve caused by saline bolus during the apnea period was used for the perfusion-related parameters. the regional recruited and overdistended pixel distribution image was derived from the difference of zeep and high peep ventilation tidal images (fig. 1 top) . the regional v-q images ( fig. 1 bottom) were derived from the difference of ventilation and perfusion images at the same peep level. a descriptive analysis was performed. normal distribution was assessed with the kolmogorov-smirnov normality test. normally distributed results were presented as mean ± sd whereas non-normally distributed results were presented as median (25th-75th percentile). the mann-whitney test was used to compare groups on continuous variables, and chi-square and fisher's exact tests were used to compare categorical variables. paired t test or wilcoxon's signed-rank test was performed to compare values at zeep and high peep, as appropriate. comparisons of two continuous variables were performed using spearman's correlation and linear regression. all comparisons were two-tailed, and p < 0.05 was required to exclude the null hypothesis. the areas under the receiver operating characteristic (auc) curves were compared using a hanley-mcneil test. the statistical analysis was performed by using the software package spss 24.0 (spss inc. chicago, il) and medcalc 11.4.3.0 software (mariakerke, belgium). a total of 33 intubated patients were enrolled, and three ards patients were excluded due to insufficient respiratory holding time (< 8 s) during the saline injection period for lung perfusion assessment. twenty-seven out of 30 patients received a high peep of 15 cmh 2 o, and 3/30 patients was performed a high peep of 12 cmh 2 o during the incremental peep trial. demographics and clinical characteristics are shown in table 1 . compared to zeep, significantly higher spo 2 , vqmatch % , and eeli were found at high peep, whereas mean arterial pressure, deadspace % , shunt % , and gi were significantly lower ( table 2) . increasing peep resulted in recruitment mainly in dorsal regions and overdistension in ventral regions. the median (25th-75th percentile) of o/r ratio was 45% (0.00-112%) and with extremely large variability (range from 0 to 773%). the numbers of patients in the low and high o/r ratio groups were 14 and 16, respectively. δvqmatch % (vqmatch % at high peep minus that at zeep) was significantly correlated with the numbers of recruited pixels (r = 0.468, p = 0.009), overdistended pixels (r = − 0.666, p < 0.001), o/r ratio (r = − 0.686, p < 0.001), and δspo 2 (r = 0.440, p = 0.015). δshunt % (shunt % at high peep minus that at zeep) was significantly correlated with the numbers of recruited pixels (r = − 0.444, p = 0.014), overdistended pixels (r = 0.544, p = 0.002), and o/r ratio (r = 0.580, p = 0.001), but not with δspo 2 (r = − 0.355, p = 0.055). δdeadspace % (deadspace % at high peep minus that at zeep) was not correlated with the parameters mentioned above. there were no significant differences in peep, pao 2 /fio 2 , and tidal volume at the baseline between the two groups ( table 3) . patients in the low o/r ratio group (14/30) had significantly higher shunt % and lower vqmatch % than those in the high o/r ratio group (16/30) at zeep but not at high peep (table 3 and fig. 2) . comparable dead-space % was found in both groups. a high peep caused a significant improvement of vqmatch % , deadspace % , shunt % , and gi in the low o/r ratio group, but not in the high o/r ratio group (table 3 and fig. 3) . diverse responses in vqmatch % (12/16 increase, 4/16 decrease), deadspace % (11/16 decrease, 5/16 increase), and shunt % (10/16 decrease, 6/16 increase) to high peep were found in the high o/r ratio group. prediction of an increase of vqmatch % > 20% to high peep ten out of 30 patients had an increase of vqmatch % > 20%, and 20/30 patients an increase of vqmatch % < 20% induced by peep increase. the auc of o/r ratio, total recruited fig. 1 illustration of the data analysis method of regional recruitment, overdistension, and v-q matching in one study patient. top: tidal variation images at zeep (left), peep (middle), and the corresponding difference image (right). in the tidal variation images, regions with low ventilation are marked in dark blue and highly ventilated regions in light blue to white. collapsed or overdistended regions are comprised in the low/nonventilated dark blue or black areas. in the difference image, ventilation gain and loss at peep compared to zeep are marked in blue and orange, respectively. middle: perfusion images at zeep (left) and peep (middle). highly perfused regions are marked in red. colorbars in arbitrary units. recruited and overdistended regions were defined based on ventilation difference image (right). bottom: regional v-q matching images at zeep (left) and peep (right) pixels, and total overdistended pixels used for prediction of an increase of vqmatch % > 20% to high peep are shown in fig. 4 . the o/r ratio has the biggest auc among the examined parameters. moreover, both overdistended pixels and o/r ratio have a significantly higher auc for predicting an increase of vqmatch % to high peep than the recruited pixels (p < 0.05). using o/r ratio of 15% resulted in a sensitivity of 81% and a specificity of 100% for an increase of vqmatch % > 20% in response to high peep. in the present study, we found that (1) it was feasible to evaluate the influence of peep on lung perfusion combining eit and hypertonic saline bolus injection. (2) the change of v-q matching was associated with regional overdistention and recruitment induced by peep increase. (3) the benefit of increasing peep might be determined by o/r ratio. when o/r < 15%, patients demonstrated more homogeneous ventilation, decrease of dead space and shunt, and increase of v-q matching and oxygenation. on the contrary, when o/r > 15%, the response to peep was rather diverse regarding dead space, shunt, and v-q matching. both shunt and dead space are the determinants of v-q matching. the primary effect of high peep was to improve v-q match by reducing shunt in ards. in theory, for regions with poor alveolar ventilation but sufficient lung blood flow, lung recruitment could decrease the intra-pulmonary shunt. in the present study, the recruited pixels were significantly correlated with δshunt % and δvqmatch % . karbing et al. recently showed that improvement of lung aeration after peep increase was not always consistent with improvement of shunt and v-q mismatching in 12 ards patients [4] . the authors speculated that poorly matched redistribution of v-q between dependent and non-dependent regions may explain the detrimental changes in shunt and v-q mismatching after peep increase. however, since the v-q matching was calculated based on global parameters, no regional information can be deduced to prove their hypothesis. with help of eit and saline bolus injection, our study elegantly showed the relationship between regional v-q matching and overdistension/recruitment. we found that not only recruitment but also overdistension occurred during peep increase. δshunt % and δvqmatch % were also significantly influenced by the degree of overdistension. the recruited pixels were mainly observed in dorsal (gravity dependent) regions, whereas the overdistended pixels were in ventral (nongravity dependent) regions. moreover, we found overdistended pixels had a significantly higher auc for prediction of an increase of vqmatch % to high peep than the recruited pixels (fig. 4) . hence, more attention should be paid on the regional overdistension induced by high peep on v-q matching. simply pursuing maximum lung recruitment without considering the adverse effects of overdistension at high peep may worsen the outcomes in mechanically ventilated patients. a recent study found that maximal lung recruitment did not reduce the duration of ventilationfree days or mortality [17] . a parameter of recruitmentto-inflation ratio calculated by systemic pressure-volume curves was proposed to assess lung recruitment and recruited volume during peep change from 15 to 5 cmh 2 o [18] . it remains challenging for physicians to balance the regional recruitment and overdistension induced by peep. eit has been used to assess the effect of peep on regional recruitment and overdistension in clinical practice [19] [20] [21] [22] [23] . franchineau et al. defined an optimal peep would keep regional collapse < 10% with minimum overdistension [20] . zhao et al. set the peep to the cross point of cumulated collapse and overdistension curve [22] . both studies calculated collapse and overdistension according to the regional compliance curves along peep changes. in order to deliver a reliable result, an incremental or decremental peep trial with a number of peep steps is required [24] . in the current study, we defined recruitment and overdistension based on the ventilation gain and loss, similar to the analysis method introduced previously [25] . further, we created the o/r ratio to quantify the balance between overdistension and recruitment. an extremely large variability of o/r ratio induced by high peep was found in the present study, which indicated diverse responses of lung recruitment and overdistension. a low o/r ratio indicated lung recruitment with little overdistention. a previous study reported a subgroup of ards patients exhibiting recruitment of up to 35% when changing peep from 5 to 15 cmh 2 o and with little to no hyperinflation assessed by ct scan at high peep [26] . on the contrary, high o/r ratio indicated lung recruitment with high overdistention. when o/r ratio was < 15%, broad beneficial responses were found in homogeneous ventilation, shunt, dead space, and v-q matching at high peep (table 3) . when o/r ratio was > 15%, diverse responses were found in ventilation distribution, shunt, dead space, and v-q matching. since the regional overdistension is unavoidable in the high o/r group, selection of high peep should be cautiously based on the patient's condition. it might be difficult to weight risk/benefit of high peep in this o/r group, and the prone position might be a good choice. moreover, we found that using o/r ratio of 15% resulted in a sensitivity of 81% and a specificity of 100% for an increase of vqmatch % > 20% in response to high peep. further study is required to validate whether using o/r ratio to select high peep or prone position for ards patients could improve the clinical outcome in clinical practice. increased dead space fraction is a feature of the early phase of ards, and it was associated with the risks of barotrauma and death [27, 28] . the effect of peep on dead space is diverse and complicated in ards patients. on the one hand, the size of dead space had been used to detect lung collapse and optimize peep level after recruitment [29, 30] , which was consistent with our [32] . both studies shared the same drawback that no regional dead space could be evaluated. combining eit and saline bolus injection, regional v-q matching provides unique information to understand the profound influence of overdistension and recruitment induced by peep. to our best knowledge, the present study is the first analysis using saline contrast eit to estimate shunt and dead space related to overdistension and recruitment after peep change. nevertheless, our study must be considered in light of its limitations. (1) our preliminary study was carried out in a single center with a relatively small number of patients, which reduces the statistical power. (2) the analyzed time intervals at zeep and the investigated peep steps were relatively short due to ethical reasons, considering the potential influence on patients. long-term effects of peep increase were not evaluated. (3) cardiac outputs of the patients were not measured. the potential changes in cardiac output induced by peep increase might have an impact on v-q matching, which was not considered in the present study. (4) the thresholds of defining the overdistended and recruited pixels, ventilation and perfusion regions, the areas under the receiver operating characteristic curves (auc) of o/r ratio, total recruited pixels, and total overdistended pixels used for prediction of an increase of vqmatch % > 20% in the incremental peep trial. * < 0.05, vs. auc of total recruited pixels and change of vqmatch % to high peep were rather arbitrary. further investigations to optimize these thresholds and validate the clinical relevance are warranted. (5) we enrolled patients with ards or high-risk ards, which might have introduced some heterogeneity. however, studying the effects of higher peep on lung recruitment seems clinically relevant for the high-risk ards patients, especially in the postoperative patients [33] . (6) the present study should be regarded as a physiologic study of how overdistension/recruitment induced by high peep impact v-q matching since a value of 15 cmh 2 o peep was not used in the actual therapy. further study is required to validate saline contrast eit method and o/r ratio for an individual mechanical setting and management (such as lung recruitment, peep titration, etc.). it was feasible to evaluate the influence of peep increase on v-q matching using eit and hypertonic saline bolus injection. o/r ratio was significantly correlated with v-q matching. therefore, this parameter might be able to predict the effects of peep on v-q matching when saline bolus injection is not available, which requires further investigations. anatomical and functional intrapulmonary shunt in acute respiratory distress syndrome bedside selection of positive end-expiratory pressure in mild, moderate, and severe acute respiratory distress syndrome effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial changes in shunt, ventilation/perfusion mismatch, and lung aeration with peep in patients with ards: a prospective single-arm interventional study chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the translational eit development study group potential for lung recruitment and ventilation-perfusion mismatch in patients with the acute respiratory distress syndrome from coronavirus disease 2019 detection of acute pulmonary embolism by electrical impedance tomography and saline bolus injection bedside evaluation of pulmonary embolism by saline contrast electrical impedance tomography method: a prospective observational study bedside lung perfusion by electrical impedance tomography in the time of covid online ahead of print acute respiratory distress syndrome: the berlin definition ardsnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure evaluation of an electrical impedance tomography-based global inhomogeneity index for pulmonary ventilation distribution indicator transit time considered as a gamma variate on the theory of the indicator-dilution method for measurement of blood flow and volume measurement of relative lung perfusion with electrical impedance and positron emission tomography: an experimental comparative study in pigs regional lung perfusion estimated by electrical impedance tomography in a piglet model of lung collapse maximal recruitment open lung ventilation in acute respiratory distress syndrome (pharlap). a phase ii, multicenter randomized controlled clinical trial potential for lung recruitment estimated by the recruitment-to-inflation ratio in acute respiratory distress syndrome. a clinical trial peep titration guided by ventilation homogeneity: a feasibility study using electrical impedance tomography bedside contribution of electrical impedance tomography to set positive end-expiratory pressure for ecmo-treated severe ards patients positive endexpiratory pressure titration at bedside using electrical impedance tomography in post-operative cardiac surgery patients positive end-expiratory pressure titration with electrical impedance tomography and pressure-volume curve in severe acute respiratory distress syndrome thoracic electrical impedance tomography in chinese hospitals: a review of clinical research and daily applications the incidence and interpretation of large differences in eit-based measures for peep titration in ards patients protective ventilation using electrical impedance tomography lung recruitment in patients with the acute respiratory distress syndrome pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome prognostic value of different dead space indices in mechanically ventilated patients with acute lung injury and ards compliance and dead space fraction indicate an optimal level of positive end-expiratory pressure after recruitment in anesthetized patients dead space fraction changes during peep titration following lung recruitment in patients with ards effects of positive end-expiratory pressure on dead space and its partitions in acute lung injury dead space analysis at different levels of positive end-expiratory pressure in acute respiratory distress syndrome patients effect of intraoperative high positive end-expiratory pressure (peep) with recruitment maneuvers vs low peep on postoperative pulmonary complications in obese patients: a randomized clinical trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank all the subjects for their participation in this study.authors' contributions hh, cy, yl, sy, and zz conceived the study protocol; hh, cy, yl, sy, and zz participated in the design and coordination of the study; hh, cy, yl, and sy collected the study data; hhw, cy, yl, sy, if, km, ff, and zz participated in the data interpretation; hh, cy, yl, sy, and zz drafted the present manuscript; hhw, cy, yl, sy, if, km, ff, and zz revised the manuscript. all authors read and approved the final version of the manuscript. received: 29 july 2020 accepted: 21 september 2020 the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the ethics review board of peking union medical college hospital approved the study protocol, and written informed consent was obtained from all participants before enrollment. not applicable. key: cord-338134-smrokdsq authors: honore, patrick m.; mugisha, aude; kugener, luc; redant, sebastien; attou, rachid; gallerani, andrea; de bels, david title: therapeutic plasma exchange as a routine therapy in septic shock and as an experimental treatment for covid-19: we are not sure date: 2020-05-15 journal: crit care doi: 10.1186/s13054-020-02943-1 sha: doc_id: 338134 cord_uid: smrokdsq nan therapeutic plasma exchange as a routine therapy in septic shock and as an experimental treatment for covid-19: we are not sure patrick m. honore * , aude mugisha, luc kugener, sebastien redant, rachid attou, andrea gallerani and david de bels we read with interest the recent editorial by keith et al. who concluded that their practice has changed based on their experience, and they now often utilize therapeutic plasma exchange (tpe) earlier in the clinical course of septic shock with multiple organ failure (mods) and acute respiratory distress syndrome (ards) rather than using it as a "rescue therapy" [1] . we would like to make some comments. they quoted several studies, including one from knaup et al., in order to support their argument [2] . they assert that tpe is unique by offering benefit on multiple levels by removing inflammatory cytokines, stabilizing endothelial membranes, and resetting the hypercoagulable state [1] . knaup et al. stated that a major difference between tpe and modern extracorporeal adsorption strategies is based on the fact that the exchange of septic shock plasma with fresh frozen plasma may not lead to an unselective depletion of pro-and anti-inflammatory cytokines and will rather replenish protective factors (within ffps) that have been consumed by the sepsis [2] . it is currently impossible when employing an unselective removal technique to know if we are doing something good by removing an excess of pro-inflammatory mediators or something wrong by removing anti-inflammatory mediators. at this time, we are unable to clearly identify at the bedside which patients are in a pro-inflammatory state that could kill them or an anti-inflammatory state that could help them to survive. the fact that the inflammation is huge during covid-19 does not justify the non-selective removal of inflammation components, when some elements may be saving patients. tpe also has the potential to cause harm by diluting or attenuating the host's adaptive response to infection by depletion of immunoglobulins and complement component 3 and 4 in individuals treated with plasmapheresis [3] . importantly, in the case of sars-cov-2 outbreak, tpe will remove the protective antibodies formed by the patient, which is not desirable. in conclusion, tpe may not restore immune homeostasis but may rather aggravate immunoparalysis [4] . we agree with the authors that this outbreak should serve as an impetus to investigate therapies targeting the pathways that lead to morbidity and mortality in these syndromes [1] . this does not mean that we have received a signed blank check to start a therapy without deeply reviewing the rationale and the quality of existing data. we appreciate dr. honore's interest and his insight, and we share his concerns regarding the need to be cautious. the points made in the letter are valid and warrant further investigation. the intent of our editorial was not to protocolize the use of tpe in sepsis and/or covid-19, rather to highlight its potential and to encourage further study [1] . the covid pandemic has been an eye-opening and humbling experience. currently, there are no proven treatments for this disease. a number of therapies have been/are being investigated, but early results have been disappointing. critically ill patients with covid continue to die at an alarming rate-a recent case series published in jama reported 88.1% mortality for patients requiring mechanical ventilation in a large health care system in new york [5] . altering the host immune response certainly comes with risk, and most patients who survive do so without direct alteration of this pathway. however, when "dysregulated," this response may lead to refractory hypotension with shock, multiple organ failure, ards, and/or death. therapies targeting specific components continue to be explored, but none have proven to be efficacious thus far (including during the current covid pandemic). readily available laboratory testing has not allowed for identification of patients likely to benefit (or those likely to worsen). at this time, in the absence of more specific labs, the clinician's challenge of evaluating patients and making the most appropriate treatment decisions must mainly be guided by the clinical parameters, as determined by currently available resources and evidence. we submitted our editorial because of enthusiasm for tpe as a potential supportive and adjunctive treatment for select critically ill, septic patients. we agree to suggest its promotion as a panacea, deserving of a blank check, would be a gross overstatement. tpe has not been appropriately studied, despite decades of evidence suggesting a potential benefit. we feel that the medical community has a responsibility to investigate its role as adjunctive therapy, through well-designed clinical trials. abbreviations mods: multi-organ dysfunction syndrome; ards: acute respiratory distress syndrome; tpe: therapeutic plasmapheresis; ffp: fresh frozen plasma a novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant covid-19 early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers the efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis complications in patients treated with plasmapheresis in the intensive care unit presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions pmh, sr, and ddb designed the paper. all authors participated in drafting and reviewing. all authors read and approved the final version of the manuscript. none.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare to have no competing interests.received: 14 april 2020 accepted: 1 may 2020 key: cord-345973-fb3gkc0f authors: thibault, ronan; seguin, philippe; tamion, fabienne; pichard, claude; singer, pierre title: nutrition of the covid-19 patient in the intensive care unit (icu): a practical guidance date: 2020-07-19 journal: crit care doi: 10.1186/s13054-020-03159-z sha: doc_id: 345973 cord_uid: fb3gkc0f five to 10% of the coronavirus sars-cov-2-infected patients, i.e., with new coronavirus disease 2019 (covid-19), are presenting with an acute respiratory distress syndrome (ards) requiring urgent respiratory and hemodynamic support in the intensive care unit (icu). however, nutrition is an important element of care. the nutritional assessment and the early nutritional care management of covid-19 patients must be integrated into the overall therapeutic strategy. the international recommendations on nutrition in the icu should be followed. some specific issues about the nutrition of the covid-19 patients in the icu should be emphasized. we propose a flow chart and ten key issues for optimizing the nutrition management of covid-19 patients in the icu. the viral epidemic caused by the new coronavirus sars-cov-2 is responsible for the new coronavirus disease 2019 (covid-19) [1] . up to 30% of the coronavirus sars-cov-2-infected patients are presenting with an acute respiratory distress syndrome (ards) requiring urgent respiratory and hemodynamic support in the intensive care unit (icu) [2] . the coronavirus sars-cov-2 is colonizing the respiratory tract but may also invade the gastrointestinal (gi) tract [3] [4] [5] [6] [7] [8] [9] [10] , neurological system, and kidneys [11] . sars-cov-2 uses the angiotensin-converting enzyme 2 receptor as an entry receptor in the lymphocytes, monocytes, lung alveolar type 2 cells, esophagus epithelial cells, enterocytes, and colonocytes [12] , creating rapid viral replication and cell damage that induce huge inflammation and increased cytokine secretion. in the most severe cases, it leads to a cytokine storm with high proinflammatory cytokine plasma levels [2] . lung histopathological changes are compatible with diffuse alveolar damage. this damage is often lethal. the primacy of the resuscitation measures should not obscure the importance of nutritional care. the length of time for recovery for patients who survive covid-19 is a key factor that nutrition is vital for. icu survivors are staying for long periods [13] . in seattle, survivor patients were ventilated for 10 days (mean) and stay in hospital for 18 days [14] . in lombardia [15] , from 1591 patients requiring icu, the median (iqr) icu length of stay was 9 (6-13) days. therefore, it is expected that covid-19 patients who survived icu would present severe malnutrition and muscle mass loss. the nutritional assessment and the early nutritional care management of covid-19 patients must be integrated into the overall therapeutic strategy, as with any critical illness and rehabilitation program. as there is a covid-19 gi and liver involvement [3] [4] [5] [6] [7] [8] [9] [10] , it may have an effect on nutrition delivery. this review is intended to help icu health professionals to optimize nutrition management of covid-19 patients, especially those with ards. this article was written in the emergency of the epidemic by an expert group, based on the international recommendations on nutrition in the icu on march 29, and will be updated according to new knowledge about the covid-19. the covid-19 patients with the most severe forms as seen in the icu are more frequently elderly and with comorbidities [16] and therefore at major risk of malnutrition and sarcopenia [17, 18] . in the absence of nutritional data specific to covid-19, the following considerations are proposed from the data related to severe respiratory infections: -severe respiratory infections induce inflammatory syndrome and hypercatabolism, with increased energy expenditure linked to ventilatory work, in turn responsible for increased energy and protein requirements; -food intake is very reduced by several factors: anorexia secondary to infection, dyspnea, dysosmia, dysgeusia, stress, confinement, and organizational problems limiting attendance at meals. most covid-19 patients admitted to the icu are at high risk of malnutrition; -infection, hypermetabolism, and physical immobilization expose to rapid muscle wasting. the worsening of malnutrition should therefore be prevented by an appropriate nutritional strategy, including adequate protein-energy delivery and stimulation of physical activity. practical guidance of the nutritional treatment of the patient with covid-19 in the icu [19] should be adapted to the covid-19 epidemic. 3. indirect calorimetry should be proposed only for patients staying for more than 10 days in the icu or those on full parenteral nutrition (pn) to avoid overfeeding. 4. refeeding syndrome (rs) [18, 20, 21] and complications related to propofol use must be prevented. 5. enteral nutrition (en) should be preferred over pn and started within 48 h of admission. 6. gastric en is generally possible, including in the prone position, and should be preferably performed using a pump with flow regulator. 7. pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making. 8. the use of en enriched with omega-3 fatty acids should be preferred in case of ards. fish oilenriched intravenous fat emulsions should be prescribed if pn is required. 9. after extubation, the nutritional support is promoting patient's recovery and rehabilitation and should be continued until the patient resumes sufficient oral intake. 10. physical activity should be promoted to preserve muscle mass and function. covid-19 is a disease at high risk of malnutrition. the most severe cases are encountered in particular, but not exclusively, in patients with a chronic disease (such as organ failure, obesity with body mass index ≥ 40, type 2 diabetes or cancers), who are elderly, and/or with polypathologies [2, 16] . these diseases often mask underlying protein malnutrition (sarcopenia). malnutrition is a factor of poor prognosis and should therefore be actively investigated, even in the absence of specific literature concerning covid-19. nutritional evaluation based on the global leadership initiative on malnutrition (glim) [19] should be adapted to the covid-19 epidemic the 2018 international consensus for malnutrition diagnosis by glim defined new criteria for the diagnosis of malnutrition [19] . according to the glim criteria, a patient is malnourished if he/she has at least one phenotypic criterion and at least one etiologic criterion. phenotypic criteria are body mass index < 20 (or < 22 if age ≥ 70 years) or weight loss > 5% within past 6 months or > 10% beyond 6 months or reduced muscle mass; etiologic criteria are reduced food intake (≤ 50% in > 1 week or reduced food assimilation (malabsorption or previous history of gi surgery) or acute disease/injury/ chronic disease-related inflammation. in the context of the covid-19 epidemic, the phenotypic criteria are poorly applicable: -because of the risk of increased viral transmission by patient contacts, weight machine and height chart are difficult to use since they must be decontaminated after each use. icu beds with integrated weight system define body weight difficult to interpret due to the fluid overload, especially in case of severe hypoalbuminemia or shock resuscitation. -similarly, bioelectrical impedance analysis and measurement of muscle strength by handgrip dynamometry are not recommended in covid-19 patients due to the risk of increased viral transmission by patient contacts. therefore, the nutritional screening at admission should be based on: -patient's or relatives' interview to determine recent weight loss before admission and body mass index. if possible, food intake may also be quickly and easily assessed with semi-quantitative methods: an analogue scale between 0 and 10/10 [22] or consumed portions (0, ¼, ½; 1) during the last lunch or dinner, as did in the nutritionday survey [23] ; taking < 7/10 should alert to likely malnutrition [22] . moreover, two etiologic criteria for malnutrition diagnosis (according to glim recommendations [19] ) are obvious in the covid-19 patients: -covid-19, as an "acute disease," is associated with acute inflammation. -according to the more recent data [24] , hypoalbuminemia is associated with a worse prognosis of covid-19. indirect calorimetry (ic) should be proposed only for patients staying for more than 10 days in the icu or those on full parenteral nutrition (pn) to avoid overfeeding ic is the reference method to assess the energy requirements in the non-covid-19 icu patients [18] . however, in the context of the covid-19 epidemic, but depending on location, some icus experience massive overload of covid-19 patients. that context precludes the performance of any sophisticated non-vital methods at the early phase of icu stay. moreover, there is still an uncertainty regarding the safe use of ic, as the usual decontamination procedures cannot be guaranteed in an epidemic context. therefore, committed ic devices and virus filters for covid-19 patients only should be considered when possible. to avoid exposure to aerosol and potential virus contamination during ic device connection/disconnection, our recommendations are, previous to connection to the ic device, to put the ventilator on standby and to clamp the tube, then connect and when connected to declamp the tube and to restart the ventilator. this way is preventing the potential spread of virus during disconnection/connection. therefore, in these conditions, we propose that ic should be performed to all patients after 3-4 days in the icu. depending on staff organization and material availability, patients staying longer than 10 days in the icu or those on full pn should be the priority. indeed, the patients on full pn are the most at risk of developing the serious complications related to overfeeding (hyperglycemia, hypertriglyceridemia, bacteremia, liver injury). alternatively, to determine calorie and protein needs, we propose the use of predictive equations according to weight (fig. 1) . introduction of nutrition support should be phased according to day (fig. 1) . the ultimate goal is to avoid underfeeding or overfeeding. importantly, obesity is associated with severe forms of covid-19. in the icu, obesity is also associated with increased protein catabolism as compared with nonobese patients [25] . it is therefore even more necessary to avoid restrictive and hypocaloric nutrition in obese patients. underfeeding is more likely in obese patients: obese patients often have increased energy expenditure compared to non-obese [20] ; initiation of nutritional support is often delayed in obese icu patients [21] . in obese icu patients, rapid weight loss would be associated with increased loss in muscle mass, weakening the immune defenses and therefore promoting covid-19 severity. refeeding syndrome (rs) [18, 26, 27] and complications related to propofol use must be prevented the rs is underestimated at icu admission [28] . covid-19 patients are often vulnerable (old, polymorbid, malnourished, sarcopenic) [29] and frequently unwell for 9-15 days [13, 30] , i.e., presenting fever, asthenia, lack of appetite, reduced food intake, leading to energy deficit before their icu admission. these characteristics promote the risks of electrolyte imbalances (i.e., refeeding syndrome). we propose to detect/prevent the rs in older patients, those with polymorbidity, no/low food intake for > 5 days, preexisting malnutrition, and abnormal electrolytes due to diuretic treatment and dialysis. plasma potassium, phosphorus, and magnesium should be measured within 6 h after nutrition support is started to detect and treat low values. for refeeding guideline, please refer to the uk national institute for health and care excellence (nice) guidelines [31] https://www.evidence.nhs.uk/search?pa= 2&q=refeeding+syndrome. specific advices regarding patients under propofol should be stated here. all the sedative drugs, including propofol and benzodiazepines, have immunosuppressive effects [32] . the "propofol infusion syndrome" (pris) is a rare complication observed when propofol is used for > 48 h and at high doses (> 4 mg/kg/h) and must be evoked in case of hemodynamic degradation or lactic acidosis without any other causative factor. the monitoring every 72 h of arterial gazometry, plasma lactate, creatine phosphokinase, and triglycerides allows anticipating the risk of pris and stop propofol. in the covid-19, the cytokine storm could lead to hemophagocytosis that could itself increase plasma triglyceride, independently from propofol use. plasma triglyceride monitoring at least every 72 h is advised in all icu covid-19 patients. moreover, propofol doses should be controlled and alternative sedation should be used if the doses are too high or the treatment is prolonged. large administration of omega-6 fatty acids is not recommended in the context of strong inflammatory response to virus load. as usually recommended in the icu [18, 33] , en should be preferred over pn. a lack of consensus among international academic societies exists about the best timing to start nutrition support after icu admission. the main reason is the heterogeneity of the icu patients (age, severity of disease, medical versus surgical cares, preexisting malnutrition, chronic diseases). all over the world, icu covid-19 patients are rather similar in terms of vulnerability (older, chronic diseases, low food intake for 5-10 days) [2, 16] and likelihood of prolonged icu stay on mechanical ventilation [14, 15] . these characteristics support the indication for early (< 48 h after admission) and progressive increase of nutrition support (usually enteral) to reach an energy target by day 4-6 days, depending on tolerance (fig. 1) . this is in line with the main available international guidelines for nutrition during critical illness and covid-19 [27] https://www.nutritioncare.org/ uploadedfiles/documents/guidelines_and_clinical_resources/nutrition%20therapy%20covid-19_sccm-aspen.pdf, https://www.auspen.org.au/auspen-news/2 020/4/6/covid-19-information. the polymeric standard en formulas should be used like in other icu patients. if polymeric en administration is associated with diarrhea, semi-elemental en can be tested as second line. to our knowledge, there is no specific indication for arginine in icu covid-19 patients. as a meta-analysis [34] reported that arginine increases mortality in sepsis and pneumonia patients, arginine should not be used in covid-19 patients. gastric en is generally possible, including in the prone position, and should be preferably performed using a pump with flow regulator in the context of ards, en is frequently delivered in the prone position. this is associated with an increased risk of gastroparesis and vomiting. all should be done to optimize en (fig. 1) . in the context of the use of hydroxychloroquine associated with azithromycin as an antibiotic therapy against the sars-cov2 virus, the preferable prokinetics is metoclopramide, to avoid any drug side effect and interferences. en during prone position has been shown to be safe in terms of large gastric residue, vomiting, or intolerance [35] . the prone position per se does not represent a limitation or contraindication for en and is recommended by the espen guidelines [18] . according to a meta-analysis [8] , 17% of the patients with severe covid-19 had gi symptoms (95% ci, 6.9-36.7%), in line with other findings [3] [4] [5] [6] [7] . in the metaanalysis, stool samples were positive for sars-cov-2 virus dna in 48.1% of the cases (95% ci, 38.3-57.9%) [8] . however, there is no evidence that covid-19 patients with recent history of diarrhea, abdominal pain, nausea, and vomiting should be contraindicated to en. in case of en intolerance, nutrition delivery should be adapted as described in this section and the "pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making" section. according to the severity of gi symptoms, en should be temporarily stopped or reduced or combined/switched to supplemental or total pn. we do not advise the systematic measurement of gastric residual volumes (grv). in ventilated patients, not measuring grv was not associated with an increased risk of ventilator-associated pneumonia [36] . aspen (https://www.nutritioncare.org/uploadedfiles/doc uments/guidelines_and_clinical_resources/nutrition%2 0therapy%20covid-19_sccm-aspen.pdf) and aus-pen (https://www.auspen.org.au/auspen-news/2020/4/6/ covid-19-information) experts are advising measuring grv for all prone patients, those under vasopressors or with gi covid-19. however, there is no clear evidence to support this. therefore, as viral load may be present in gastric contents, the number of grv measurements should be reduced. grv may not be measured in those patients with stable hemodynamic or low dose of vasopressors, including those in the prone position. for others, the decisions should be made case by case, in accordance with the usual icu department protocols. feeding tube placement and grv measurement are agp. gastric content and stools can contaminate health professionals. therefore, introduction of nasogastric or postpyloric tube, grv measurement, or handling of stools should be made very cautiously according to strict protection protocols. in ventilated patients with insufficient sedation, it could happen that patients are agitated, coughing, or vomiting during the tube placement procedure. these patients should be better sedated or paralyzed before the feeding tube placement. in case gastric en is complicated with vomiting or gastroparesis, jejunal en may be considered. however, the nasojejunal tube placement is very challenging as it is an agp. therefore, any procedure requiring transfer to radiology suites or endoscopy should be avoided. only bedside introduction of nasoduodenal or nasojejunal tubes may be recommended, but they are not always available or successful. we may rather recommend the use of pn in case en is not tolerated (see the "pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making" section). en should be performed as much as possible using a pump with flow regulator. in the event of a shortage of pumps with flow regulator, it is necessary to reserve them as a priority for the icus. in non-intubated patients, it seems preferable to not use en rather than doing it without pumps with flow regulator, because of the risk of aspiration pneumonia. indeed, underfeeding is likely to have less severe consequences than aspiration pneumonia. a recent retrospective study has shown that early en in paralyzed patients was associated with less hospital mortality, and there is no increase in ventilator-associated pneumonia [37] . however, in this study, paralysis duration was short: 48 h. in covid-19 patients, paralysis is usually longer. there is no data about how to feed the icu covid-19 patients who are paralyzed for > 48 h. in our experience, there is no increase in en complications in these patients. therefore, we propose to adapt nutrition support as generally done in case of gi intolerance (see the "pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-by-case decision making" section). as there is no data about feeding under vasopressors in the icu covid-19 patients, we propose to refer to a recent review [38] and follow the espen recommendations [18] : "the use of concomitant vasopressors (especially with stable or decreasing doses) should not preclude a trial of en […]. in very unstable patients, en may not have priority." pn is indicated if en is impossible, contraindicated, or insufficient and should be prescribed using a case-bycase decision making as usually recommended in the icu [18, 33] , pn is indicated whenever en is impossible or contraindicated or in addition to en as long as it is insufficient (supplemental pn). many patients are still receiving high-flow nasal cannula (hfnc) therapy or non-invasive ventilation in many centers [39, 40] . from a practical point of view, based on the chinese experience [39] , these patients are almost not fed orally or enterally. therefore, we could advocate the use of pn arguing that "being fed by pn" is better than "being not fed." as most severe patients have a central line, pn should be administered through a central venous line. in case there are too many drugs on the central line, peripheral pn could be used. in the specific context of covid-19, the use of supplemental pn could be advocated if en in the prone position is associated with vomiting, in case of severe hypoxemia (pao 2 /fio 2 < 50 mmhg with fio 2 > 80%), or in general, in the situation when the gut is not functioning [18, 41] (fig. 1) . in that context, supplemental pn should not be started before day 4 [18] . as a general principle and as the covid-19 is a new and unknown disease, we also advocate that pn would be prescribed using a case-by-case decision making, always having in mind that pn is at high risk of overfeeding and hyperglycemia over 10 mmol/l that must be avoided [18, 42] . mild-to-moderate liver injury, including elevated amino transferases, hypoproteinemia, and prothrombin time prolongation, is a sign of severe covid-19 [10] . liver function tests should be monitored like in any other icu patients receiving en or pn. the use of en enriched with omega-3 fatty acids should be preferred in case of ards. fish oil-enriched intravenous fat emulsions should be prescribed if pn is required a systematic review and meta-analysis on fish oil (fo) enteral supplementation suggests an advantage for eicosapentaenoic acid (epa) and docosahexaenoic acid (dha) acid supplementation in ards patients in terms of length of ventilation and length of icu stay, but not mortality [43] . however, these conclusions were based on low-quality studies. a cochrane analysis found that enteral epa and dha may improve oxygenation and length of ventilation and length of stay, but these findings were mainly based on low-quality evidence studies [44] . negative outcome associated with administration of enteral fo has been only observed when administered in a bolus and with a low protein regimen [45] . the immunoregulator effects of epa and dha may have a beneficial impact in the severe cytokine storm observed in sars-cov-2 ards. therefore, we suggest that en enriched with 3.5 g/day epa and dha can be administered in this disease, not in a bolus. higher amounts up to 9 g/day have been administered safely [43] . fo-based intravenous lipid emulsions have been extensively analyzed in a meta-analysis [46] including 49 prospective randomized controlled studies with intervention groups receiving omega-3 fatty acids compared to standard intravenous lipid emulsions (iles), as a part of pn covering > 70% of the energy provision. mortality was not decreased significantly, but a significant decrease was observed in relative risk of infection (40% lower) with omega-3 fatty acid-enriched iles, in icu and in hospital lengths of stay. risk of sepsis was also reduced by 56%. this latest analysis increases our knowledge on foenriched lipid emulsions. if pn including iles is required in this population suffering from covid-19 ards, foenriched lipid emulsions should be prescribed. the provision of omega-3 fatty acids increases the epa and dha plasma levels [47] . the recommended fo doses are 0.1-0.2 g/kg/day. after extubation, the nutritional support is promoting patient's recovery and rehabilitation and should be continued until the patient resumes sufficient oral intake after extubation, the nutritional strategy must be adapted according to certain situations. after a median of 28 days at hospital [13] [14] [15] 30] , patients are likely to be malnourished. in most patients, en should be continued as patients are transitioned to oral diet but not sufficiently to cover their protein-energy needs. this is critical to enhance covid-19 recovery. post-extubation swallowing disorders are frequent-10 to 67% of patients [17] -and at risk of insufficient oral intake, therefore malnutrition. after extubation, approximately 24% of elderly patients require en in addition to their oral food intake [18] . in the context of the covid-19 epidemic, this proportion would be expected to be higher, due to prolonged resuscitation and the intensity of the inflammatory and catabolic syndrome. based on the espen recommendations [18] , we propose the following: -in any situation: in case of dysphagia, provide a diet with a suitable texture. the energy and protein intake must be adapted to the needs. a suitable physical activity or muscle strengthening exercising must be offered. -in case of post-extubation swallowing disorders: continue en but assess the risk of aspiration pneumonia. if there is, try to carry out en at the postpyloric site. if en is not possible (e.g., if swallowing rehabilitation may require removal of the feeding tube), propose a temporary pn. -in case of tracheostomy: favor oral, fractional, enriched feeding with oral nutritional supplements. if the energy and protein needs are not covered (< 70% of the needs), consider supplemental pn by avoiding overnutrition and hyperglycemia > 10 mmol/l. depending on the individual clinical condition, mobilization at bedside will be encouraged to preserve muscle reserves and function and enhance recovery. it will be adapted to the patient's capacity for autonomy, in a context of limited availability and access by physiotherapists for priority respiratory care. mobilization will be intensified as soon as the clinical improvement allows. optimized nutrition care of the icu covid-19 patients is important to maintain gi tract function, sustain immune defenses, and avoid severe loss of muscle mass and function. as for any other icu patients, the latter is crucial to promote short-and long-term recovery. dedicated studies about the nutrition in the covid-19 patients are now awaited to enrich our knowledge about the metabolism of this new disease and adapt the nutrition support strategy. a novel coronavirus from patients with pneumonia in china clinical features of patients infected 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route of 2019-ncov infection: a bioinformatics analysis based on single-cell transcriptomes clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study covid-19 in critically ill patients in the seattle region -case series baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region are patients with hypertension and diabetes mellitus at increased risk for covid-19 infection? espen guideline on clinical nutrition and hydration in geriatrics espen guideline on clinical nutrition in the intensive care unit glim criteria for the diagnosis of malnutrition -a consensus report from the global clinical nutrition community measured energy expenditure compared with best-practice recommendations for obese, critically ill patients-a prospective observational study initiation of nutritional support is delayed in critically ill obese patients: a multicenter cohort study use of 10-point analogue scales to estimate dietary intake: a prospective study in patients nutritionally at-risk decreased food intake is a risk factor for mortality in hospitalised patients: the nutritionday survey clinical and biochemical indexes from 2019-ncov infected patients linked to viral loads and lung injury obesity and the metabolic response to severe multiple trauma in man monitoring nutrition in the icu espen expert statements and practical guidance for nutritional management of individuals with sars-cov-2 infection refeeding syndrome in the critically ill: a literature review and clinician's guide presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the newyork city area clinical course and risk factors for mortality of adult incovid-19 patients in wuhan, china: a retrospective cohort study refeeding syndrome: what it is, and how to prevent and treat it immunosuppressive aspects of analgesics and sedatives used in mechanically ventilated patients: an underappreciated risk factor for the development of ventilator-associated pneumonia in critically ill patients guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition should immunonutrition become routine in the critically ill patient? a systematic review of the evidence enteral nutrition in patients receiving mechanical ventilation in a prone position effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial early enteral nutrition in patients undergoing sustained neuromuscular blockade: a propensity-matched analysis using a nationwide inpatient database enteral nutrition can be given to patients on vasopressors novel coronavirus pneumonia diagnosis and treatment plan surviving sepsis campaign on the management of critically ill adults with coronavirus disease 2019 (covid-19) early enteral nutrition in critically ill patients: escim clinical practice guidelines parenteral nutrition in the critically ill patient current evidence on ω-3 fatty acids in enteral nutrition in the critically ill: a systematic review and metaanalysis immunonutrition for acute respiratory distress syndrome (ards) in adults nih nhlbi acute respiratory distress syndrome network of investigators 2011 enteral omega-3 fatty acid, and linolenic acid, and antioxidant supplementation in acute lung injury ω-3 fatty-acid enriched parenteral nutrition in hospitalized patients: systematic review with meta-analysis and trial sequential analysis four-oil intravenous lipid emulsion effect on plasma fatty acid composition, inflammatory markers and clinical outcomes in acutely ill patients: a randomised control trial (foil fact) publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions ronan thibault, philippe seguin, fabienne tamion, claude pichard, and pierre singer drafted the article. the author(s) read and approved the final manuscript. availability of data and materials not applicable ethics approval and consent to participate not applicable consent for publication not applicable key: cord-335033-cwhm7v0s authors: vergano, marco; bertolini, guido; giannini, alberto; gristina, giuseppe r.; livigni, sergio; mistraletti, giovanni; riccioni, luigi; petrini, flavia title: clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the italian perspective during the covid-19 epidemic date: 2020-04-22 journal: crit care doi: 10.1186/s13054-020-02891-w sha: doc_id: 335033 cord_uid: cwhm7v0s nan on february 21, 2020, the first person-to-person transmission of severe acute respiratory syndrome coronavirus 2 (sars-cov2), the virus causing coronavirus disease 2019 (covid-19), was identified in italy. in the following days, despite the restrictive public health measures applied to avoid the spread of the infection [1] , the number of cases sharply increased. as of march 8, 2020, italy was the 2nd most affected country in the world. in one of the largest reports from china, 5% of covid-19 patients required admission to the intensive care unit (icu) [2] . since the beginning of the covid-19 outbreak, the availability of icu beds has been recognized as one of the major public health concerns in italy, where a total of 5090 icu beds (8.42/100,000 inhabitants) were reported in 2017 [3] . despite further efforts have been done to contain the number of cases and extraordinary measures have been put in place, the dramatic increase of icu admission abruptly overwhelmed the icu capacity, mostly in lombardy and in the nearby regions of northern italy. from the evidence available so far, a considerable proportion of subjects diagnosed with covid-19 infection requires ventilatory support due to severe hypoxemia in the context of interstitial pneumonia. the interstitial lung disease is potentially reversible, but the acute course of the disease can last several days, and ventilatory support may be needed for weeks [4] . these clinical considerations imply that caring for patients with severe pneumonia from covid-19 can be very demanding in terms of the number of devices and staff required. as of march 6, 2020, the italian society of anesthesia, analgesia, resuscitation and intensive care (siaarti) issued a series of recommendations [5] and relevant ethical considerations to better inform the clinicians involved in the care of critically-ill covid-19 patients, in a setting where a disproportionate number of patients requiring life-sustaining treatments was rapidly saturating both the existing and the newly set-up icu beds. the most relevant recommendations are summarized in table 1 . the emerging epidemic is leading to a substantial increase in the number of patients requiring prolonged ventilatory support for acute respiratory failure, potentially resulting in severe imbalances between the population clinical needs and the overall availability of icu resources. in this scenario, criteria for icu admission (and discharge) may need to be driven not only by the principles of clinical appropriateness and proportionality of care, but also by criteria of distributive justice and appropriate allocation of the healthcare resources, that may be more limited than usual. the primary aim of these recommendations is therefore to supply a common framework for the admission of patients to intensive care treatments in resource-limited circumstances. these recommendations should be shared maximally within all the involved healthcare providers. bioethical reasoning has inspired several operative instructions for the field of disaster medicine. in this area, healthcare providers must be supported during their difficult decision-making process. as an extension of the principle of proportionality of care, in the context of a severe shortage of icu resources, these should be preferentially allocated to patients with the higher possibility of therapeutic success. therefore, the aim is to privilege the greater chance to successfully overcome critical illness with a greater probability to maintain a good quality of life. a single patient's actual need for icu treatments should be therefore integrated with additional criteria for icu admission, taking into account the type and severity of the current disease, comorbidity, the presence and reversibility of organ failures, and the potential for recovery. it follows that within the foregoing context, the "first come, first served" criterion for icu admission does not necessarily have to be followed. because of the rare occurrence of large-scale catastrophic events, the healthcare staff may not be very familiar with the criteria applied for triage during mass casualty events. the availability of resources may not always be part of the clinical decision-making process operated on a single patient, until resources become so limited that it is not possible to treat all patients who may hypothetically benefit from a specific treatment. the application of restrictive (rationing) policies is justifiable only if all the relevant stakeholders ("task forces," hospitals, institutions) have already tried to increase the availability of resources and have already assessed the feasibility and safety to transfer patients to other hospitals. as previously mentioned, a change in the icu admission policy should be shared maximally among the staff involved. moreover, the patients who are affected by the application of new, more stringent criteria of eligibility for icu admission (and/or their proxies) should be allocation of icu resources is a complex and delicate task. criteria for icu admission and discharge under exceptional, resource-limited circumstances must be flexible and should be locally adapted according to the availability of resources, the potential for inter-hospital patient transfer, and the ongoing or foreseen number of hospital and icu admissions. these criteria apply to every patient potentially in need of icu admission, not only to covid-19 infected patients. triage principles and criteria age, comorbidities, and the functional status of any critically ill patient should carefully be evaluated. a longer and, hence, more "resource-consuming" clinical course may be anticipated in frail elderly patients with severe comorbidities, as compared to a relatively shorter and potentially more benign course in healthy young subjects. the underlying principle would be to save limited resources which may become extremely scarce for those who have a much greater probability of survival and life expectancy, in order to maximize the benefits for the largest number of people. in the worst-case scenario of complete saturation of icu resources, a "first come, first served" criterion is not recommended, as it would ultimately result in denying access to icu care to a large number of potentially curable patients. the presence of advance healthcare directives or advance care planning should be carefully evaluated, especially for patients affected by severe chronic illnesses. these plans should be shared as much as possible between the patient, their proxies, and all the healthcare staff involved in patient care. a decision to deny admission to the icu by applying a "ceiling of care" should always be motivated, communicated, and documented. the decision to withhold invasive mechanical ventilation does not necessarily imply that other, non-invasive, modalities of ventilatory support should also be withheld. the decision to withhold or withdraw life-sustaining treatments must always be discussed and shared among the healthcare staff and, when possible, the patients and/or their proxies. a second opinion (e.g., from regional healthcare coordination centres, or from other recognized or designated experts) may be useful when dealing with particularly difficult or distressing cases. appropriate palliative care must always be provided to hypoxemic patients when a decision to withhold or withdraw life-sustaining treatments is made. palliative care should be provided according to national or international recommendations, as a matter of good clinical practice. every admission to the icu should be considered and communicated as an "icu trial." the appropriateness of life-sustaining treatments should be re-evaluated daily, considering the patient's history, current clinical course, wishes, expected goals, and proportionality of icu care. when a patient is not responding to prolonged lifesustaining treatments, or severe clinical complications arise, a decision to withhold or withdraw further or ongoing therapies should not be postponed in a resource-limited setting during an epidemic. networking and family care networking among healthcare professionals is essential to share clinical expertise. dedicated time and resources should be anticipated for team debriefing and monitoring of burnout symptoms or moral distress among the healthcare staff once time permits. also, the impact of restricted visiting policies on families and proxies should be considered, especially when the death of a loved one occurs during times of complete restriction of family visits. informed of the extraordinary nature of the measures in place, as a matter of duty of transparency and to maintain confidence in the health service. an additional aim of the recommendations is to support the clinicians when dealing with individual patients, as hard and complex decisions may be ethically and emotionally demanding. the response of milan's emergency medical system to the covid-19 outbreak in italy clinical characteristics of coronavirus disease 2019 in china italian ministry for health. statistical report on the national health service clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study siaarti clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations all the authors contributed to the draft and the critical revision of the article and provided final approval of the version submitted for publication. the authors did not receive any funding for this project.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare no competing interests.author details key: cord-323327-08p122lw authors: van de veerdonk, frank l.; netea, mihai g. title: blocking il-1 to prevent respiratory failure in covid-19 date: 2020-07-18 journal: crit care doi: 10.1186/s13054-020-03166-0 sha: doc_id: 323327 cord_uid: 08p122lw covid-19 is an emerging disease that can manifest itself as asymptomatic or mild respiratory tract infection in the majority of individuals, but in some, it can progress into severe pneumonia and acute respiratory distress syndrome (ards). inflammation is known to play a crucial role in the pathogenesis of severe infections and ards and evidence is emerging that the il-1/il-6 pathway is highly upregulated in patients with severe disease. these findings open new avenues for host-directed therapies in patients with symptomatic sars-cov-2 infection and might in addition to antiviral treatment be enough to curb the currently unacceptably high morbidity and mortality associated with covid-19. although the majority of patients with covid-19 are asymptomatic or have mild sars-cov-2 infections, many patients have been hospitalized and admitted to intensive cares (icus) and mortality is significant. understanding this outbreak, including the effectiveness of supportive, immune-modulatory, and antiviral treatments, is essential. an important aspect of severe covid-19 is a hyperinflammatory status, and immunomodulatory therapy might therefore be an important aspect in the treatment of covid-19. although icu patients have been treated with glucocorticoids, some experts have even argued, based on studies in middle-eastern respiratory syndrome coronavirus (mers-cov), severe acute respiratory syndrome (sars), influenza, and respiratory syncytial virus (rsv), that they are likely to do more harm than good [1, 2] . however, a more recent study showed that early short-course corticosteroids during admission were associated with fewer icu admissions [3] , and a yet to be published study on dexamethasone argues that it can save lives especially in mechanically ventilated patients. other immune modulatory treatments of interest include blocking the il-1 or il-6 pathway, the use of interferon-β, and many others. there are currently only small observational trials that contribute to the evidence for the benefit or harm of these interventions in covid-19. in addition to the lack of available treatments known to be effective, insight into the pathophysiology of this coronavirus needs to be urgently addressed. this is essential in the pathway towards developing new, or repurposing existing, therapies that can be used in the treatment of patients with sars-cov-2. the novel coronavirus sars-cov-2 is highly likely to have similarities to other coronaviruses such as sars-cov, with which it has the strongest sequencing similarities, and other severe respiratory virus infections such as influenza. the most severely ill patients infected with sars-cov or influenza seem to develop an immune phenotype that can be described as an inflammasomemediated hyperinflammatory status, causing respiratory failure and secondary infections [4] [5] [6] [7] [8] [9] . autopsy in young, previously healthy, patients that died during the h1n1 influenza 2009 pandemic revealed evidence of "cytophagocytosis" in the lung [10] . this phenomenon is a hallmark of macrophage activation syndrome (mas), or named secondary hlh (shlh) [11, 12] . lethal complications of influenza are consistent with inflammasome-mediated disease with signs of mas [11, [13] [14] [15] . inflammasomes are protein complexes that activate caspase-1 protease that in turn processes proinflammatory cytokines from the il-1 family (e.g., il-1β, il-18) into active cytokines. a whole-exome study performed in fatal cases of h1n1 with signs of mas found a high percentage of mutations in genes that are linked to genetic causes of diseases similar to mas/hlh, suggesting that the genetic background of the patient predisposes to developing mas in influenza [16] . underscoring the importance of the inflammasome/ il-1 pathway in mas is the observation that a monogenetic mutation in the inflammasome underlies primary mas [17] . in the case series of critically ill patients with sars from toronto and singapore, ards and multiple organ failure were frequently observed [8, 18] . ards was thought to be due to an exacerbated innate host response to sars-cov [19, 20] . similar pulmonary hyperinflammation was seen on the histology in mers patients [21] . lung histology in covid-19 shares similarities to sars, mers, and influenza [22] . another study revealed high il-18-circulating concentrations [23] , a cytokine that is associated with mas [24] , and mas has also been reported in sars [25] . in sars-cov-2 infection, elevated il6 and ferritin concentrations have also been described [26] . in other studies with sars-cov-2 pneumonia, patients that needed icu admission more often had leukocytosis, higher neutrophil counts, lower lymphocyte counts, elevated d-dimer, and highly elevated ldh, and the main reason patients were admitted to the icu was ards [27] [28] [29] . however, currently, it becomes clear that only a minority of patients with covid-19 develop mas/hlh. many other patients show signs of a cytokine storm syndrome, but do not fulfill the criteria of mas/hlh. we and others have identified an il-1/il-6-driven innate immune response [30] [31] [32] [33] [34] [35] [36] . interestingly, tnf concentrations in plasma were not significantly elevated in the early stages of disease in critically ill patients compared to patients admitted to the ward: median 24.0 pg/ml [iqr 16.5-33.5] and 21.5 pg/ml [iqr 16.0-33.5], respectively [30] . this might explain that hemodynamic instability is not a classical presentation of covid-19, since both tnf and il-1 as cytokines are needed to cause hemodynamic problems [37] , arguing that the hyperinflammatory innate immune response initially is mainly an overactive il-1/il-6 response. also, the classical coagulopathy associated with covid-19 is different by not fulfilling the criteria of classical diffuse intravascular coagulopathy (dic), despite d-dimers being profoundly elevated in many critically ill patients [38] . this all points to a unique underlying pathophysiology in covid-19 that might be partially explained by the local ace2 deficiency in the lung and subsequent effects on the kallikrein-kinin system [39] . next to inflammation and coagulopathy, covid-19 has a clear vascular component with an "endothelitis" that has been observed in the lungs of patients that died [22, 40] . these are unique features of the disease, underscoring that sars-cov-2 can infect and inflame endothelial cells and make blood vessels leak. clinical and laboratory features of mas include sustained fever, hyperferritinemia, and high il-18 concentration in circulation, pancytopenia, fibrinolytic consumptive coagulopathy, and liver dysfunction [11, 12, 24] . controlling this excessive immune activation and organ damage can be achieved in various ways. with mas in the context of other triggers, the focus of treatment is on interrupting the cytokine storm, because cytokines such as il-1 maintain the persistent drive of inflammasome activation (fig. 1) . il-1 can induce production and release of more il-1, a process described as an autoinflammatory loop (fig. 1) . breaking this loop can be done by corticosteroids or chemotherapy and has been suggested for h5n1 infection [41] . however, these treatment strategies will also impair host defense against bacteria and fungi and will make patients prone to secondary infections that are a major cause of death of complicated viral pneumonitis [4, 6] . one of the safest ways to stop this overwhelming innate immune response can be accomplished by using il-1 receptor (il-1r) blockade or drugs that target il-1 signaling [42, 43] . this approach, especially for the treatment of secondary mas without underlying cancer, has recently been reported [44] . anakinra is a bio-engineered form of the naturally occurring interleukin-1 receptor antagonist (il-1ra) that blocks the action of interleukin-1 (fig. 1) . it is routinely used in patients with autoimmune and inflammatory disorders and mas [44] . anakinra has been used in several studies for sepsis and septic shock. studies that recruited in total almost 2000 patients demonstrated that although anakinra did not reduce the overall all-cause mortality, survival was increased in the subgroup of sepsis patients with features of mas (ferritin elevations in excess of 2000 ng/ml, coagulopathy, and liver enzyme elevations) [45] [46] [47] [48] . its safety profile and wide therapeutic margin on the one hand, and the central role of il-1 in the cytokine storm of mas on the other hand, warrants assessing anakinra as a potential therapeutic in severe coronavirus infection [49] . in tracking the effectiveness of the treatment, ferritin and il-18 circulating concentrations are accepted biomarkers. ferritin is an established laboratory test that is available in almost all hospitals in the western world and can thus provide a simple and rationale biomarker for the development and resolution of mas and can be used to follow the effect of anakinra on mas-like inflammation in covid-19. it has recently been suggested to be aware of mas and use a hscore to calculate and consider immunosuppressive treatment such as corticosteroids, anakinra, tocilizumab, or jakinibs [50] . a recent study showed that treating patients with covid-19 that fulfilled these criteria with anakinra showed a beneficial response compared to historical outcomes [51] . however, three patients out of 8 died in spite of treatment, and patients who full-fill these criteria are likely to be so severely ill that any single intervention has a very marginal chance to drastically improve the outcome. in addition, a case series of 3 patients with leukemia were treated with anakinra based on extreme ferritin levels and hyperinflammatory status with beneficial clinical effects [52] , and a case series of 5 patients with severe covid-19 also showed a response to anakinra [53] . we propose to use immunomodulatory therapy with anakinra in an earlier phase then after admission on the icu. first, the start of early treatment will prevent shlh instead of treating it, which gives a better chance to the patient to survive this very severe complication. second, anakinra has only mild immunosuppressive effects since it does not decrease the capacity to clear bacterial or fungal infections, and there are even data to support the assumption that blocking il-1 might increase certain components of dysregulated host defense [54, 55] . moreover, in contrast to jakinibs, anakinra will not directly block the ifn-stat1/stat2 pathway critical for host defense against viral infections. third, in contrast to tocilizumab (an il-6 inhibitor), it targets and inhibits the core mechanism in the pathogenesis of mas, namely the hyperactive inflammasome loop (fig. 1 ). in addition, anakinra will decrease il-6 production since il-1 is a potent inducer of il-6, and thus, the suggested beneficial effects of tocilizumab are likely to be seen also in anakinra. anakinra will not only block il-1β but also il-1α which is released due to epithelial and endothelial damage and, in this way, targets the tissue-driven inflammatory response. finally, the safety profile of anakinra is very good and the short half-life makes it possible to stop fast once undesired effects are seen such as neutropenia, which is not possible with tocilizumab. these arguments have led to the selection of anakinra as an immunomodulatory treatment option in several ongoing trials. a recent and larger study supports the use of anakinra in covid-19 fig. 1 rationale for use of anakinra in severe coronavirus. the sars-cov-2 will cause epithelial damage leading to the release of il-1α that will (1) recruit neutrophils and monocytes to the site of infection and (2) induce il-1β in monocyte/macrophages. moreover, the 2019 ncov will induce pro-il-1β in monocyte/macrophages which in turn will induce more il-1 that will recruit and activate more innate immune cells. this autoinflammatory loop where il-1 (il-1α and il-1β) can induce production and release of more il-1 has to be tightly regulated because an ongoing loop will activate and recruit more innate immune cells independent of the initial trigger. anakinra blocks the il-1 receptor (il-1r) and thus will prevent autoinflammation by blocking effects of il-1α released from dead epithelial cells, as well as il-1β produced by immune cells. il-1-induced il-6 will also be blocked. the autoinflammatory loop can exacerbate from increase innate immune response into uncontrolled mas a spectrum that associates with increasing ferritin levels van de veerdonk and netea critical care (2020) 24:445 patients in the early phase and reports that high dose intravenous anakinra started in patients outside of the icu was safe and resulted in clinical benefit in 72% of patients [56] . another recent covid-19 study included 52 consecutive patients for anakinra treatment and 44 historical patients. admission to the icu for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group and the treatment effect of anakinra remained significant in the multivariate analysis [57] . treating patients that are critically ill during a pandemic with a novel pathogen is a major challenge. as long as we do not have a vaccine or effective antiviral drugs, we need other strategies to help patients with covid-19. one strategy that is urgently needed is to prevent disease progression from symptomatic to icu. in the icu, covid-19 has many features including thromboembolic events, fibrosis, and "endothelitis," conditions that are all difficult to treat. we propose that targeting the innate inflammatory response with anakinra in combination with supportive care and the best antiviral available could result in a drastic decrease of icu admissions. one pitfall to date could be that using anakinra only in shlh as proposed [50] might fail to help patients because shlh is already associated with a high mortality despite treatment. we propose that when a clinician considers to dampen hyperinflammation with anakinra, this should be done on the ward or at entry of icu due to several strong arguments: its safety profile and clinical experience in sepsis, the rationale to prevent full-blown shlh, and the possibility to stop the drug without having undesirable long-term effects of anakinra. flvdv and mgn have both reviewed the literature and wrote the review. the authors read and approved the final manuscript. availability of data and materials not applicable. ethics approval and consent to participate not applicable. not applicable. clinical evidence does not support corticosteroid treatment for 2019-ncov lung injury adjuvant corticosteroid therapy for critically ill patients with covid-19 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the recovery stage by single-cell sequencing the role of interleukin-1 in septic shock. yearb intensive care emerg med coagulation abnormalities and thrombosis in patients with covid-19 kallikrein-kinin blockade in patients with covid-19 to prevent acute respiratory distress syndrome endothelial cell infection and endotheliitis in covid-19 cytotoxic therapy for severe avian influenza a (h5n1) infection a case of macrophage activation syndrome successfully treated with anakinra macrophage activation syndrome treated with anakinra benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase iii, randomized, double-blind, placebo-controlled, multicenter trial. the interleukin-1 receptor antagonist sepsis investigator group recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. results from a randomized, double-blind, placebo-controlled trial. phase iii rhil-1ra sepsis syndrome study group initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebocontrolled multicenter trial anakinra therapy for non-cancer inflammatory diseases covid-19: consider cytokine storm syndromes and immunosuppression favorable anakinra responses in severe covid-19 patients with secondary hemophagocytic lymphohistiocytosis il-1 blockade with anakinra in acute leukaemia patients with severe covid-19 pneumonia appears safe and may result in clinical improvement safety and efficacy of early high-dose iv anakinra in severe covid-19 lung disease novel strategies for targeting innate immune responses to influenza il-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans interleukin-1 blockade with high-dose anakinra in patients with covid-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study anakinra for severe forms of covid-19: a cohort study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-320637-jn8dh4vk authors: nosaka, nobuyuki; yashiro, masato; yamada, mutsuko; fujii, yosuke; tsukahara, hirokazu; liu, keyue; nishibori, masahiro; matsukawa, akihiro; morishima, tsuneo title: anti-high mobility group box-1 monoclonal antibody treatment provides protection against influenza a virus (h1n1)-induced pneumonia in mice date: 2015-06-11 journal: crit care doi: 10.1186/s13054-015-0983-9 sha: doc_id: 320637 cord_uid: jn8dh4vk introduction: provision for the emergence of an influenza pandemic is an urgent issue. the discovery of a novel anti-influenza therapeutic approach would increase the effectiveness of traditional virus-based strategies. this study was undertaken to evaluate the therapeutic effects of anti-high mobility group box-1 (hmgb1) monoclonal antibody (mab) treatment on influenza a virus (h1n1)-induced pneumonia in mice. methods: nine-week-old male c57bl/6 mice were inoculated with h1n1, then anti-hmgb1 mab or control mab were administered intravenously at 1, 24 and 48 hours after h1n1 inoculation and the survival rate was analyzed. lung lavage and histopathological analysis were performed on days 3, 5, 7 and 10 after inoculation. results: anti-hmgb1 mab significantly improved the survival rate of h1n1-inoculated mice (1 out of 15 versus 8 out of 15 deaths in the anti-hmgb1 mab-treated group versus the control mab-treated group, p < 0.01), although the treatment did not affect virus propagation in the lungs. the treatment also significantly attenuated histological changes and neutrophil infiltration in the lungs of h1n1-inoculated mice. this was associated with inhibition of hmgb1 and suppression of inflammatory cytokine/chemokine expression and oxidative stress enhancement, which were observed in h1n1-inoculated mice. the expression of receptor for advanced glycation end products and nuclear factor κb was attenuated by the treatment. conclusions: anti-hmgb1 mab may provide a novel and effective pharmacological strategy for severe influenza virus infection in humans by reducing the inflammatory responses induced by hmgb1. electronic supplementary material: the online version of this article (doi:10.1186/s13054-015-0983-9) contains supplementary material, which is available to authorized users. the first influenza pandemic of this century, the 2009 h1n1 pandemic, has taught us many lessons [1] . the 2009 a (h1n1) influenza virus was a relatively mild pathogen for the majority of patients, although up to 20 % of patients developed progressive, severe h1n1-induced pneumonia requiring hospitalization [2] [3] [4] . the next influenza pandemic is predicted to arise in the near future. tremendous advances have been made in the development of anti-influenza drugs in the last few decades [5, 6] ; however, their therapeutic effects are not guaranteed because of the need to administer these agents early after onset, and the emergence of resistant virus strains [7, 8] . additionally, the protective effects and the production and availability of influenza vaccines are also limited [9] . this situation underlies the pressing need to define novel therapeutic targets involved in disease pathogenesis and progression. excessive cytokine production is considered to be a key contributor to the pathophysiology of severe influenza infection [10] . shi et al. reported inhibition of tumor necrosis factor-alpha (tnf-α) with etanercept, an agent that provided protection against h1n1 infection in mice [11] . the inhibition of an inflammatory cytokine, therefore, represented a promising novel strategy against influenza infection. in this study, we focused on high mobility group box-1 (hmgb1), originally identified as a ubiquitous dna-binding protein [12] , which is now also recognized as a damage-associated molecular pattern molecule [13] . hmgb1 has been proposed to be a crucial mediator in the pathogenesis of many diseases, including sepsis [14] , autoimmunity [15] , acute lung inflammation [16] and several severe viral infections [17] [18] [19] . hmgb1 can be released passively from necrotic cells and/or actively secreted by macrophages or monocytes into the extracellular milieu [20] . extracellular hmgb1 can elicit the production of proinflammatory cytokines that induce inflammatory responses through several immune receptors, including the toll-like receptor 4 (tlr4) [21] and the receptor for advanced glycation end product (rage) [22, 23] . moreover, intranuclear hmgb1 has also been reported to play a significant role in the replication of influenza viruses [24] . recently, we found that anti-hmgb1 monoclonal antibody (mab) markedly inhibited fluid percussioninduced brain edema in rats by inhibiting hmgb1 translocation [25] . these results prompted us to evaluate the therapeutic effects of anti-hmgb1 mab administration in severe pneumonia induced by influenza virus in anticipation of development of the drug. here we provide compelling data demonstrating that anti-hmgb1 mab may provide a novel and effective pharmacological therapeutic strategy for severe influenza virus infection by reducing the inflammatory responses induced by hmgb1. this study was approved by the animal use committee of okayama university graduate school of medicine, dentistry and pharmaceutical sciences (no. oku-2014502) and was conducted in accordance with national institutes of health guidelines. eight-week-old male c57bl/6 mice (21-24 g body weight) were purchased from charles river laboratories (yokohama, japan). they were housed in a specificpathogen-free animal facility at 25°c with a 12-hr light/ dark cycle and fed a standard pellet diet (oriental mf; oriental yeast ltd., tokyo, japan). influenza virus a/puerto rico/8/34 (h1n1), a mouseadapted strain, was used throughout the study. the virus was propagated in 10-day-old embryonated chicken eggs. the virus titer was quantitated by a plaque assay using madin-darby canine kidney cells and its 50 % mouse lethal dose (mld 50 ) was 100 plaque-forming units (pfu). nine-week-old mice were anesthetized by intraperitoneal injection of ketamine (50 mg/kg) and pentobarbital (30 mg/kg). they were then inoculated intranasally with 100 pfu (1 mld 50 ) of h1n1 suspended in 25 μl of sterile phosphate-buffered saline. the animals were allowed to recover and analyzed as described below. the day of virus inoculation was defined as day 0. administration of anti-hmgb1 mab to h1n1-inoculated mice the mice were randomly assigned to two groups after virus inoculation, and an anti-hmgb1 mab (#10-22, immunoglobulin g 2a subclass, 2 mg/kg) [26] or classmatched control mab (anti-keyhole limpet hemocyanin) was administered intravenously via the caudal vein at 1, 24 and 48 hr after virus inoculation. these mab were produced by our group as described previously [26] . the dose of anti-hmgb1 mab (2 mg/kg/mouse) was considered sufficient, because a larger dose (4 mg/kg/ mouse) did not further reduce the levels of hmgb1 and cytokines in the lungs. we injected anti-hmgb1 mab in triplicate after virus inoculation, as the levels of hmgb1 remained elevated during the observation period (10 days). survival was observed until day 28 (15 mice per group). no other parameters were measured in the mice. pathological analyses were performed on days 3, 5, 7 and 10 after h1n1 inoculation (10 mice per group at each time point). the mice were humanely euthanized and their blood and bronchoalveolar lavage fluid (balf) was sampled for measurement of cytokines, chemokines and hydroperoxides. the surgical procedures for pathological analysis and lung histological examination were performed as described previously [27] . immunohistochemical analysis was performed using an antibody against granulocytedifferentiation antigen (biolegend, san diego, ca, usa) [28] to detect neutrophil infiltration into the lung according to the manufacturer's instructions. the lung injury score was calculated as previously described [29] . briefly, four readily identifiable pathological processes were graded semiquantitatively on a scale of 0 to 4: alveolar and interstitial edema, hemorrhage, margination and infiltration of inflammatory cells, and formation of bronchiolitis. a score of 0 represented normal lung, 1 represented mild, 2 was moderate, 3 was severe, and 4 denoted very severe changes. for each mouse, the lung injury score was calculated by adding the individual grades (the mean value of five sections) for each category. the histology was reviewed by two pathologists in a blinded manner (nn and sf). bronchoalveolar lavage was performed as previously described [27] . briefly, the right lung was lavaged with 1 ml of cold phosphate-buffered saline. the recovered balf was collected and centrifuged, and the supernatant was stored at −80°c prior to cytokine analysis. the total cell number in the balf was calculated from the cell number in 200 μl of sediment. the percentage of neutrophils was determined and the total neutrophil number in the balf was calculated and expressed per animal. total rna was extracted from the middle portion of the left lung using rneasy plus mini (qiagen, hilden, germany). total rna was reverse-transcribed to cdna using retroscript (applied biosystems, foster city, ca, usa) according to the manufacturer's instructions. briefly, 1 μg total rna was combined with random decamers and heated to 75°c for 3 minutes. the rna-random decamer mixture was combined with reverse transcriptase buffer, dntp mix, rnase inhibitor and moloney murine leukemia virus reverse transcriptase. the rna was reverse-transcribed at 43°c for 60 minutes, and the enzyme was inactivated at 92°c for 10 minutes. the cdna was used as a template for pcr using the 7500 real-time pcr system (applied biosystems). the probe and primers for the analysis of the expression of influenza virus type a (m gene) mrna were as follows: taqman probe, 5′-6ccctcaaagccgagatcgcaca gagac-3′; forward primer, 5′-cgttctctctatcatc ccgtcag-3′; reverse primer, 5′-ggtcttgtctttag ccattccatg-3′ [genbank nc_002016]. for analysis of signaling pathways, we performed real-time pcr with the sybr premix ex taq (takara biomedicals, shiga, japan) according to the manufacturer's protocol. the sense and antisense primers used for analysis of the expression of mrna were as follows: glyceralaldehyde-3-phosphate dehydrogenase (gapdh), 5′-tgacgtgccgcctggag aaa-3′ and 5′-agtgtagcccaagatgcccttcag-3′ [genbank nm_008084]; rage, 5′-ctagagcctgggt gctggttc-3′ and 5′-gtttccattctagctgctgg ggc-3′ [genbank nm_007425]; nf-κb (p65), 5′-atgtg catcggcaagtgg-3′ and 5′-cagaagttgagttt cgggtag-3′ [genbank nm_009045]. the expression of gapdh was used to normalize cdna levels. the pcr products were also analyzed by melting curve analysis to ascertain the specificity of amplification. the levels of hmgb1 and rage were measured using commercially available enzyme-linked immunosorbent assay kits (hmgb1: shino-test, kanagawa, japan; rage: r&d systems, minneapolis, mn, usa). interleukin 6 (il-6), tnf-α and chemokine (c-x-c motif) ligand 1 (cxcl-1) were measured with a mouse cytokine/chemokine-magnetic bead panel (millipore, billerica, ma, usa) in a luminex 100 system (millipore). the serum concentration of hydroperoxides (whole oxidant capacity of serum against n,n-diethylparaphenylenediamine in acidic buffer) was measured as described previously [27] . the measurement unit was carr u. it has been previously established that 1 carr u corresponds to 0.08 mg hydrogen peroxide/dl [30] . data are expressed as the mean ± sem. comparisons were performed with the mann-whitney u test using prism 6.0 software (graphpad software, san diego, ca, usa). the p value of the difference in survival was determined by the log-rank (mantel-cox) test. p <0.05 was considered statistically significant. of the mice inoculated with 100 pfu (1 mld 50 ) influenza h1n1 virus and treated with anti-hmgb1 mab (2 mg/kg, intravenously), 93.3 % were protected from influenzainduced death, whereas 53.3 % of infected mice administered control mab died (fig. 1a) . subsequently, the viral load was determined in lung homogenates. because the mice began to die on day 10, time points of days 3, 5, 7 and 10 after inoculation were selected for the following measurements. there was no difference in the number of viral m rna copies in the lung at any of the time points examined between anti-hmgb1 mab-treated mice and control mab-treated mice upon h1n1 infection (fig. 1b) . after h1n1 infection, anti-hmgb1 mab-treated mice had significantly lower levels of hmgb1 both in serum and balf at all of the time points examined compared with the control mice (fig. 1c, d) . anti-hmgb1 mab significantly reduces pulmonary injury with suppression of neutrophil infiltration in the lung after h1n1 inoculation h1n1-inoculated control mice presented with diffuse edema, inflammatory cellular infiltration of the alveoli and interstitium of the lung, hemorrhage, and thickened airways. treatment with anti-hmgb1 mab attenuated the histopathological changes evident in the lung (fig. 2a) . additionally, anti-hmgb1 mab significantly reduced the lung injury score compared with control mice at days 3 and 7 after h1n1 inoculation (fig. 2b) . histologically, influenza virus inoculation increased neutrophil infiltration in the lung, although anti-hmgb1 mab treatment attenuated this effect (fig. 2c) . the neutrophil number in the balf increased in both the anti-hmgb1 mab and control groups; however, the neutrophil number remained significantly lower in mice treated with anti-hmgb1 mab compared with the control mab at days 5, 7 and 10 after h1n1 inoculation (fig. 2d) . these results indicated that anti-hmgb1 mab treatment significantly suppressed neutrophil infiltration in the lungs of h1n1-inoculated mice. anti-hmgb1 mab inhibits the release of il-6, tnf-α and cxcl-1, and attenuates rage expression in the lung after h1n1 inoculation investigation of the balf demonstrated that anti-hmgb1 mab-treated mice had significantly lower production of il-6, tnf-α and cxcl-1 on day 3 after h1n1 inoculation compared with control mice (fig. 3a) . reverse-transcription pcr in the lung homogenates showed that anti-hmgb1 mab-treated mice had significantly attenuated rage and nf-κb (p65) expression on day 3 after virus inoculation compared with control mice (fig. 3b) . in addition to mrna analysis, we measured rage protein levels in balf from anti-hmgb1 mab-treated mice and control mice after inoculation of h1n1 by an enzyme-linked immunosorbent assay. anti-hmgb1 mab-treated mice had significantly lower production of rage at days 5, 7 and 10 after h1n1 inoculation (fig. 3c) . the serum concentration of hydroperoxides was also significantly lower in anti-hmgb1 mab-treated mice compared with control mice at all of the time points examined (fig. 4) . this result indicated that anti-hmgb1 mab treatment attenuates the oxidative stress that is observed in h1n1-inoculated mice. in the battle against severe influenza, clinicians are beginning to recognize that it is the immune response of their patient that should be modulated. that is, the involvement of inflammatory mediators in the pathogenesis of influenza has been recognized as a major issue [31] . after hmgb1 was first shown to have an additional function as a late mediator of endotoxin lethality [14] , it has since been revealed as a protein with inflammatory cytokine activity in the pathogenesis of influenza [32] [33] [34] , as well as in many other inflammatory diseases. recently, hmgb1 has attracted the attention of many researchers as a therapeutic target for the treatment of various diseases [35] . several researchers have already investigated hmgb1 and influenza and suggested the anti-influenza effects of different inhibitory agents of hmgb1, including ethyl pyruvate [36] and some chinese herbs [37] . in this study, we evaluated the therapeutic effects of anti-hmgb1 mab on severe h1n1-induced pneumonia in mice. we initially established an influenza-induced mouse model of pneumonia with 50 % lethality. subsequently, 2 mg/kg of anti-hmgb1 mab was administered by intravenous injection in triplicate after virus inoculation. the results demonstrated that systemic suppression of hmgb1 to its normal basal level by anti-hmgb1 mab could protect against severe h1n1-induced pneumonia with almost complete survival. we also showed that anti-hmgb1 mab attenuated rage expression, suggesting that rage plays an important role in the pathophysiological mechanism of anti-hmgb1 mab. hou et al. recently reported the effects of a rabbit anti-hmgb1 polyclonal antibody against h5n1 influenza infection [32] . however, no report has identified the protective mechanism of anti-hmgb1 antibody against h1n1 influenza infection. our findings revealed the effectiveness of anti-hmgb1 mab against influenza infection, with a lower dose administered intravenously fig. 2 effects of anti-high mobility group box 1 (anti-hmgb1) monoclonal antibody (mab) treatment on lung histology after h1n1 inoculation. a. photomicrographs of lung tissue samples stained with hematoxylin and eosin on days 3, 5 and 7 after h1n1 inoculation. these are representative of five independent experiments. control mab group lung tissue showed aggravating diffuse alveolar and interstitial edema, inflammatory cellular infiltration, hemorrhage and bronchiolitis (upper row). in the anti-hmgb1 mab group lung tissue, these features were less severe (lower row). scale bar = 100 μm. b. lung injury scores. data represent the mean (± sem) of five independent experiments; *p <0.05 and **p <0.01 vs control by mann-whitney u test. c. photomicrographs of lung tissue samples stained with granulocyte-differentiating antigen (gr-1) on day 10 after h1n1 inoculation. these are representative of five independent experiments: (a) h1n1 inoculation, control group; and (b) h1n1 inoculation, anti-hmgb1 mab group. arrowheads indicate gr-1 expressing, positively stained (brown) cells. scale bar = 100 μm. d. neutrophil numbers in the bronchoalveolar lavage fluid. dotted line indicates the normal basal level. data represent the mean (± sem) of 10 mice; *p <0.05 and **p <0.01 vs control by mann-whitney u test compared with the study by hou et al. [32] . the antibody used in our study was monoclonal and recognized the c-terminal sequence of hmgb1. using this anti-hmgb1 mab, we have previously demonstrated its beneficial effects on different types of inflammatory disease, such as ischemic and traumatic brain injury [25, 26] . the primary structure of hmgb1 is conserved, with 99 % amino acid sequence homology between rodent and human. therefore, the results in our study may be applicable to influenza infection in humans. moreover, we have also developed a humanized anti-hmgb1 mab (data not shown). consequently, this study is a significant step forward in the clinical application of anti-hmgb1 mabs for a diverse range of inflammatory diseases in humans, including tissue injury. cytokines and chemokines contribute to the overall pathology of lung injury, and several have been well documented in h1n1-induced pneumonia [33, [38] [39] [40] . we found that in h1n1-inoculated mice, anti-hmgb1 mab significantly suppressed the local production of il-6 and tnf-α, key cytokines orchestrating the pathophysiology of highly virulent influenza strains [11, 41] . il-6 is rapidly released during the acute phase of influenza infection and its elevated levels are associated with disease severity triggered by h1n1 infection [42] . tnf-α has been shown to correlate with morbidity and mortality in influenza-infected subjects [11, 43] . moreover, the cxcl-1 level was also significantly suppressed in mice treated with anti-hmgb1 mab. cxcl-1 is a chemokine that directs the trafficking of circulating neutrophils to sites of inflammation or injury [44] . these effects on cytokines and chemokines help to explain our observations of a decreased local inflammatory response, attenuated infiltration of neutrophils and improved survival after h1n1 inoculation in anti-hmgb1 mab-treated mice. our key finding is that treatment with anti-hmgb1 mab resulted in suppressed expression of rage. rage is the primary binding receptor for hmgb1, and the interaction of rage and hmgb1 induces an inflammatory response via nf-κb activation [13] . van zoelen et al. [23] previously reported the importance of rage in the pathogenesis of influenza-induced pneumonia. pulmonary rage upregulation was associated with influenza-induced pneumonia, and rage-deficient mice showed increased resistance to influenza-induced pneumonia. additionally, hmgb1-induced signaling can result in the expression of rage via a positive feedback loop [45] . therefore, treatment with anti-hmgb1 mab itself could restrict rage expression in h1n1-induced pneumonia by blocking hmgb1-induced signaling, resulting in suppression of the inflammatory response. interestingly, however, the attenuation of rage expression was seen only in the early phase of infection (day 3) in anti-hmgb1 mab-treated mice, although hmgb1 level was suppressed significantly in both serum and balf at all time points. correspondingly, there was no significant difference in the expression of nf-κb between the two groups in the later phase of infection (days 7 and 10). these findings help to explain the observation that few cytokines differed significantly in expression between the two groups in the later phase of infection. soluble rage (srage) might provide a key to answer this paradox. we found in this study that the rage level in balf, which should be srage, was significantly higher in control mice than in anti-hmgb1 mab-treated mice. without a transmembrane domain, srage is reported to circulate out of the cell and act as a decoy by preventing ligands, including hmgb1, from binding to rage, therefore functioning as a negative feedback on rage interactions with its ligands [46, 47] . the hyper-expression of srage in balf might result in decreased cytokine levels. further research on the downstream signaling pathways of the hmgb1-rage axis in influenza-induced pneumonia is warranted to clarify these speculations. tlr4 signaling is involved in influenza infection [48] . in addition to rage, tlr4 is one of the receptors for hmgb1. therefore, it is possible that neutralization of hmgb1 may affect tlr4 expression, leading to an altered cytokine response in the lungs. tlr4-mediated hmgb1 signaling may induce deleterious effects of hmgb1. we therefore measured the levels of tlr4 expression in the lungs after anti-hmgb1 mab treatment. as a result, neutralization of hmgb1 did not affect tlr4 expression in the lungs compared with the control (additional file 1). thus, it is likely that tlr4 signaling is not directly involved in the altered cytokine response and lung pathology after anti-hmgb1 mab treatment. we believe that rage-mediated hmgb1 signaling is important in this model. to test this hypothesis, a specific rage antibody could be used or a small interfering rna specific for rage could be employed. it has been shown that mice with a rage deficiency were protected against influenza virus infection [23] . further studies will be necessary to address these points. another key finding of this study is that anti-hmgb1 mab treatment attenuated the serum concentration of hydroperoxides in h1n1-inoculated mice. this finding indicates that treatment with anti-hmgb1 mab might contribute to a comprehensive suppression of not only local cytokines and chemokines but also systemic oxidative stress. our group recently reported that administration of the redox-active protein thioredoxin-1 ameliorated h1n1-induced pneumonia in mice via its antioxidative properties, suggesting that an antioxidative strategy may be a key therapeutic regimen for influenza-induced pneumonia [27] . therefore, it is also important to assess the oxidative stress response in influenza-induced pneumonia [49] . however, our findings warrant further study as we have not yet studied the antioxidative mechanism of the anti-hmgb1 mab. although severe viral pneumonia tends to be rare during outbreaks of seasonal influenza, many cases of primary viral pneumonia were observed in the recent influenza pandemic, especially in the young [50, 51] . even after the 2009 h1n1 pandemic, the world faces the rising burden of viral respiratory infections, including highly pathogenic avian influenza, severe acute respiratory syndrome-associated coronavirus and middle east respiratory syndrome coronavirus [52] . acute respiratory distress syndrome caused by these new viruses is an immediate challenge. hmgb1 was also reported to be associated with the pathogenesis of acute respiratory distress syndrome [16] . given the limited benefit of anti-viral drugs, anti-hmgb1 mab, which provides a protective effect against the host immunological response, shines new light on the treatment of emerging viral infections. pandemic preparedness and response-lessons from the h1n1 influenza of 2009 critically ill patients with 2009 influenza a(h1n1) infection in canada critically ill patients with 2009 influenza a(h1n1) in mexico critical care services and 2009 h1n1 influenza in australia and new zealand influenza treatment and prophylaxis with neuraminidase inhibitors: a review favipiravir 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2009 pandemic h1n1 influenza-associated encephalopathy hmgb-1 as a target for inflammation controlling systemic release of high mobility group box 1 protein during severe murine influenza using complementary and alternative medicines to target the host response during severe influenza influenza viruses clinical aspects and cytokine response in severe h1n1 influenza a virus infection cytokine and chemokine responses in pediatric patients with severe pneumonia associated with pandemic a/h1n1/2009 influenza virus symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses interleukin-6 is a potential biomarker for severe pandemic h1n1 influenza a infection fatal outcome of human influenza a (h5n1) is associated with high viral load and hypercytokinemia cxcl1 regulation in human pulmonary epithelial cells by tumor necrosis factor convergence and amplification of toll-like receptor (tlr) and receptor for advanced glycation end products (rage) signaling pathways via high mobility group b1 (hmgb1) receptor for advanced glycation endproducts (rage), its ligands, and soluble rage: potential biomarkers for diagnosis and therapeutic targets for human renal diseases soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases the tlr4 antagonist eritoran protects mice from lethal influenza infection pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals pneumonia and respiratory failure from swine-origin influenza a (h1n1) in mexico the (h1n1) 2009 pandemic influenza pneumonia among adult patients in japan emerging respiratory viral infections: mers-cov and influenza we thank dr soichiro fushimi, mr yasuharu arashima and mr haruyuki watanabe (department of pathology and experimental medicine, okayama university graduate school of medicine, dentistry and pharmaceutical sciences), and dr nobuko yamashita and dr masao yamada (department of virology, okayama university graduate school of medicine, dentistry and pharmaceutical sciences) for their excellent support for this study. this work was supported by the japanese ministry of health, labour and welfare (h24-shinko-ippan-002) and the japanese ministry of education, culture, sports, science and technology (25670465) (both to dr morishima). intravenous administration of anti-hmgb1 mab significantly improved the survival rate and attenuated lung histopathological changes in a murine model of influenzainduced pneumonia. the protective effects of anti-hmgb1 mab might be explained by its blockade of the interaction between hmgb1 and rage, a key mechanism in the initiation of inflammatory and oxidative responses. these results suggest that anti-hmgb1 mab represents a possible therapeutic pharmacological strategy for severe influenza-induced pneumonia in humans. intravenous administration of anti-hmgb1 monoclonal antibody significantly improved the survival rate and attenuated lung histopathological changes in a murine model of influenza-induced pneumonia. intravenous anti-hmgb1 monoclonal antibody inhibited systemic and local hmgb1 levels and suppressed inflammatory cytokine/chemokine expression and oxidative stress, which were all o bserved in h1n1-inoculated mice. the expression of receptor for advanced glycation end products (rage) was attenuated by anti-hmgb1 monoclonal antibody treatment. additional file 1: effects of anti-high mobility group box 1 (anti-hmgb1) monoclonal antibody (mab) treatment on the expression of toll-like receptor 4 (tlr4). the results were normalized to the expression of glyceralaldehyde-3-phosphate dehydrogenase (gapdh) mrna. the basal expression level of normal mice was calibrated as 1.0 (dotted line). data represent the mean (± sem) of 5 to 10 mice. the sense and antisense primers used for the analysis of the expression of tlr4 were as follows: 5′-gcactgttcttctcctgcc-3′ and 5′-gtttcctgtcagtatcaag-3′ [genbank nm_021297]. there was no statistical difference between groups as determined by the mann-whitney u test.abbreviations (s)rage: (soluble) receptor for advanced glycation end products; balf: bronchoalveolar lavage fluid; cdna: complementary deoxyribonucleic acid; cxcl-1: chemokine (c-x-c motif) ligand 1; gapdh: glyceralaldehyde-3phosphate dehydrogenase; hmgb1: high mobility group box 1; il-6: interleukin 6; mab: monoclonal antibody; mld 50 : 50 % mouse lethal dose; nf-κb: nuclear factor kappa b; pfu: plaque-forming unit; sem: standard error of the mean; tlr4: toll-like receptor 4; tnf-α: tumor necrosis factor alpha. the authors declare that they have no competing interests. key: cord-304746-7yzybukk authors: li, xinye; pan, xiandu; li, yanda; an, na; xing, yanfen; yang, fan; tian, li; sun, jiahao; gao, yonghong; shang, hongcai; xing, yanwei title: cardiac injury associated with severe disease or icu admission and death in hospitalized patients with covid-19: a meta-analysis and systematic review date: 2020-07-28 journal: crit care doi: 10.1186/s13054-020-03183-z sha: doc_id: 304746 cord_uid: 7yzybukk background: cardiac injury is now a common complication of coronavirus disease (covid-19), but it remains unclear whether cardiac injury-related biomarkers can be independent predictors of mortality and severe disease development or intensive care unit (icu) admission. methods: two investigators searched the pubmed, embase, cochrane library, medline, chinese national knowledge infrastructure (cnki), wanfang, medrxiv, and chinaxiv databases for articles published through march 30, 2020. retrospective studies assessing the relationship between the prognosis of covid-19 patients and levels of troponin i (tni) and other cardiac injury biomarkers (creatine kinase [ck], ck myocardial band [ck-mb], lactate dehydrogenase [ldh], and interleukin-6 [il-6]) were included. the data were extracted independently by two investigators. results: the analysis included 23 studies with 4631 total individuals. the proportions of severe disease, icu admission, or death among patients with non-elevated tni (or troponin t [tnt]), and those with elevated tni (or tnt) were 12.0% and 64.5%, 11.8% and 56.0%, and 8.2% and. 59.3%, respectively. patients with elevated tni levels had significantly higher risks of severe disease, icu admission, and death (rr 5.57, 95% ci 3.04 to 10.22, p < 0.001; rr 6.20, 95% ci 2.52 to 15.29, p < 0.001; rr 5.64, 95% ci 2.69 to 11.83, p < 0.001). patients with an elevated ck level were at significantly increased risk of severe disease or icu admission (rr 1.98, 95% ci 1.50 to 2.61, p < 0.001). patients with elevated ck-mb levels were at a higher risk of developing severe disease or requiring icu admission (rr 3.24, 95% ci 1.66 to 6.34, p = 0.001). patients with newly occurring arrhythmias were at higher risk of developing severe disease or requiring icu admission (rr 13.09, 95% ci 7.00 to 24.47, p < 0.001). an elevated il-6 level was associated with a higher risk of developing severe disease, requiring icu admission, or death. conclusions: covid-19 patients with elevated tni levels are at significantly higher risk of severe disease, icu admission, and death. elevated ck, ck-mb, ldh, and il-6 levels and emerging arrhythmia are associated with the development of severe disease and need for icu admission, and the mortality is significantly higher in patients with elevated ldh and il-6 levels. graphical abstract: [image: see text] conclusions: covid-19 patients with elevated tni levels are at significantly higher risk of severe disease, icu admission, and death. elevated ck, ck-mb, ldh, and il-6 levels and emerging arrhythmia are associated with the development of severe disease and need for icu admission, and the mortality is significantly higher in patients with elevated ldh and il-6 levels. keywords: cardiac injury, biomarkers, covid-19, meta-analysis, mortality coronavirus disease (covid-19) has spread worldwide, becoming a public health and medical care challenge in many countries. as of april 25, 2020, covid-19 had spread to 213 countries, areas or territories, with 2,719, 897 confirmed cases and 187,705 confirmed deaths worldwide [1] . covid-19, the clinical manifestation of severe acute respiratory syndrome coronavirus-2 (sars-cov-2) infection, is characterized by respiratory tract symptoms. severe cases can involve acute respiratory distress syndrome (ards) and shock [2] . covid-19 is considered mainly a respiratory tract disease, but cardiovascular complications can also occur, eventually leading to sudden deterioration [3, 4] . a large-scale study including 44,672 patients reported that cardiovascular disease was the risk factors for fatality of covid-19 patients [5] . intensive care unit (icu) occupancy is very fluid, and covid-19 patients still require better evidence-based cardiovascular treatment [6] . inciardi et al. reported the case of a patient who recovered from the influenza-like syndrome but then developed symptoms of heart failure [3] . a recent study recommended that cardiac biomarkers should be evaluated in all hospitalized patients with confirmed covid-19 [7] . however, there has been less concern about cardiac complications in other published studies. data such as those from transthoracic echocardiography, cardiac magnetic resonance imaging (mri), coronary angiography, and other examinations of cardiovascular diseases, as well as the biomarkers of cardiac injury have been less often described or are even missing. recent case reports have suggested that acute cardiac injury can cause cardiac dysfunction, leading to cardiogenic shock and the proclivity for malignant arrhythmia [8] . another study reported that covid-19 was associated with myocarditis and arrhythmia [9] . studies have shown that cardiac injury is related to higher in-hospital mortality rate [4] and is commonly observed in severe covid-19 cases [9] . therefore, paying attention to the occurrence of cardiac complications in patients with covid-19 and performing risk stratification may greatly reduce patient mortality rates, especially of those with severe disease or requiring icu admission. to our knowledge, this is the first study to comprehensively evaluate the impact of cardiac injury and its related biomarkers on mortality and other prognosis in patients infected with sars-cov-2. this meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analysis statement [10] . two investigators (x.l. and y.x.) independently conducted a comprehensive search of the relevant literature published until march 30, 2020, in the pubmed, embase, cochrane library, medline, chinese national knowledge infrastructure (cnki), wanfang, medrxiv, and chinaxiv databases. combinations of the relevant medical subject heading (mesh) terms, key words, and word variants of "novel coronavirus," "coronavirus disease 2019," "covid-19," "2019-ncov," "sars-2-cov," "clinical or characteristic," and "relative risk or rr" were utilized to identify all potentially relevant studies. after the elimination of duplicates, the titles and abstracts of all retrieved studies were assessed by two independent reviewers (y.l. and n.a.) to eliminate irrelevant articles. any disagreements were settled by consensus or by a third reviewer. language restrictions were not applied during filtering, to maximize search sensitivity. the inclusion criteria were as follows: (1) diagnosis of covid-19 according to the world health organization interim guidance [11] and (2) (2) studies with overlapping or unusable data. the primary outcome was the incidence of death, severe disease, or icu admission in covid-19 patients with elevated tni levels versus nonelevated tni levels. the secondary outcomes were as follows: (1) incidences of elevated tni, ck, ck-mb, ldh, or interleukin-6 (il-6) of the non-severe disease/non-icu versus severe disease/icu groups; (2) incidences of elevated tni, ck, ck-mb, ldh, or il-6 of the survivors versus non-survivors groups; (3) tni, ck, ck-mb, ldh, or il-6 levels of the non-severe disease/non-icu versus severe disease/icu groups; (4) tni, ck, ck-mb, ldh, or il-6 levels of the survivors versus non-survivors groups; (5) incidence of arrhythmia (defined as newly occurring of any type) of the non-severe disease/non-icu versus severe disease/icu groups. two investigators (x.l. and x.p.) independently extracted the relevant data from the eligible studies using predesigned forms. disagreements were resolved by consensus. if the mean and standard deviation (sd) of the laboratory findings were not directly given, we used the estimation formula based on the median, range, and sample size [12] . definitions used for severity assessment, icu admission, and cardiac injury were also extracted. two researchers (x.p. and n.a.) independently assessed the quality of the included studies, using the newcastle-ottawa quality assessment scale [13] . studies were defined as high quality if a score of 7 or higher was attained [13] . potential publication bias was evaluated using the visual inspection of funnel plots and formal testing with the egger's testing [14] . effect estimates are presented as relative risk (rr) or standard mean differences (smd) with 95% confidence interval (ci). the i 2 statistic was used to quantify the heterogeneity across studies. i 2 > 50% suggested significant statistical heterogeneity [15] . in this case, a random-effects model was used considering the intraand interstudy variation. otherwise, the pooled effect was calculated using a fixed-effects model. all analyses were performed using stata 16.0 (statacorp, college station, tx, usa). values of p < 0.05 were considered statistically significant. we identified 1898 studies using the predefined search terms. after the removal of duplicates and filtering of titles and abstracts to exclude irrelevant articles, 67 records remained. the full text of the 67 records was reviewed; of them, 44 records were excluded for the following reasons: data not available (n = 17), literature review or letter or case report (n = 12), unrelated to relevant predictive factors (n = 13), and meta-analysis (n = 2). finally, 23 studies were included in this metaanalysis, of which one was not written in english. the flow diagram of this study selection is shown in fig. 1 . the primary characteristics of the 23 included studies are listed in table 1 , with 4631 individuals incorporated. the sample size of 16 studies was greater than 100. the definition of cardiac injury was extracted ( table 2 ). the clinical characteristics of all included patients with covid-19 are shown in additional file 1: table s1 . overall, 16 studies reported cardiac injury biomarkers, and 4 reported arrhythmias. all the results calculated using stata are shown in table 3 . fig. 3c ). twelve studies including 2174 individuals reported the ck levels or the number of patients with above-normal ck levels. the incidence of elevated ck in the severe disease/icu group was significantly higher than that in the nonsevere disease/non-icu group (12.9% and 23.2%, respectively; rr 1.98, 95% ci 1.50 to 2.61, p < 0.001; i 2 = 0.0%, fig. 4a) . the mean ck level was significantly higher in severe disease/icu group than in the nonsevere disease/non-icu group (smd 0.39, 95% ci 0.11 to 0.67, p = 0.006; i 2 = 69.0%, fig. 4b ). the proportion of patients with an elevated ck-mb level in the non-severe disease/non-icu and severe disease/icu groups was 14.1% and 45.7%, respectively. patients in the severe disease/icu admission group were at higher risk of developing an elevated ck-mb level than those in the nonsevere disease/non-icu group (rr 3.24, 95% ci 1.66 to 6.34, p = 0.001; i 2 = 79.8%, fig. 4c ). of the 2532 patients from 15 studies, 29.7% of those in the non-severe disease/non-icu group versus 60.1% of the severe disease/ icu group had elevated ldh levels. covid-19 patients with elevated ldh levels were at significantly increased risk of developing severe disease or requiring icu admission (rr 2.20, 95% ci 1.55 to 3.12, p < 0.001; i 2 = 79.7%, fig. 5a ). ldh levels were significantly higher in the severe disease/icu admission group than in the non-severe disease/non-icu group (smd 1.15, 95% ci 0.61 to 1.70, p < 0.001; i 2 = 92.7%, fig. 5b ) and in nonsurvivors than in survivors (smd 2.86, 95% ci 0.67 to 5.06, p = 0.01; i 2 = 98.6%, fig. 5c ). arrhythmia and il-6 the incidence of arrhythmia was 3.1% in the non-severe disease/non-icu group versus 43.8% in the severe disease/icu group. patients with newly occurring arrhythmias were at a higher risk of developing severe disease or requiring icu admission (rr 13.09, 95% ci 7.00 to 24.47, p < 0.001; i 2 = 42.0%, fig. 6a ). il-6 levels were significantly higher in the severe disease/icu group than in the non-severe disease/non-icu group, as well as in non-survivors than in survivors (smd 0.54, 95% ci 0.27 to 0.81, p < 0.001; i 2 = 0.0%, fig. 6b ; smd 1.28, 95% ci 1.00 to 1.57, p < 0.001; i 2 = 13.7%, fig. 6c , respectively). this systematic review and meta-analysis of 23 highquality retrospective studies systematically evaluated the risk of severe disease, icu admission, or death associated with covid-19-related cardiac injury performance. our findings are as follows: (1) covid-19 patients with elevated tni levels are at significantly higher risk of developing severe disease, requiring icu admission, or death; (2) elevated ck, ck-mb, ldh, and il-6 levels and emerging arrhythmia are associated with the development of severe disease or requirement for icu admission; and (3) mortality rates are significantly higher among patients with elevated ldh and il-6 levels. cardiac injury was defined as a serum cardiac biomarker level (e.g., troponin i) above the 99th percentile upper reference limit or new abnormalities seen on electrocardiography (ecg) and echocardiography [2] . ck, ck-mb, and ldh are also indicators associated with cardiac injury [37, 38 ]. an elevated cardiac tni level has high specificity for cardiac injury and is a preferred biomarker of cardiac injury. overall, in 8 studies including 1028 patients, the rates of elevated tni or tnt in the nonsevere disease/non-icu admission group and severe disease/icu admission group were 2.3% and 36.9%, respectively; in the total population, elevated tni or tnt bnp b-type natriuretic peptide, ck creatinine kinase, ck-mb creatinine kinase-myocardial band, icu intensive care unit, ldh lactate dehydrogenase, il-6 interleukin-6, n number, na not available, nt-probnp n-terminal pro-b-type natriuretic peptide, rr risk ratios, smd standard mean occurred at a rate of 11.9%. our analysis suggests that covid-19 patients with elevated tni levels are at higher risk of developing severe disease, requiring icu admission, and death. two studies from wuhan (one with 416 cases, another with 187 cases) reported higher mortality among patients with cardiac injury than among those without (51.2% vs. 4.5%; p < 0.001; 59.6% vs. 8.9%, p < 0.001, respectively) [4, 36] . patients with cardiac injury had higher serum concentrations of nt-probnp than those without cardiac injury [36, 39] . patients with cardiac injury more commonly developed ards, were more likely to have ventricular tachycardia (vt) or ventricular fibrillation (vf), and had higher mortality rates than those without vt or vf [36, 39] . tni has great prognostic significance for patients with covid-19 as well as those with other influenza virus infections. in a study of 75 inpatients with sars, acute myocardial infarction was the cause of 2 of 5 deaths [40] . elevated tni levels are also common in infections caused by other influenza virus subtypes [41] [42] [43] [44] [45] . tni may play an important role in predicting the acute or long-term risk of influenza virus infection. other biomarkers closely related to cardiac injury, such as ck, ck-mb, and ldh, were also selected in the meta-analysis. our analysis showed that those with elevated ck, ck-mb, and ldh were at a higher risk of developing severe disease or requiring icu admission. the ldh level had a predictive value for death. previous studies suggested that ck at icu admission serves can be used as a biomarker of the severity of 2009 pandemic influenza a (ph1n1) infection [46] . elevated tni and ck-mb levels indicate cardiac injury such as viral myocarditis or myocardial infarction as well as multiple organ injury [47] . initial reports showed that the possible pattern of myocardial injury is the early presentation of primary cardiovascular symptoms, as well as changes on echocardiography and ecg [3, 6, [48] [49] [50] . stress cardiomyopathy, supply demand mismatch (type ii myocardial infarction), and myocarditis, sometimes similar to st-segment elevation myocardial infarction, are all possible mechanisms [3, 6, 49] . in a study describing a single case without a history of cardiovascular disease, the patient had myocardial injury, and diffuse edema was seen on cardiac mri [3] . twelve lead ecg showed minimal diffuse st-segment elevation and an st-segment depression with t-wave inversion of lead v1 and avr. even in the absence of respiratory tract or infection symptoms, sars-cov-2 infection may cause cardiac involvement. however, it is a pity that an endomyocardial biopsy was not performed; thus, there was no histological evidence [3] . cardiac injury is an important prognostic factor for covid-19. it is rational to presume that the virus affects the myocardium, and once patients develop severe pneumonia, cardiac injury or dysfunction is more likely to occur, leading to deterioration. in a study of critically ill patients, including 21 who had sars-cov-2 infection in the usa, the incidence of cardiomyopathy was high (n = 7 [33%]) [51] . in a patient without fever and respiratory symptoms, the initial ecg showed diffuse st elevations and an admission tni level of 7.9 ng/ml, but angiography demonstrated non-obstructive coronary artery disease. after fig. 3 forest plots comparing of the proportion of patients with elevated troponin i or troponin t levels in the severe disease/icu group and in the non-severe disease/non-icu group (a), the troponin i levels in the severe disease/icu group and in the non-severe disease/non-icu group (b), and the proportion of patients with elevated troponin i or troponin t levels in the survivors and non-survivors groups (c). icu, intensive care unit; rr, risk ratios; smd, standard mean treatment, this patient improved in the short term, but the long-term effects of myocardial injury remain to be determined [8] . the etiology of cardiac dysfunction may be multifactorial and related to infective myocarditis and/or ischemia. pathological findings suggested a few interstitial fig. 4 forest plots comparing of the proportion of patients with elevated creatinine kinase levels in the severe disease/icu group and in the non-severe disease/non-icu group (a), the creatinine kinase levels in the severe disease/icu group and in the non-severe disease/non-icu group (b), and the proportion of patients with elevated creatinine kinase-myocardial band levels in the severe disease/icu group and in the non-severe disease/non-icu group (c). icu, intensive care unit; rr, risk ratios; smd, standard mean mononuclear inflammatory infiltrates in the myocardial interstitial [52] . viral invasion may cause direct cardiac injury, and covid-19-induced cytokine storm may also have toxic effects on the myocardium [53] . cytokine storm may play a role in the development of ards and fulminant myocarditis. in our analysis, 3 studies reported the laboratory findings of il-6 levels in 526 patients. il-6 levels were significantly higher in the severe disease/ fig. 5 forest plots comparing of the proportion of patients with elevated lactate dehydrogenase levels in the severe disease/icu group and in the non-severe disease/non-icu group (a), the lactate dehydrogenase levels in the severe disease/icu group and in the non-severe disease/non-icu group (b), and the lactate dehydrogenase levels in the survivors and non-survivor groups (c). icu, intensive care unit; rr, risk ratios; smd, standard mean fig. 6 forest plots comparing of the risk of developing to severe disease or requiring icu admission among patients with or without newly occurring arrhythmias (a), the interleukin-6 levels in the severe disease/icu group (b), and in the non-severe disease/non-icu group and the interleukin-6 levels in the survivors and non-survivors groups (c). icu, intensive care unit; rr, risk ratios; smd, standard mean icu groups than non-severe disease/non-icu groups, as well as in non-survivors than in survivors. cardiac involvement reportedly occurred a few days after the influenza syndrome, suggesting the mechanisms of a potential myocyte dissemination of the virus activating the immune system, eventually leading to the onset of heart failure [3] . a study reported that, compared to survivors, non-survivors had increased concentrations of creactive protein, decreased lymphocyte counts, and significantly reduced numbers of cd3 + cd8 + t cells, resulting in an immune response [54] . anti-il-6, as a drug targeting cytokine pathway and based on its mechanism of action, has potential benefits in covid-19related ards and pneumonia [55] . our analysis also found that the patients with emerging arrhythmia are at a higher risk of developing severe disease or requiring icu admission. in a study of 41 patients with covid-19, atrial fibrillation occurred in 2 of 3 severe and critical patients with tachycardia, with a peak heart rate of 160 bpm [22] . newly occurring arrhythmias are often closely related to cardiac injury. the incidence of ventricular arrhythmias (vt/vf) among 187 patients with covid-19 was 5.9%, primarily affecting those with elevated cardiac troponin levels [36] . one study reported that 5 of 6 acute myocardial injury patients had more than two kinds of ecg abnormalities, including st-t/q curve abnormality, atrioventricular block, and arrhythmia [28] . severe pneumonia increases the resistance of the pulmonary circulation, increasing the pressure of the right atrium, and leading to atrial tachyarrhythmia. antiviral drugs such as hydroxychloroquine may also prolong the qt interval. alternatively, the virus directly damages the myocardium and the cardiac conduction system, causing multiple ventricular premature and atrioventricular block. more attention is needed on arrhythmia among severe disease/icu admission covid-19 patients. however, in the studies reviewed here, ecg or echocardiography was rarely performed and the occurrence of arrhythmia was rarely reported. this meta-analysis included the largest sample size and is the first to analyze the correlation of cardiac injury biomarkers and arrhythmia with mortality and other prognosis. our systematic review and meta-analysis indicate that patients with elevated tni (tnt) levels are at significantly higher risk of developing severe disease, requiring icu admission, or death. our analysis also reveals that patients with elevated ck, ck-mb, and ldh levels and emerging arrhythmia were at a higher risk of developing severe disease, requiring icu admission. ldh levels also have predictive value for death. therefore, we strongly recommend the close monitoring of cardiac injury-related biomarkers in covid-19 patients, especially during the acute disease phase. the current clinical attention given to cardiac injury may be insufficient, and the strong infection of the virus makes cardiovascular examinations such as mri, echocardiography, and coronary angiography difficult to perform [56] . the evaluation of cardiac injury biomarkers combined with cardiac examinations may help better assessments of the condition. there are few reports on cardiac injury in covid-19 patients, and a large amount of evidence is still needed to make the necessary risk predictions and stratifications. the present results provide some evidence for covid-19 treatment guidelines. in the future, it well be necessary to strengthen the monitoring of cardiac injury biomarkers, combined with echocardiography [57] , ecg, mri, and other cardiac examinations, in patients with severe sars-cov-2 infection. when circulation support is needed in severe covid-19 cases, the use of an intra-aortic balloon pump or extracorporeal membrane oxygenation may be considered [8] . covid-19) pandemic. accessed 25 clinical features of patients infected with 2019 novel coronavirus in wuhan cardiac involvement in a patient with coronavirus disease 2019 (covid-19) association of cardiac injury with mortality in hospitalized patients with covid-19 in wuhan clinical determinants for fatality of 44,672 patients with covid-19 covid-19 pandemic-some cardiovascular considerations from the trench a care pathway for the 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storm associated with pneumonia and acute respiratory distress syndrome in covid-19 patients catheterization laboratory considerations during the coronavirus (covid-19) pandemic: from acc's interventional council and scai using echocardiography to guide the treatment of novel coronavirus pneumonia publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. received: 30 april 2020 accepted: 15 july 2020 supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03183-z.additional file 1: table s1 . clinical characteristics of patients with covid-19. all the data supporting the conclusions of this article are included within the article. this article is meta-analysis and does not require ethics committee approval or a consent statement. all authors have agreed to the publication of this manuscript. the authors declare that they have no competing interests. key: cord-326124-jtpsydy5 authors: adam, elisabeth h.; schmid, benedikt; sonntagbauer, michael; kranke, peter; zacharowski, kai; meybohm, patrick title: fibrin-derived peptide bβ15-42 (fx06) as salvage treatment in critically ill patients with covid-19-associated acute respiratory distress syndrome date: 2020-09-24 journal: crit care doi: 10.1186/s13054-020-03293-8 sha: doc_id: 326124 cord_uid: jtpsydy5 nan to the editor, after sars-cov-2 first occurred in china in december of 2019, it set out to become a global pandemic. critically ill patients constitute about 2-9% of all infected patients and progress from pneumonia and hypoxemia to multiorgan dysfunction, for which acute treatment options are scarce [1] . currently, there is no clinical evidence supporting the efficacy and safety of a drug against any coronavirus in humans, including sars-cov-2. here, we describe the empirical salvage treatment of critically ill covid-19 patients in two german tertiary care university hospitals with fx06 (f4 pharma, vienna, austria), a naturally occurring peptide derived from the neo-n-terminus of fibrin (bβ15-42). fx06 is known for its immunomodulatory properties [2] and was already investigated in clinical trials demonstrating convincing efficacy while being tolerated well with a favorable safety profile [3] . this observational case series includes six patients during their treatment in the intensive care unit. the respective institutions' ethics committees approved the post hoc analysis of patient records for scientific purposes. the diagnosis of ards was based on the criteria put forth by the berlin definition. six mechanically ventilated patients suffering from moderate to severe ards upon icu admission were treated with i.v. fx06 (400-600 mg per day; 3-7 days). five out of these six patients additionally needed ecmo treatment during the course of their illness. detailed clinical information is given in table 1 . mean oxygenation ratio improved over the first 3 days after the beginning of fx06 application, returned to baseline and increased steadily afterwards from day seven on (fig. 1a) . il-6 serum concentrations as a marker of inflammation activity were instantly declining from day one (fig. 1b) . norepinephrine dosages decreased initially after the initiation of fx06 therapy before returning to nearbaseline values after some days (data not shown). renal replacement therapy was necessary in four patients. overall, four out of six patients survived. both deceased patients (pats. 2 and 4 in table 1 ) died from multi-organ failure due to septic shock most likely from secondary bacterial (co)infection. hence, we saw no indication that the application of fx06 was in any way related to a patient's death. in summary, we observed substantial improvement in lung function following fx06 administration, which may be attributed to its immunomodulatory properties [3] and its function to preserve the endothelial barrier [4] . patients treated with fx06 displayed a remarkable increase of their oxygenation indices, which we consider to be indicative of the normalization of the pulmonary vascular walls through the aforementioned underlying mechanisms. this was also mirrored in the radiographic diagnostics in five out of all six patients, reflecting a normalization of the interface between the alveolar space and an enhanced tissue integrity. various coagulation factors, including fibrin degradation products, modulate the inflammatory response by influencing leukocyte migration and cytokine production [5, 6] . the decrease in il-6 after fx06 is therefore considered to be attributed to these immunomodulatory effects. based on our experience, the salvage use of fx06 in severe covid-19-associated ards could be an effective therapy to improve pulmonary function and vascular leakage in the most severely ill patients. a prospective randomized, controlled study to better elucidate this hypothesis is on preparation. pathological findings of covid-19 associated with acute respiratory distress syndrome fx06 (fibrin-derived peptide bbeta15-42)-a potential candidate for myocardial reperfusion therapy effect of intravenous fx06 as an adjunct to primary percutaneous coronary intervention for acute st-segment elevation myocardial infarction results of the f.i.r.e. (efficacy of fx06 in the prevention of myocardial reperfusion injury) trial peptide bβ15-42 preserves endothelial barrier function in shock cellular sources of tissue factor in endotoxemia and sepsis fibrinogen and fibrin induce synthesis of proinflammatory cytokines from isolated peripheral blood mononuclear cells publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are extremely thankful for all our staff nurses and support personal enabling us to successfully treat the high number of patients with sars-cov-2induced ards. this work was performed at frankfurt university hospital, department of anesthesiology and intensive care medicine, frankfurt, germany, and wuerzburg university hospital, department of anesthesiology, wuerzburg, germany. authors' contributions kz and pm designed the study. ea, bs, and pm analyzed and interpreted the patient data and wrote the manuscript. ms, ts, and hn aided in interpreting the results and worked on the manuscript. all authors read and approved the final manuscript. this study was funded by institutional funds of both university hospitals. fx06 was provided by the manufacturer (f4 pharma, vienna, austria). no further external funding, especially none through the pharmaceutical manufacturer, was provided. the universities of frankfurt and wuerzburg are in part owners of the patent of fx06. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the study was approved by the local ethics committee (university hospital frankfurt, frankfurt, germany) (#20-643). not applicable. the authors declare that they have no competing interests. 1 key: cord-352227-827987jf authors: chernevskaya, ekaterina; beloborodova, natalia; klimenko, natalia; pautova, alisa; shilkin, dmitrii; gusarov, vitaliy; tyakht, alexander title: serum and fecal profiles of aromatic microbial metabolites reflect gut microbiota disruption in critically ill patients: a prospective observational pilot study date: 2020-06-08 journal: crit care doi: 10.1186/s13054-020-03031-0 sha: doc_id: 352227 cord_uid: 827987jf background: high serum levels of certain aromatic microbial metabolites (amm) are associated with severity and mortality in critically ill patients. omics-based studies suggest gut dysbiosis and reduced microbiome diversity in critical conditions. however, the landscape of gut microbial metabolites is still to be outlined, not to mention the interplay correlation between the metabolome and gut microbiome in critically ill patients. the aim of this study was to analyze the association between serum and fecal levels of amm and compare them with the composition of gut microbiota in critically ill patients in the acute and chronic stages. methods: in this prospective observational pilot study, we analyzed the temporal dynamics of the gut microbiome and the amm spectrum across two distinct subgroups—acute critical ill (aci) patients with nosocomial pneumonia and chronically critically ill (cci) patients (9 subjects each group)—as well as performed comparison with 23 healthy volunteers. the amm levels for each patient were measured using gc-ms in simultaneously taken serum and fecal samples (sfs). these parameters were compared with 16s rrna fecal microbiome profiles. results: the observed proportions of bacterial taxa suggest a significant gut dysbiosis in the aci and the cci patients. stronger imbalance in microbiome composition and dynamics observed in the aci patients compared to the cci ones resonates with a higher severity in the former group. the total levels of amm in serum samples were higher for the aci patients than for the cci patients (3.7 (1.4–6.3) and 1.1 (1.0–1.6) μm, respectively; p = 0.0003). the qualitative composition of the sfs was also altered. we discovered significant associations between gut microbial taxa levels and metabolite concentrations in blood serum as well as in feces in each of the aci and the cci patients. conclusions: aromatic microbial metabolite profiles in the gut and the serum are interlinked and reflect a disruption of the gut microbial community in critically ill patients. the importance of studying the qualitative and quantitative composition of gut microbiota in critically ill patients has been supported by a number of studies in recent years [1, 2] . the 16s rrna sequencing microbiome assays allow us to assess the total prokaryotic community including uncultivable species in such patients. dramatic changes in microbiota composition are caused primarily by hypoxia, hypercapnia, administration of drugs to suppress gastric secretion, vasoactive drugs, sedation, and analgesics which compromise the motility of the gastrointestinal tract, and cause a deficiency of nutrients in the intestine due to parenteral and enteral nutrition that deprives the microbiome of nutrients-for example, microbially accessed indigestible carbohydrates-and, of course, the use of antibiotics [3] . the "critical state microbiome" was characterized by an imbalance of commensal ("health-maintaining") and opportunistic pathogenic bacteria, which made patients more susceptible to nosocomial infections, sepsis, and organ failure [4] . for example, the decay of commensal bacteria, mostly anaerobic, can lead to an overgrowth of enterococcus [5] which is correlated with organ failure, length of stay in icu, and mortality [2] . despite the fact that no single reference structure for the gut community is known to date, there appears to be a functional homeostasis for a well-functioning microbiota "organ" in healthy individuals, which is directly related to metabolic balance in the human organism [6] . more than 30% of metabolites in the human body originate from gut microbiota and may contribute to host disease risk [7] . among different classes of metabolites produced by members of human gut microbiota, investigation of aromatic microbial metabolites (амм) is of particular interest [8] . our experimental and clinical studies confirmed the biological activity of амм and their involvement in the pathogenesis of bacterial infections. these substances affect the functions of mitochondria by producing active oxygen species, decreasing the rate of oxidation of naddependent substrates [9] , and suppressing the phagocyte activity of neutrophils in vitro [10] . the effects observed in vitro caused by the action of the amm were similar to those in septic patients, and an increase in the concentration of these metabolites has been proposed as one of the causes of mitochondrial dysfunction in sepsis [11] . the following amm are potentially involved in the pathological process: phenyllactic acid (phla), phenylpropionic acid (phpa), phenylacetic acid (phaa), p-hydroxyphenylacetic acid (p-hphaa), and p-hydroxyphenyllactic (p-hphla) acid. амм levels reflect the severity of the bacterial inflammatory process: they increase in patients with a local proinflammatory disease and reach a maximum level during severe sepsis and septic shock [12] . our hypothesis regarding the bacterial origin of амм was supported by the results obtained with isolates of clinically significant species of bacteria [13] . for example, staphylococcus aureus, klebsiella pneumoniae, and escherichia coli produce phla and p-hphla, while non-fermenting (aerobic) gram-negative bacteria (including acinetobacter and pseudomonas) are capable of forming p-hphaa [14] . in microbial communities, phenylcarboxylic acids (phca) play an important role in the mechanisms of interspecies competition. phpa and p-hphaa, metabolites of human gut anaerobic bacteria, suppress the growth of e. сoli and s. aureus [15] . phla and p-hphla suppress the growth and reproduction of fungi [16] . in a healthy individual, metabolites containing lactic acid residue (phla and p-hphla) are not detected in the feces because they undergo deep biodegradation to end products under the action of anaerobic bacteria [17] . given that амм are involved in the mechanisms of interspecies interactions of microorganisms, a prolonged imbalance of амм in the interior environment of a host might affect the composition and metabolic activity of gut microbiota and, as a result, disrupt the equilibrium between the macro-and microorganisms. the anaerobic bacteria of gut microbiome are thought to take part in the metabolism of phenylcarboxylic acids of endogenous origin: the suppression of metabolic activity of the microbiota might promote the accumulation of amm [18] . a gc-ms analysis of 187 low molecular weight metabolites in the blood of 239 critically ill patients identified seven metabolites including p-hphla to be the most predictive of a 28-day lethality [19] . however, no data is currently available either on the production of amm by the gut microbiota in critically ill patients or on their associations with microbial taxa in vivo. moreover, the dynamics of microbiota in chronically critically ill patients who survive in acute critical illness and with prolonged dependence on mechanical ventilation and other intensive care therapies are yet to be studied. meanwhile, сhronic critical illness is a serious and growing problem for healthcare systems: mortality exceeds that for most malignancies, and functional dependence on medical care persists for most survivors [20] . thus, the study of metabolic activity and the identification of links between qualitative and quantitative characteristics of the microbiota of critically ill patients is highly relevant. the aim of this study was to analyze the association between the serum and fecal levels of amm and compare them with the composition of the gut microbiota in critically ill patients in the acute and chronic stages. this study was approved by the institutional review board of the n. pirogov national medical surgical center and the local ethics committee of the federal research and clinical center of intensive care medicine and rehabilitology. it was conducted in the icu of the two abovementioned centers from february 2016 to may 2017. formal consent for participation in this study was obtained from each patient or his/her legal representative. forty-seven pairs of serum and fecal samples (sfs) were simultaneously collected from critically ill patients: 24 sfs from 9 patients with acute critical ill (aci) patients with nosocomial pneumonia (3 (3, 4) days after admission to icu), 23 sfs from 9 chronically critically ill (cci) patients in the course of prolonged neurorehabilitation (90 (67-100) days after admission to icu) after different forms of acquired brain injury such as traumatic brain injury or stroke. blood (from a central venous catheter) and gut microbiome samples were collected in the morning at regular intervals: in aci patients-on days 1, 3, and 7-9 after the diagnosis of pneumonia; in cci patients-once a week for a month. to compare serum metabolite levels, we used serum samples from 23 healthy volunteers (for 5 of them, fecal samples were also collected on the same day). microbiome samples were obtained by collecting a small amount of feces as a rectal swab and dissolving it in 1 ml of sterile saline solution; after thorough mixing, it was divided into two eppendorf tubes. all samples were frozen and stored at − 30°с prior to analysis which included gc-ms, biomarkers, and general clinical analyses and laboratory tests. the baseline clinical and laboratory characteristics of the critically ill patients are shown in table 1 . all patients received high-calorie fiber-free enteral tube feeding; in the aci group, the enteral nutrition was initiated within 48 h of admission. none of the patients received renal replacement therapy. most patients required some form of a respiratory support and antibiotic intake (data available in supplementary tables 1 and 2). fecal dna extraction, sequencing library preparation for the 16s rrna gene (v2, v3, v4, v6-7, v8, and v9 regions), and sequencing were performed on an ion torrent personal genome machine (pgm) platform (life technologies; carlsbad, ca, usa) using an ion 16s metagenomics kit (life technologies; carlsbad, ca, usa) as previously described [21] . data analysis was performed in the knomics-biota system [22] and manual r scripts (interactive reports and the raw reads are publicly available online at https:// biota.knomics.ru/amm-and-gut-microbiome-2019). reads were analyzed using qiime 1.9.1 [23] . they were trimmed to remove bases with phred scores lower than 20, then reads shorter than 75% of the initial length were discarded. reads were classified using a closed-reference otu picking (vsearch algorithm [24] ) against a 16s rrna sequence database (greengenes v. 13.5 [25] , 97% otu similarity). the classified reads for each sample were randomly rarefied to even coverage (5000 reads per sample). read counts of microbial species, genera, and families were calculated as the sum of reads classified as otus belonging to the respective taxon. the relative abundance of each taxon was calculated by dividing the number of its rarefied reads by the total read count for the sample. the alpha diversity of the communities was estimated via the shannon index at the level of otus. benzoic acid (ba, ≥ 99.5%), 2,3,4,5,6-d 5 -benzoic acid (internal standard, ≥ 99 atom % d, ≥ 99%), phenylpropionic acid (phpa, ≥ 99%), phenyllactic acid (phla, ≥ 98%), 4hydroxyphenylacetic acid (p-hphaa, ≥ 98%), homovanillic acid (hva, ≥ 97%), 4-hydroxyphenyllactic acid (p-hphla, ≥ 97%), 3,4-dihydroxybenzoic acid (internal standard, ≥ 98%), 4-hydroxyphenylpropionic acid (p-hphpa, ≥ 98%), 4-hydroxybenzoic acid (p-hba, ≥ 99%), n,o-bis (trimethylsilyl) trifluoroacetamide (bstfa, contains 1% trimethylchlorosilane, 99% bstfa), and hexane (≥ 97.0%) were obtained from merck (germany); the sulfuric acid, acetone, diethyl ether, and sodium chloride were laboratory reagent grade and obtained from khimreactiv (russia). serum samples were thawed at room temperature prior to use. all gc-ms analyses were performed on a trace gc 1310 gas chromatograph equipped with an isq lt mass spectrometer using a tr-5ms capillary column (95% poly (dimethylsiloxane) + 5% phenyl polysilphenylene-siloxane phase, 30 m × 0.25 mm, df = 0.25 μm) obtained from thermo scientific (thermo electron corporation, usa). the column flow was constant at 1.5 ml min −1 with helium as the carrier gas, split 1:20. the gc analysis was wbc (4-9 × 10 9 /l) 12.7 (9.6-15.1) 9.6 (7.6-10.6) ns inotropes 5/9 1/9 ns sofa sequential organ failure assessment, pct procalcitonin, wbc white blood cells, bmi body mass index performed in 27 min with a starting oven temperature of 80°с (hold time 4 min), a ramp of 10°с min −1 to 250°c and a ramp of 20°с min − 1 to 280°с (hold time 5 min). the inlet temperature was 200°с, and the injection volume was 1 μl. full-scan mass spectra were recorded with a m/z range of 50-480 in the electron-impact mode at 70 ev, using xcalibur 2.2 software. the ms source was 200°с and the gc-ms interface was kept at 250°с. the scan rate was 3 scans/s; the cathode delay time was 4 min. trimethylsilyl derivatives of the phcas were identified using retention times and characteristic m/z. mass spectral data for the trimethylsilyl derivatives of the phcas were proved by the nist mass spectrum library. the retention times and characteristic m/z values of trimethylsilyl derivatives of the phcas have been described in detail in our previous study [26] . quantitative analyses of the amm in serum samples were carried out using the following internal standards: 2,3,4,5,6-d 5 -benzoic acid for ba and phpa; 3,4-dihydroxybenzoic acid for phla, p-hba, hva, p-hphaa, p-hphpa, and p-hphla. the concentrations of the amm were calculated using the calibration curve equations described in our previous study [26] . quantitative analyses of the amm in fecal samples were not performed due to sample heterogeneity. the results on the phca in fecal samples were illustrated as the proportion of each acid among all amm (%). the conditions for liquid-liquid extraction of the amm have been previously described [26] . briefly, a 200-μl aliquot of serum and a 100-μl aliquot of aqueous solution of internal standards (7.5 mg l −1 ) were diluted with 800 μl of distilled water. solid sodium chloride (0.3-0.5 g) and a 15-μl aliquot of concentrated sulfuric acid were added. an extraction with diethyl ether was carried out (2 × 1 ml). the ether extract was evaporated at 40°с and derivatized with bstfa (40 μl, 90°с, 30 min). the solution was cooled at 5°с for 30 min and diluted with 400 μl of n-hexane, and 1 μl of the final solution was injected into the gc-ms system. in the case of the feces, a solid sample (usually in 1.5 ml eppendorf) was diluted in 1 ml of distilled water and vortexed for 2 min and a 200-μl aliquot of the solution was subjected to the described sample preparation protocol for the serum. quantity concentration values were calculated for serum metabolite levels using the previously described method [26] . for fecal metabolites, absolute quantitative concentrations could not be reliably obtained. therefore, the levels of metabolites in the feces were converted into relative values proportionally in a way that for each sample, the total levels of all measured metabolites in the feces were equal to one. a between-group comparison of microbial taxa abundances was performed for arcsin-sqrt transformed abundance values at each taxonomic level. the significance of the associations was evaluated using a mixed-effect model, where the patient identifier was included as a random effect. an adjustment for multiple comparisons was carried out using the benjamini-hochberg method separately at each taxonomic level. the same approach was applied for the analysis of the associations between taxa abundances and levels of metabolites in the serum and the feces. only the taxa with transformed abundance levels of > 0.002 in > 5 samples and only the metabolites with non-zero values in > 5 samples were considered in these analyses. a similar mixed-effect model with a patient identifier as a random effect was applied to investigate the alpha diversity between-group analysis and associations between alpha diversity and the level of metabolites, as well as for testing the statistical significance of correlations between the levels of metabolites in the blood and feces (along with the pearson correlation coefficient). only the metabolites with non-zero values in > 5 samples were considered here. a microbe-metabolite graph was constructed based on the identified associations between the levels of metabolites in the blood and feces as well as between the levels of metabolites and abundance of bacterial genera. in addition, genera co-occurrence was assessed by applying a spiec-easi algorithm to non-rarefied abundance tables [27] . genera detected at < 10 reads per sample on average or in < 10 samples were excluded. in the spiec-easi algorithm, neighbors were selected using the meinshausen and bühlmann method, and the model selection was performed using the stars algorithm (huge r package [28] ) (number of lambda iterations = 10, minimum lambda ratio = 0.3). the critical conditions of patients are partially reflected in their gut microbial community structure (genus-level composition is shown in supplementary figure 1, 2 ; the detailed interactive reports are available online at https:// biota.knomics.ru/amm-and-gut-microbiome-2019). the proportions of bacterial taxa in each group suggest a significant dysbiosis (fig. 1) . as a major feature, there is a strong enrichment in microbes associated with inflammation-enterobacteriaceae, enterococcus, streptococcus, and staphylococcus, coupled with a depletion of commensal microbes. their relative abundance does not typically exceed 1% in healthy subjects (as estimated in the same population using similar approaches) [29] [30] [31] . microbiome compositions were different between the aci and cci groups. particularly, the [ruminococcus] gnavus species and erysipelotrichaceae family were more abundant in the cci group than in the aci group (adj. p = 0.01 and 0.06, respectively; fig. 1 ); for both taxa, these differences were also reflected at higher taxonomic ranks. unlike the cci group, the aci group included nonsurvivors (in total 7 survivors and 2 non-survivors). due to the imbalance between the two survival categories and small sample size, a reliable comparison between them could not be performed. noteworthy, a selection of grampositive microorganisms was observed in non-survivors: one patient on the first day had an extremely high level of staphylococcus aureus (70.9%) compared with other patients (less than 0.1%); the other patient had more than 40% streptococcus spp. in the fecal sample. the alpha diversity of the gut microbial community was lower in the aci group compared to that in the cci group (5.2 ± 1.7 vs. 6.2 ± 1.0, shannon index, p = 0.0627; fig. 2a) . the mean value of the shannon diversity index in the healthy population estimated in the previous study was 6.2 ± 0.6 [29] . the dynamics of alpha diversity during hospitalization are shown in fig. 2b , c. while it sharply decreased in the aci group, it remained relatively stable in the cci one. overall, the observed stronger imbalance in the gut microbiome composition and dynamics in the aci patients than in the cci group corresponds with a higher severity in the former group. the summary levels of microbial metabolites (∑amm) in the serum samples were higher for the aci patients than for the cci patients (3.7 (1.4-6.3) and 1.1 (1.0-1.6) μm, respectively; p = 0.0003). for each of the groups, the distribution was different than in samples of the healthy subjects-2.0 (1.4-2.3) μm (p < 0.05) (fig. 3) . the qualitative composition of sfs was also different compared to the healthy subjects (fig. 4) . we observed a prevalence of ba, p-hphla, p-hphpa, and p-phaa in the aci group with a higher level of ba in the gut and hva in the serum of non-surviving patients and a predominance of hydroxylic acids (p-hphaa and p-hphpa) in the cci samples. on the contrary, the sfs of the healthy subjects were characterized by an absolute prevalence of phpa as well as by low (around 2 μm) levels of all amm. overall, the serum as well as the fecal amm profiles appeared to be disrupted in critically ill patients, with a more pronounced alteration for the aci group and especially in non-survivors (fig. 4) . we compared the levels of all amm between feces and serum in a paired way (fig. 5) . there were only a few metabolites for which these levels were correlated. in the cci group, a positive samemetabolite correlation was observed for phla (pearson correlation, r = 0.4232), p-hphpa (r = 0.6153), and p-hphla (r = 0.3905). in the aci group, a similar effect was observed only for phpa (r = 0.4682); fig. 4 comparison of the amm qualitative profiles in serum and feces. the amm profiles in feces and serum from the healthy subjects (n = 23), the aci patients (survivors, n = 7; non-survivors, n = 2), and the cci (n = 9) patients. the data are presented as the median within-group proportion of each acid among all amm. ba benzoic acid, phpa phenylpropionic acid, phla phenyllactic acid, p-hba p-hydroxybenzoic acid, p-hphaa phydroxyphenylacetic acid, p-hphpa p-hydroxyphenylpropionic acid, hva homovanillic acid, p-hphla p-hydroxyphenyllactic acid fig. 5 correlations between aromatic metabolite levels in feces and serum. the size of circles denotes the absolute value of the pearson correlation coefficient between metabolite levels; blue colors show negative and red positive correlations. asterisks denote significant associations (***raw p < 0.01, **raw p < 0.05) and trends (*raw p < 0.1). phpa phenylpropionic acid, phla phenyllactic acid, p-hba p-hydroxybenzoic acid, p-hphaa p-hydroxyphenylacetic acid, p-hphpa p-hydroxyphenylpropionic acid, hva homovanillic acid, p-hphla p-hydroxyphenyllactic acid noteworthy, the correlation patterns did not overlap between the two groups of patients. there were also several associations between feces and serum levels of distinct metabolites. in the cci group, the p-hphla level in the feces correlated with the levels of two metabolites in the serum-phla (r = 0.3796) and p-hphaa (r = 0.4182). the phla level in feces also positively correlated with p-hphla in serum (r = 0.3620). in the aci group, the p-hphpa level in the feces correlated with hva (r = 0.4392) and p-hphaa (r = 0.3517) in serum. additionally, in the aci group, the p-hphaa in the feces strongly correlated with p-hphla in the serum (r = 0.4880) (the opposite observation was made in the cci group-i.e., for p-hphaa in the serum vs. p-hphla in the feces). we examined associations between and within three types of measurements: microbial genera levels and metabolite concentrations in blood serum and in feces. this analysis was conducted separately for the aci and for the cci group. healthy control samples were not included due to the lack of microbiome data. the associations are summarized on the graph (fig. 6) . the analysis of the clusters of co-occurring microbes and correlations of these clusters with metabolites revealed interesting differences between the aci and the cci groups. one of the microbial clusters similar between the two groups included opportunistic pathogens: klebsiella, serratia, and unclassified enterobacteriaceae. in the cci group, the cluster was not associated with any of the metabolites neither in the serum nor in the feces. however, in the aci group, it had positive associations with hva and p-hphaa in the serum and negative with hva in the feces. as shown above, high serum hva levels were revealed for non-survivors in the aci group. previously, we have observed increased hva and p-hphaa levels in patients with septic shock [32] . in the cci group, there was another microbial cluster including gut opportunists enterococcus, unclassified enterococcaceae, and peptostreptococcus that was negatively associated with p-hba in feces. both groups of patients also included a number of cooccurring bacterial clusters previously observed in healthy gut microbiota [29, 31] . the largest cluster in the aci group included commensal microbes: unclassified lachnospiraceae, clostridiaceae and coriobacteriaceae, ruminococcus, blautia, oscillospira, and dorea. the same bacteria formed several distinct clusters in the cci group. however, the cluster had significant associations with metabolite levels only in the aci group-the positive associations with phpa levels in feces and serum and p-hphpa levels in feces. the described graphs include associations between bacterial genera and metabolites. the associations between all taxonomic level taxa and metabolite levels are additionally listed in table 2 . overall, the number of discovered associations between microbiome composition and metabolites was lower for the cci group. for some metabolites (p-hphpa, hva, and p-hphaa), the associations were fig. 6 microbe-metabolite interactions in critically ill patients. in the graphs, the nodes are bacterial genera (red) and metabolites in blood (green) and feces (blue). the edges denote significant positive (gray-colored) and negative (red-colored, dotted) associations only observed in the aci group, while for p-hphla and p-hba, only in the cci group. the associations with microbes were quite unique between serum and fecal metabolite levels. the only common association was [ruminococcus]-positive correlation with phpa in the aci group. interestingly, some of the associations had opposite directions for metabolites measured in feces and serum: the hva serum level in the aci group was positively associated with some proinflammatory bacteria (serratia, klebsiella) in the serum and negatively, in the feces. in addition to the analysis of individual taxa, the alpha diversity of the microbial community was also compared with amm concentrations. we detected positive association between alpha diversity and p-hphpa fecal level in the aci group (shannon diversity index, fdr = 0.0017). in this prospective observational pilot study, taxonomic and metabolic characteristics of gut microbiota were evaluated in critically ill patients and healthy subjects. the dynamics of the metagenome were compared between the aci and cci patients to shed light on the evolution of the microbial community in the icu during transition from acute to chronic state. we discovered a pronounced dysbiosis with a prevalence of proinflammatory taxa and a reduced diversity in both groups of patients-in agreement with the results of previous studies [1, 2] . there were profound changes in the qualitative and quantitative profiles of amm in comparison with the healthy subjects. the major findings of this study were associative patterns between clusters of microbial taxa and aromatic metabolite levels (in serum and feces). we observed certain differences in baseline microbiome composition of the aci and cci groups of patients. the cci group had higher relative abundance of erysipelotrichaceae family and [ruminococcus] gnavus species-opportunists that could contribute to the chronic illness severity. the members of erysipelotrichaceae appear to be highly immunogenic and can potentially overgrow in the gut after treatment with broad-spectrum antibiotics [33] [34] [35] . multiple studies associate the enrichment of the mucus-dwelling [ruminococcus] gnavus taxon with inflammatory bowel diseases [36] [37] [38] (in our cohort, it was about an order of magnitude greater than reported in healthy subjects). these findings, along with the overall unstability of the patients' microbiota (supplementary figs. 1 and 2) , will be validated in our further studies with a higher number of subjects in each group. we observed qualitative and quantitative imbalance of microbial metabolites in two groups of patients in comparison with healthy subjects. the profile of amm in the cci group can be described as "less and mess" (a low quantity and modified composition) characterized by a significantly lower concentration of phpa and sum of amm in comparison with the healthy subjects. at the same time, the summary levels of microbial metabolites in the serum samples were higher for the aci patients. earlier, we have shown that the sum of three amm (p-hphaa, p-hphla, phla) reflects the severity of disease in patients admitted to icu as good as conventional scales apache ii and sofa [32, 39] and their concentrations increased in dynamics in non-survived patients [26] , due to their production by pathobionts, such as staphylococcus aureus, klebsiella pneumonia, acinetobacter baumanii, pseudomonas aeruginosa, and escherichia coli [40, 41] . remarkably, we discovered that associations between microbial taxa clusters and metabolite concentrations in blood serum and feces varied between the aci and cci groups. in the aci group (including patients with pneumonia), a significant positive correlation between serum and feces was observed for phpa metabolite only. at the same time, in cci patients (without any locus of infection), such link was observed for phla, p-hphpa, and p-hphla metabolites. this suggests the existence of microbial networks involved in aromatic compound metabolism which undergo disruption in a critically ill host, and the degree of such disruption might vary in acute and chronic illness. further studies based on genomic reconstruction of the respective pathways will elucidate the robustness of such networks and roles of particular species in their ecology. our hypothesis was that not only the gut might contribute to metabolic activity but also other sites of infection-for example, lungs, as in cases of aci patients with nosocomial pneumonia. accordingly, in the aci group, the serum level of hva is positively associated with klebsiella and serratia genera but these associations were negative for feces. hva is a major catecholamine metabolite, a deaminated and o-methylated metabolite of dopamine [42] . the strong correlations between p-hphaa and hva and the presence of shock and also the possibility of bacterial biodegradation of p-hphaa into inhibitors of catecholamine synthesis confirm the involvement of amm in the pathogenesis of septic shock [32] . for example, k. pneumoniae [43] , p. aeruginosa [44] , and other gram-negative species are capable of degrading p-hphaa to 3,4-dihydroxymandelic acid (dhma) and 3,4-dihydroxyphenylacetic acid (dopac), with the subsequent formation of hva. the results of a previous pilot study suggested associations between endogenous catecholamines and features of the bacterial lung microbiome that contribute to the pathogenesis of respiratory infections [45] . the catabolism of these compounds in vitro followed by growth has been demonstrated for many microorganisms including p. aeruginosa [46, 47] . interestingly, phpa levels were close to undetectable in both groups. the phpa deficiency was observed in various serious diseases including sepsis [41] . in our cohort, one of its precursors-p-hphpa-has a positive correlation with gram-positive bacteria (including christensenellaceae, oscillospiraceae families, and [ruminococcus] genera) commonly representing a healthy microbiome (table 2) . presumably, the presence of such bacteria allows maintaining a long-lasting adequate metabolism even in critical conditions. the christensenellaceae and oscillospiraceae families have previously been shown to include microorganisms with potential health benefits: they are associated with lower body mass index (bmi) [48] and contribute to the formation of secondary bile acids [49, 50] . one of the interesting associations which we found was between akkermansia and p-hphla in the cci patients. a. muciniphila is a mucin-degrading bacterium of the verrucomicrobia phylum linked to metabolism in animals and humans due to its potential antiinflammatory properties [51, 52] . however, the microbe has been also linked to proinflammatory pathways, playing an important role in neurodegenerative disease [53] -an intriguing fact in the context of our cci group including neurorehabilitation patients. although its relation to p-hphla metabolism has not been assessed, the ability to produce the compound (as well as phla) was demonstrated in vitro for some strains of the species lactobacillus and bifidobacterium species [14] , while species of anaerobic bacteria (bacteroides fragilis, b. thetaiotaomicron, clostridium perfringens) were linked to reduced levels of this acid [18] . further study is needed to evaluate the potential role of the p-hphla as a factor that can reflect the gut microbiota dysbiosis and whether extreme alterations in gut microbiota are associated with patient neurological disorders. the present study has some limitations. firstly, in this pilot project, the sample size is rather small and further studies will be conducted to validate the observed links of critical illness severity with the gut microbiota composition dynamics and metabolome. the antibiotic use was extensive, with the set of antibiotics and their classes widely varying from subject to subject. although it did not allow a direct statistical adjustment for this factor, we did not observe distinct differences between the cci and the aci groups. although all patients received similar enteral nutrition, in the aci, the first sample was collected before its start. also, inotropic support rate and bmi were different between the groups. overall, together with different diagnoses, the observed heterogeneity for many factors is typical in icu setting and may have confounded our results. our results highlight the complexity of metabolic interactions between the members of the gut microbial ecosystem, especially when the diversity declines dramatically in critical conditions. this concept can be well demonstrated by community-level microbial ecology models based on genomic metabolic reconstructions, where it is shown that, despite marked resource competition at the level of whole assemblies, microbial communities harbor metabolically interdependent groups which recur across diverse habitats. cooperating groups can make efficient use of limited resources through metabolite exchange, providing a survival advantage and enabling coexistence in diverse niches [54] . we believe that understanding the metabolic language of microorganisms and moving from the concept of single pathogens to a holobiont will serve as a catalyst for the development of new disease prevention and treatment strategies based on a multi-omics approach. overall, there is a great challenge in improving clinical predictive models for critically ill patients using microbiome-related parameters. its urgence is being supported by the currently developing situation of treating covid-19 patients faced by clinicians in icu worldwide: secondary bacterial infections are likely to worsen the outcomes [55] , with some of the opportunists originating from the gut. our results confirm that amm are promising biomarkers that can be routinely measured using gc-ms to facilitate therapeutic decisions. the method advantages include simple sample preparation, cost-effectiveness, and short time of analysis (several hours). additionally, although 16s rrna analysis is yet to become rapid enough to be applicable in icu, our findings highlighted clinically relevant biomarker taxa that can be analyzed using quicker tests like taxonspecific qpcr tests [56] . we identified a distinct gut microbiome composition in chronically and acute critically ill patients, with the latter characterized by extremely low diversity. a relationship was found between the alterations of microbiome and changes in serum and fecal profiles of aromatic microbial metabolites. variation of these associative patterns between two groups of the patients suggests different scenarios of microbiome imbalance-mediated contribution to the risks of disease severity. analysis of aromatic metabolites combined with microbiome survey is a promising way for improving efficacy of surveillance and treatment in icu. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03031-0. metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients impact of antibiotics on the gut microbiota of critically ill patients microbiota-targeted therapies on the intensive care unit extreme dysbiosis of the microbiome in critical illness the role of the intestinal tract as a source for transmission of nosocomial pathogens functional redundancy-induced stability of gut microbiota subjected to disturbance gut microbiota composition and activity in relation to host metabolic phenotype and 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inevitability of the covid-19 coronavirus becoming endemic development of qpcr platform with probes for quantifying prevalent and biomedically relevant human gut microbial taxa available online 15 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank dr. ilya volkov and dr. alexander plugov for their help in sequencing the samples. also authors' contributions ec and nb designed the study. ec, vg, and ds worked with patients. ap performed the gc-ms analysis. ea, nk, and at performed the data analysis. ea, nv, ap, nk, and at wrote the manuscript. all authors read and approved the final manuscript. none. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. not applicable. the authors declare that they have no competing interests. key: cord-331395-12bff84n authors: li, jingwen; yu, xiaxia; hu, shaoping; lin, zhicheng; xiong, nian; gao, yi title: covid-19 targets the right lung date: 2020-06-15 journal: crit care doi: 10.1186/s13054-020-03033-y sha: doc_id: 331395 cord_uid: 12bff84n nan jingwen li 1 † , xiaxia yu 2 † , shaoping hu 3 , zhicheng lin 4 , nian xiong 1,5* and yi gao 2* previous imaging studies of covid-19 suggested that bilateral lungs be affected [1] . in this study, we noticed a side-preference of lung lesions in covid-19. the lesions on the right lung were significantly larger and developed faster than those on the left. moreover, the level of right-over-left preference of lung injury was significantly correlated with the potential need for intensive care and inpatient mortality. pulmonary lesions were imaged by a total of 253 high resolution computed tomographic (ct) chest scans of 103 covid-19 patients at wuhan red cross hospital. of the 103 patients with a median (interquartile range (iqr)) age of 63 (47-70) years, 57 were males, 41 were in the intensive care unit (icu), and 64 were deceased during hospitalization. at the time of the study, only 1 patient was still in the icu. the median (iqr) length of known hospital stay was 16 (10-24) days. two independent assessments of the images were conducted. first, one physician visually evaluated the level of injury on either side of the lung and provided percentage-based semiquantitative scores on the injury of the lung for either side (0: no, 1: < 5%, 2: 6-25%, 3: 26-50%, 4: 51-75%, 5: > 75% injury). second, an automatic deep learning-based algorithm [2] extracted the three-dimensional (3d) features of all lesions that were validated by physicians. then, quantitative volumetric analysis and comparisons were carried out for rightversus left-side lesions' volumes and their growth speed. as a result, 70% (31/103) ct scans showed that the lesion volume of the right lung was larger than that of the left lung. figure 1 shows a typical case in panels a and b. in addition to the first-time ct of each patient, we studied 253 longitudinal ct images of 103 patients (2-3 time points/patient). in order to facilitate the discussion below, here we denoted delta (δ) as the difference of the volume of the lesion on the right lung and that of the lesion on the left lung. a potential association between the age and δ was also analyzed. the results showed that the older the patient, the larger the δ (χ 2 test for linear terms, f = 11.9466, p < 0.0001) (fig. 2a) . moreover, the non-survivors had bigger δ than the survivors (one-sided t test, p < 0.0001) (as shown in fig. 1c ). smooth curves were fitted for δ and a log risk ratio was used for death. these results indicated the lowest risk ratio when the δ was around 0, and the differences between the left and right lungs were minimal. the risk for death increased with larger δ (p = 0.013, fig. 2b) . in order to understand which side was correlated with a severe form of the disease, fisher's extract test was used to compare the fatality risk of patients with smaller lesions on the left side to those with larger lesions on the left. the results suggested that patients with large lesions on the right lung be at a high mortality risk during hospitalization (or = 2.662, p value = 0.0252 (fig. 2c, d) . for instance, foreign bodies are likely to be aspirated in the right bronchus because of the short, wide, and straight path [3] . tuberculosis prefers the right upper lobes [4] , which might be attributed to the oxygen distribution ratio. in covid-19, the right sidepreference was consistent with a reported autopsy result that the right lung was subject to hemorrhage [5] . these results draw care attention to the right lung in this novel pneumonia. fig. 1 a 3d renders the highlights of a lesion on the right lung (view from posterior). b 3d extraction of the lesions. c comparison of δ in nonsurviviors and survivors (one-sided t test, p < 0.0001) fig. 2 statistical analysis. a correlation between age and delta. age was categorized into five groups. b association between δ and relative death ratio. c comparison of mortality in patients with δ < 0 and δ ≥ 0. mortality rate of non-survivors was shown in cyan; mortality rate of survivors was shown in red. d contingency table for δ and mortality radiological findings from 81 patients with covid-19 pneumonia in wuhan, china: a descriptive study mcmc guided cnn training and segmentation for pancreas extraction foreign body aspiration into the lower airway in chinese adults characterizations in digital chest x-ray of 459 pulmonary tuberculosis clinical pathology of critical patient with novel coronavirus pneumonia (covid-19) publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions zl, nx, and yg helped in the conception and design of the study. jl and sh contributed to data collection. xy and yg contributed to data analysis and draft writing. yg and nx contributed to the final version of the manuscript before submission. all authors commented on previous versions of the manuscript and read and approved the final manuscript. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.ethics approval and consent to participate wuhan red cross hospital provided the waiver of consent before participation in the study. not applicable. the authors declare that they have no competing interests. key: cord-346307-xejs2va1 authors: rysz, susanne; jalde, francesca campoccia; oldner, anders; eriksson, lars i.; lundberg, johan; fagerlund, malin jonsson title: treatment with angiotensin ii in covid-19 patients may not be beneficial date: 2020-09-04 journal: crit care doi: 10.1186/s13054-020-03233-6 sha: doc_id: 346307 cord_uid: xejs2va1 nan we read with great interest the recent article by zangrillo et al. regarding infusion of angiotensin ii (angii) in covid-19 [1] , stating that angii vasopressor treatment may be logical in the setting of covid-19 patients requiring vasopressor support. the authors refer to the athosiii trial as support for the use of angii in catecholamine-resistant vasodilatory shock despite the known concern for thrombotic and infectious complications associated with angii [2] . in addition, the authors suggest to use angii in covid-19 patients recently exposed to angiotensin-converting enzyme inhibitors. we believe that both these statements raise some concern. sars-cov-1 downregulates ace2 with a subsequent increase in angii levels creating a disruption akin to over activating the renin-angiotensin-aldosterone system (raas) [3] . in a recent covid-19 case series, angii levels were markedly elevated and linearly associated with viral load and lung injury [4] . moreover, in a prepublished report currently under journal review, infusion of angii in a porcine model rapidly (within hours) induced a clinical syndrome closely reflecting the one seen in covid-19 patients, including histological changes in the lungs with severe thickening of the alveolar walls, possible hyaline membranes, and clotting of vessels, as previously reported in the human covid-19 phenotype [5] . we suggest that much of the pathophysiology in icu patients with covid-19 is potentially driven by a loss of the inhibition of the raas, causing supranormal concentrations of angii [5] . in our opinion, the use of angii in covid-19 patients is therefore at present most questionable. rather, we propose further evaluation of a plausible contributing mechanism of raas behind pathophysiology seen in covid-19. we thank dr. rysz and colleagues for their correspondence [6] . in response, we note that their concerns about the increased risk of thrombosis and infection with angiotensin ii have no statistical substance. in addition, for objectivity, other adverse effects would also have to be similarly considered, such as a 34% reduction in adverse effects leading to discontinuation compared to placebo, or the 34% reduction in respiratory adverse events, or the absolute 6.4% reduction in serious adverse events compared to placebo [7] . the endocytosis of ace2 following contact with the covid-19 virus could be decreased by conformational changes in ace2 secondary to angiotensin ii binding to it. in addition, such binding could itself decrease the ability of the virus to bind to the receptor and enter the cell. such hypothetical interactions, however, remain unmeasured. moreover, it is not a surprise that angiotensin ii levels are higher in patients with greater viral load and illness severity. such high levels can easily represent the response to inflammatory vasodilatation and the body's attempt to restore perfusion pressure. finally, the infusion of angiotensin ii in the porcine model cited by the correspondents is clearly irrelevant to angiotensin therapy in humans as described in our report [1] . we administered 20 ng/kg/min [1] , while the investigators escalated to 80 ng/kg/min within 60 min and then all the way to 240 ng/kg/min. in other animals, the dose was up to 640 ng/kg/min. at such toxic doses which were 10 to 30 times those administered to our patients, it is no surprise that toxic, even lethal side effects developed. until more relevant experiments are performed or clear evidence emerges that angiotensin ii infusion is injurious in covid-19 patients, the data are strong that angiotensin ii is a safe and effective vasopressor agent [8] especially in patients with high renin levels [9] . angiotensin ii infusion in covid-19-associated vasodilatory shock: a case series brings more questions than answers angiotensin-converting enzyme 2: sars-cov-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ace2 clinical and biochemical indexes from 2019-ncov infected patients linked to viral loads and lung injury covid-19 pathophysiology may be driven by a loss of inhibition of the renin-angiotensin-aldosterone system. prepri nt (version 2) available at research square treatment with angiotensin ii in covid-19 patients may not be beneficial. crit care angiotensin ii for the treatment of vasodilatory shock the athos-3 trial, angiotensin ii and the three musketeers renin and survival in patients given angiotensin ii for catecholamine-resistant vasodilatory shock not applicable authors' contributions sr, jl, and mjf drafted the paper. all authors critically reviewed the manuscript. all authors read and approved the final version of the manuscript. availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-325694-xx6m60hv authors: kneyber, martin c. j.; engels, bernadette; van der voort, peter h. j. title: paediatric and adult critical care medicine: joining forces against covid-19 date: 2020-06-16 journal: crit care doi: 10.1186/s13054-020-03074-3 sha: doc_id: 325694 cord_uid: xx6m60hv nan paediatric and adult critical care medicine: joining forces against covid-19 martin c. j. kneyber 1,2* , bernadette engels 1 and peter h. j. van der voort 2, 3 the increasing number of covid-19 intensive care unit (icu) admissions in our hospital necessitated increasing the number of physical icu beds and staffing. this could be done by redeploying paediatric critical care physicians and nurses to adult icus. however, paediatric icus (picu) are exclusively located in university hospitals in the netherlands, hence redeployment potentially could reduce capacity for critically ill children [1] . we thus decided to maintain our current picu capacity and to re-open, for adult covid-19 care, the part of our picu that was closed due nursing staff shortage [2] . the main hurdle was how to staff the unit. picu physicians and nurses advocated to remain in their environment and use the well-established working relationships within the picu bedside team when caring for the adult covid-19 patients because the general principles of intensive care medicine would not be different between children and adults [3] . also, the clinical phenotype of adults with covid-19 matched perfectly the research focus of our picu, providing opportunities to study respiratory system mechanics in these adults [4] . to increase availability of picu nurses, we upgraded their employment contract to 1 full-time equivalence, and all granted leaves of absence were revoked until further notice after consulting human resources and approval of the board of directors. the entire nursing team was split into two. one group of nurses originally coming from the adult icu before becoming a picu nurse were exclusively allocated to the covid-19 part of our picu. these nurses and our own picu consultants were the primary care providers. an adult intensive care unit consultant reviewed patient plans twice a day to guarantee quality of adult critical care [5] . the 6-bedded covid-19 unit located in the picu opened at the end of march and remained open for six weeks. our icus admitted 98 adult covid-19 patients, 12 of them were treated in the picu by paediatric nurses and intensivists. all but one of these 12 survived to picu discharge (table 1) . preserving the picu team ensured a rapid transition and boosted morale. this period proved to be a unique collaboration between paediatric and adult intensivists and unforgettable experience. it made picu practitioners stronger in many ways and sets in motion a stronger relationship between paediatric and adult critical care medicine in our hospital. also, picu occupancy remained > 80%, supporting our decision not to reduce picu capacity and not to redeploy staff. the necessity for centralization of pediatric intensive care repurposing a pediatric icu for adults a history of pediatric critical care medicine recommendations for mechanical ventilation of critically ill children from the paediatric mechanical ventilation consensus conference (pemvecc) caring for critically ill adults with coronavirus disease 2019 in a picu: recommendations by dual trained intensivists publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. the authors drafted the manuscript and approved the final version. not applicable.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. none to disclose for both authors.author details 1 key: cord-327622-ezgufe24 authors: kaur, ramandeep; weiss, tyler t.; perez, andrew; fink, james b.; chen, rongchang; luo, fengming; liang, zongan; mirza, sara; li, jie title: practical strategies to reduce nosocomial transmission to healthcare professionals providing respiratory care to patients with covid-19 date: 2020-09-23 journal: crit care doi: 10.1186/s13054-020-03231-8 sha: doc_id: 327622 cord_uid: ezgufe24 coronavirus disease (covid-19) is an emerging viral infection that is rapidly spreading across the globe. sars-cov-2 belongs to the same coronavirus class that caused respiratory illnesses such as severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers). during the sars and mers outbreaks, many frontline healthcare workers were infected when performing high-risk aerosol-generating medical procedures as well as when providing basic patient care. similarly, covid-19 disease has been reported to infect healthcare workers at a rate of ~ 3% of cases treated in the usa. in this review, we conducted an extensive literature search to develop practical strategies that can be implemented when providing respiratory treatments to covid-19 patients, with the aim to help prevent nosocomial transmission to the frontline workers. coronavirus disease (covid-19) cases were first reported to the world health organization on december 31, 2019 [1] . since then, this illness has spread exponentially in over 200 countries. as of june 9, 2020, there were 7,039,918 confirmed cases of the covid-19 disease globally [2] . even though the exact mode of covid-19 transmission has been debatable, the route of covid-19 transmission is reported to be from personto-person contact and exposure to respiratory droplets (> 5-10 μm) [3] , whereas airborne transmission (< 5 μm) during aerosol-generating procedures remains under investigation [4, 5] . based on the initial data reported [6] [7] [8] [9] [10] [11] [12] , around 5-30% of covid-19 patients develop signs of severe respiratory distress requiring intensive care unit (icu) admission to receive advanced respiratory support in terms of oxygen therapy, non-invasive and invasive ventilatory support with prone positioning (table 1) . standard droplet and contact precautions (gowns, gloves, mask) are known to reduce the risk of contracting severe acute respiratory syndrome (sars) [13] but not under all circumstances, especially when performing high-risk procedures such as intubation [14] . a recent systematic meta-analysis showed that a physical distance of 1 m or more and wearing a mask is optimum to reduce person-to-person virus transmission and to keep healthcare workers (hcws) from contracting the sars-cov-2 infection [15] . during the sars outbreak, many table 1 use of respiratory interventions in covid-19 patient population study huang et al. [5] (n = 41) wu et al. [6] (n = 201) wang et al. [7] (n = 138) guan et al. [8] (n = 1099) yang et al. [9] (n = 52) arentz et al. [10] (n = 21) grasseli et al. [11] (n = 1591) richardson et al. [12] (n = 5700) frontline hcws were infected via nosocomial transmission due to failure to implement adequate infection control precautions, especially when performing aerosolgenerating medical procedures (agmps) [16] [17] [18] , such as bronchoscopy, intubation, suctioning, invasive and non-invasive ventilation (niv), bag mask ventilation, and nebulization [19] [20] [21] . in a prospective study, macintyre et al. [22] reported that clinicians who performed agmps were at greater risk of acquiring the infection as compared to those who were not involved in such procedures [ [23] . until further high-quality evidence, including well-conducted randomized controlled trials, is available to demonstrate the definite role of agmps in spreading nosocomial infection, it is best to use the data available from past outbreaks to implement additional safeguards. in this review, we performed a comprehensive literature search to present practical strategies (table 2) to reduce the risk of nosocomial transmission when delivering agmps to patients with covid-19. these suggestions are to be utilized in addition to the cdc recommendations available for proper personal protective equipment (ppe) for hcws. a literature search was performed via pubmed and scopus databases using the following keywords: ("coronavirus" or "covid-19" or "severe acute respiratory syndrome" or "sars" or "middle east respiratory syndrome" or "mers" or "h1n1") and ("aerosol generating procedures" or "nosocomial infection"). publication types included systematic review, meta-analysis, randomized clinical trials, and observation studies. the study population involved hcws providing respiratory care including agmps to patients infected with sars, mers, influenza a virus subtype h1n1 (h1n1), or covid19. in vitro studies investigating the role of exhaled air dispersion when providing agmps were also included. published letters, book chapters, conference abstracts, and editorials were excluded. the literature search was limited to articles published until may 2020. the detailed selection process conducted is shown in fig. 1 . a common clinical finding with covid-19 is cough [7] . coughing, speaking, laughing, and breathing have been associated with generation of bio-aerosols capable of carrying the virus [46, 47] . the bio-aerosols can range from 0.1 to 100 μm, and particles smaller than 1 μm have been reported to disperse to greater distances and remain airborne for several hours [5, 48, 49] . large particles tend to settle directly on surfaces surrounding the patients, with reports of surface swabs testing positive across the patient's room [5, 50] . a recent experimental study indicated that the covid-19 virus can remain viable and infectious in aerosol for hours and on surface for days [51] and virus-laden aerosol deposition plays a role in surface contamination [4] . some medical procedures that cause/irritate patients to cough or sneeze, such as bronchoscopy and nasal-pharyngeal suctioning, lead to the generation of bio-aerosols from patients. in contrast, other medical procedures do not "generate" bio-aerosols but increase the dispersion of bio-aerosols generated by infectious patients, such as niv and highflow nasal cannula (hfnc) oxygen therapy [5, 19] . based on cdc guidelines, hcws performing agmps should wear n95 or high-level respirators along with eye protection, gloves, and a gown. furthermore, the number of personnel entering patient's room during agmps should be limited and procedures should be ideally performed in an airborne infection isolation room [52] . supplemental oxygen therapy is essential for patients with hypoxemic respiratory failure. while supplemental oxygen has not been shown to generate bio-aerosols, they may have a role in dispersing them. in an in vitro study using a human simulator with smoke (< 1 μm aerosol of solid particles) exhaled through airway, hui et al. examined the exhaled air dispersion during oxygen delivery via nasal cannula. the results showed that exhaled air dispersion increased as oxygen flow was increased from 1 to 5 l/min and substantial exposure occurred within 1 m from the bed in a negative pressure ventilation room [24] . a substantial increase in lateral exhaled air dispersion is reported as the oxygen flows increased [25] [26] [27] . the same group of researchers using a similar model reported that both nonrebreather and air-entrainment masks increased exhaled air dispersion [25] [26] [27] . exhaled air dispersion distance was further with the air-entrainment mask than simple and nonrebreather masks [53] . placing a simple surgical mask on patient's face has been reported to reduce the exhaled dispersion distance [28, 29] and the influenza a virus load [30] during a cough. surgical masks and n95 masks are similarly effective at preventing influence virus exposure [30] . placing either mask on a patient with confirmed covid-19 can help reduce the dispersion of bio-aerosols [15] . based on these findings, when a standard nasal cannula is used to deliver low-flow oxygen therapy, a surgical mask should be placed over the patient's face. the air-entrainment mask should be avoided for patients with covid-19, if possible. if higher delivered f i o 2 is needed, a closed non-breather mask with a filter could be considered [54] . oxygen delivery via hfnc has become widely used in patients with acute hypoxemic respiratory failure due to its benefits of meeting or exceeding patient inspiratory flow demand, reducing oxygen dilution, and washing out pharyngeal dead space [55] . hfnc has been shown to reduce the need for endotracheal intubation when compared to conventional oxygen delivery devices [56] . two retrospective studies examining the effects of hfnc in patients with acute hypoxemic respiratory failure secondary to covid-19 showed that hfnc was able to maintain adequate oxygenation and reduced the need for niv and mechanical ventilation [32, 57] . exhaled smoke dispersion, from a manikin during hfnc treatment, was shown to significantly increase with increased flow rate [58] . interestingly, the dispersion distance from the hfnc at 60 l/min was shorter than an air[24] [25] [26] [27] [28] 3 in vivo [29] [30] [31] • use nasal cannula and place a surgical/procedure mask on the patient's face • avoid venturi mask • avoid nonrebreather mask unless it is filtered 2 high-flow nasal cannula 1 in vitro [32] 2 in vivo [15, 31] • proper nasal cannula fitting • place a surgical/procedure mask over hfnc on the patient's face (fig. 2) 3 nebulization 2 in vitro [33, 34] 2 in vivo [22, 35] • use metered dosed inhaler with spacer when possible • avoid using small volume nebulizer unless it is filtered (fig. 3a , b) • use nebulizer in line with hfnc or via ventilator 4 lung expansion and airway clearance therapy* 3 in vivo [22, 35, 36] • if using ippb, place a filter between circuit and mask or mouthpiece, or on expiratory port • if possible, avoid cough inducing therapies such as intermittent percussive ventilation and cough assist • during high-frequency chest wall oscillation therapy, place a surgical/ procedure mask on the patient's face 5 non-invasive ventilation* 2 in vitro [37, 38] 2 in vivo [39, 40] • use tight fit oral mask without leaks, consider helmet or total face mask if available • avoid using nasal mask • when using non-heated-wire single-limb circuit, place a filter between the non-vented mask and the expiratory port ( fig. 4a ) • if humidification is required, heated wire single-limb circuit with filter placed at the expiratory port for non-invasive ventilator (fig. 4b) • avoid cool aerosol for tracheostomy patient, instead use hme. if the patient needs frequent suctioning (more than once every hour), place an in-line suction catheter with t-piece connected to cool aerosol or heated humidification, the other end of t-piece connected to a filter (fig. 6) . additionally, if the patient has cuffless tracheotomy, place a procedure mask on patient's face • avoid using t-piece trials. if needed, use the setup with a filter described above 8 extubation* • when removing the endotracheal tube, simultaneously turn off the ventilator • avoid disconnecting ett from the ventilator circuit before extubation to reduce spray of contaminated aerosols 9 transport • place a filter between the artificial airway and the transport ventilator circuit • use hme that has filter function (hme-f) • consider clamping the ett before disconnection from ventilator circuit 10 bronchoscopy assist* 2 in vivo [44, 45] • for spontaneously breathing patients, place a surgical mask on patient's face (fig. 7a, b) • use niv mask with examination port for patients on niv (fig. 7d) • use swivel adapter to insert bronchoscope for intubated patient (fig. 7c) abbreviations: hfnc high-flow nasal cannula, ippb intermittent positive pressure breathing, hme heat moisture exchanger, ett endotracheal tube, niv non-invasive ventilation *based on cdc guidelines, these procedures should ideally be performed in airborne infection isolation rooms entrainment or nonrebreather mask [53] . a randomized controlled, crossover non-inferiority study trial reported no difference in gram-negative bacterial and total bacterial counts between hfnc at 60 l/min and simple oxygen mask at 8 l/min when air sample collection plates were placed at 0.4 or 1.5 m away from the patient [31] . it is important to note that a substantial increase of exhaled smoke dispersion was reported when the nasal cannula connection with patient nares was loose [58, 59] . because of these findings, it is suggested that a surgical or procedure mask be worn by patients receiving hfnc (fig. 2) . regular checks on the proper position and connection of the nasal cannula interface under the mask are also necessary. aerosol therapy has been identified as a high-risk procedure for nosocomial transmission, due to its active generation of aerosol, which may carry viruses into the environment [19, 60] . hui and colleagues found the maximum exhaled air dispersion distance was ≥ 0.45 m when a small volume jet nebulizer (svn) was connected to a mask at a gas flow of 6 l/min [33] . this distance was even further than niv at maximum settings (ipap 18 cmh 2 o, epap 4 cmh 2 o), using the same study method [33] . two clinical observational studies also found droplet counts significantly increased immediately after svn started to generate aerosol, particularly, the aerosol/droplet count within small and medium size range 1-5 μm, when compared to the baseline level or other procedures including oxygen therapy and niv [35] or bronchoscopy examination [44] . nevertheless, the aerosol/droplets generated by a nebulizer may not contain a virus; however, if the nebulizer is contaminated, the aerosol can carry viruses to the surrounding environment. mcgrath and colleagues [34] found that mass concentrations of aerosols/droplets were significantly reduced after placing a filter at the end of the mouthpiece for nebulizers. therefore, if aerosol therapy is indicated for covid-19 patients, svn should be avoided unless filtered, and inhalers including metered dose inhaler (mdi) and dry power inhalers (dpis) are preferred for spontaneous breathing patients who can tolerate their use without generating additional cough [61] . with mdi, a spacer with one-way valve is suggested to reduce the need for coordination and to increase lung deposition [62] . if patients are unable to use mdis or dpis, or the required medication is only available in the form of a solution, such as antibiotics, antivirals, mucokinetics, or prostanoids, nebulizers via mouthpiece with a filter placed distal to the reservoir tubing ( fig. 3a and b) should be utilized. for patients who cannot tolerate a mouthpiece or require medication administered over a prolonged period of time, such as continuous bronchodilator for asthmatic patients [63] or inhaled epoprostenol for patients with pulmonary hypertension or hypoxemia [64, 65] , in-line placement of a nebulizer with hfnc setup is recommended. this setup has two advantages: (1) more comfortable and better tolerated when compared to a mask or mouthpiece [63] and (2) a surgical mask to reduce the aerosol dispersion distance or aerosol mass concentration can be placed on the patient [53, 56] . when hfnc is utilized to deliver aerosol treatment, gas flow needs to be set relatively low if possible (10-20 l/min for adults and 0.25 l/kg/min for children), to improve the aerosol delivery efficiency [66, 67] and reduce the dispersion. vibrating mesh nebulizers or valved t-pieces for jet svns can reduce the need to break the ventilator circuit when nebulization is provided during invasive ventilation. little evidence is available regarding lung expansion therapy and nosocomial infection. lung expansion therapy is designed to treat and prevent pulmonary atelectasis. intermittent positive pressure breathing (ippb) utilizes short-term positive pressure ventilation via mask or mouthpiece to promote lung expansion. due to the risk of causing a cough response that might disperse bio-aerosols [21] , ippb should be used judiciously and with filters placed between the breathing circuit and the mask or mouthpiece. the number of particles emitted by cough from an infected patient was greater than that from a recovered patient (p < 0.001) [36] . bronchial hygiene therapies such as intermittent percussive ventilation and vibratory positive expiratory pressure irritate the airway causing the patient to cough forcefully, potentially emitting virusladen aerosols. placing a filter between these devices and patient's mouth is suggested. when intermittent percussive ventilation is utilized, nebulization via its integrated nebulizer should be avoided as the filter placed between the device outlet and patient will capture aerosols. additionally, high-frequency chest wall oscillation can be used for secretion clearance. in addition to hcws wearing proper ppe, a surgical or procedure mask worn by patients receiving the therapy may be helpful. overall, in patients with confirmed covid-19, avoid the indiscriminate use of bronchial hygiene therapies that may not be clinically indicated [61] . niv has been utilized in 10-50% of covid-19 patients in published clinical reports [6] [7] [8] [9] [10] [11] [12] . even though niv delivered by helmet was effective in terms of reducing intubation rate and 90-day mortality rate among ards patients [68] , its role in patients with severe ards remains controversial [69] . during the mers outbreak, niv was commonly used to treat acute hypoxic respiratory failure, but it had a high failure rate and was not associated with improved patient outcomes [70] . niv produces a jet of exhaled gas through the exhalation port or leak from the connection of patient's interface and ventilator, increasing dispersion distance of patient-generated bio-aerosol, and therefore it is counted as an agmp [20, 39] . consequently, niv should be used with caution for covid-19 patients and additional modifications to minimize or reduce exhaled gas/aerosol dispersion are required. in an experimental study, hui et al. reported significant exhaled air dispersion within a 0.5-m radius of the human simulator receiving niv and higher pressure settings increased the spread of exhaled air. however, the exhaled air dispersion is limited if the mask fit is appropriate [37] . when comparing helmet to total face mask, hui et al. [38] in another study demonstrated that niv application via a double-limb circuit ventilator with filters and a helmet with good seal was effective in reducing exhaled air dispersion. in contrast, niv applied via a total mask through a single-limb circuit ventilator caused increased exhaled air dispersion [38] . non-vented masks were shown to have less air dispersion as compared to vented mask [71] . thus, when vented masks are used, additional precautions for protection of the hcw may be appropriate. hcws that are in close proximity to patients receiving niv need to wear high respiratory personal protection including n95 or powered air-purifying respirator (papr). secondly, the niv circuits can be modified to place a filter. during the sars outbreak, cheung et al. demonstrated that a filter placed before the fixed exhalation port in the single-limb circuit was effective in reducing the incidence of nosocomial transmission among hcws [40] . however, due to the lack of a control group, the results of this study should be interpreted cautiously. additionally, simonds et al. showed that modifying niv circuit with a filter was effective in reducing the droplet counts [35] . thus, a filter should be placed between the non-vented mask and the exhalation port to reduce environmental contamination of bioaerosols (fig. 4a) . notably, humidification should be avoided in this type of circuit as the viral filter may capture water vapor in the circuit, resulting in occlusion for exhalation. if humidification is necessary, a modified exhalation port is needed to place a filter at the outlet (fig. 4b ). an alternative is using a dual-limb circuit ventilator with filters to deliver niv. this would allow for both humidification and the reduction in exhaled gas/ aerosol dispersion. regardless of interface/ventilator, the risk of a leak between the patient and the mask interface cannot be overlooked. choosing an appropriate interface size and type, along with the appropriate circuits and ventilators, is crucial. a good fitting oral mask is preferred and avoid using a nasal mask for patients with covid-19. if unable to get a good seal with an oral mask, consider using a total face mask or a helmet, if available. clinicians who perform or assist in endotracheal intubation are directly exposed to patient's lower airway where high concentrations of virus is accumulated. additionally, in patients with an intact cough or gag reflex, intubation may increase exhaled air dispersion [72] . therefore, intubation is considered high risk [73] . the risk of being infected when performing or assisting intubation (rr, 13.29; 95% ci, 2.99-59.04; p = 0.003) was found in the outbreak of sars in a canadian icu [39] . since then, high levels of ppe and negative pressure environments have been recommended to protect clinicians during intubation [74] . to reduce the exposure time to the sars-cov-2, the most experienced provider should perform intubation to avoid multiple attempts. video-laryngoscope has shown to be useful when intubating patients with covid-19 to increase the distance between the provider and the patient airway [74] . for a difficult airway, bronchoscopy is preferred to assist intubation, if a skilled provider is present [75] . rapid sequence intubation is also recommended, in order to minimize cough during the procedure [42, 76] . aerosol boxes [77] as well as protective shields made of glass [78] have been described as practical barriers to limit exposure to patient's exhaled droplets during intubation. while potentially useful, a documented reduction in disease transmission has not been reported and concerns regarding adequate airway view and appropriate ergonomics during intubation have been raised [79] . pre-oxygenation prior to intubation plays a crucial role in avoiding complications during intubation. multiple randomized controlled trials have shown that the utilization of hfnc for pre-oxygenation can help reduce the incidence of hypoxemia during intubation [55, 80] . the cost-effectiveness and the high risk of transmission from high gas flows should be taken into consideration before using it for pre-oxygenation prior to intubation. the traditional method of using manual ventilation via resuscitator and mask for patients prior to intubation also has some risks. exhaled gas dispersion distance has been shown to be 16-27 cm during fig. 7 a bronchoscope insertion via the nose. b bronchoscope insertion via the mouth. c bronchoscope insertion via the endotracheal tube. d bronchoscope insertion via the niv mask manual ventilation, which is similar to the distance between clinicians and the patient's airway [41] . placing a filter between resuscitator and mask (fig. 5) has been found to significantly reduce the exhaled gas dispersion distance [41, 43, 81] . for patients requiring mechanical ventilation via artificial airways, a ventilator with a dual-limb, heated wire circuit in conjunction with filters placed at the ventilator exhalation outlet is crucial [61, 73] . in addition, breaking the ventilator circuit connection should be limited and circuit changes should only be done when visibly soiled [82] . approximately 8-13% mechanically ventilated patients receive tracheostomy to facilitate the long-term need for ventilatory support [83] . for patients with covid-19, open tracheostomy is recommended over percutaneous dilational tracheostomy to reduce the risk of aerosol transmission [84] . recently, pichi et al. described standard steps to promote a safe and effective method when performing open tracheostomy in patients with covid-19 [85] . bertroche et al. [86] created a negative pressure cover to limit the exposure to the aerosols, but these methods need further investigation on the efficacy in reducing nosocomial infections. when transporting a mechanically ventilated covid-19 patient, it is suggested that a filter hme be placed between the artificial airway and the transport ventilator circuit [53] . before pausing the icu ventilator, consider clamping the endotracheal tube (ett) to prevent derecruitment and minimize the spread of bio-aerosols when transitioning patients from the icu ventilator to the transport ventilator [5, 87, 88] . when returning to the icu, clamp the ett and leave the filter connected to it to prevent accidental exposure. when ready for transition to the icu ventilator, disconnect the bacteria filter and place the patient on the ventilator before unclamping ett. the most common methods to perform a spontaneous breathing trial are t-piece trial and pressure support ventilation (psv). subirà and colleagues [89] reported that successful extubation occurred in 82.3% of patients in the psv group compared to 74.0% in the t-piece group (difference, 8.2%; 95% ci, 3.4-13.0%; p = 0.001). with these findings, in conjunction with the need to avoid opening patient's airway to the environment, psv is preferred for covid-19 patients. when a t-piece is needed, hcws should take safety precautions to minimize the exposure to a patient's airway, such as using the in-line suction catheter's t-piece with one end connecting humidified oxygen while the other end is connected to a filter (fig. 6) . this setup can also be applied for tracheostomy patients who are weaned from mechanical ventilation, particularly for patients who need frequent suctioning (more than once an hour), as this device keeps airway sealed and the filter protects hcws during suctioning. however, the filter can be clogged as it captures water vapor; hence periodically checking and replacing the filter are necessary. a filter hme can also be used to provide passive humidity [90] while humidified oxygen via a tracheostomy mask should be avoided. additionally, if the patient has a cuffless tracheostomy tube in place, a procedure mask on patient's face may reduce bio-aerosol dispersion. the process of extubation induces a cough reflex which may spread aerosols; therefore, it is imperative to use proper precautions when removing an ett [91] . during extubation, it is important to maintain the connection of the ventilator circuit and suction catheter to the ett, in order to avoid aerosol dispersion from the ventilator circuit. the extubation procedure should be performed by two hcws. in an in vitro study, a clear plastic drape was shown to significantly reduce aerosol dispersion during the extubation process; however, the feasibility of this practice requires further investigation [92] . bronchoscopy examination is considered an agmp and may be related to an increased risk for transmission of infectious airborne particles [19] . thompson et al. [45] found that bronchoscopy was associated with increased probability of aerosol generation and increased viral copies among different agmps for h1n1-positive patients. o'neil et al [44] found an increase in particle concentration when a nebulized medication administration was performed before and after bronchoscopy, while bronchoscopy examination itself did not increase concentration compared to baseline. according to the american association for bronchology and interventional pulmonology guidelines, bronchoscopy procedures are relatively contraindicated for patients with suspected or confirmed covid-19 infections when less invasive diagnostic procedures are inconclusive [93] . urgent bronchoscopy procedures should only be considered if intervention is deemed as lifesaving in patients with (1) massive hemoptysis, (2) benign or malignant severe airway obstruction, (3) suspicion of secondary infectious etiology, or (4) malignant condition that results in endobronchial obstruction. in the event a covid-19 patient requires bronchoscopic intervention, it is recommended that the patient be placed in negative pressure isolation room and personnel should don appropriate droplet precaution ppe, including a powered air-purifying respirator or n95 mask [93] . some additional precautions might also be considered to protect hcws from exposure during bronchoscopy [94, 95] . (1) for spontaneously breathing patients, if the bronchoscope is inserted via the nares, a surgical or procedure mask should be placed to cover the face (fig. 7a) . if inserted via the mouth with a bite-block, a surgical or procedure mask with a small hole cut for bronchoscope insertion should be placed on the patient's face (fig. 7b) . (2) for non-invasively ventilated patients, a special niv mask with an examination port should be used (fig. 7d) . (3) for invasively ventilated patients, a swivel adapter should be used to facilitate the bronchoscope insertion and to maintain ventilation (fig. 7c) . due to the risk of patient coughing and deep breathing during the procedure, pulmonary function testing is considered a platform for covid-19 transmission. as a result, the american thoracic society recommends limiting testing to only those with immediate treatment needs [95] and, if possible, testing should only be performed upon symptom improvement and negative realtime polymerase chain reaction tests [96] . when performing pulmonary function tests, hcws should adhere to strict infection control measures and use high specification disposable in-line viral/bacterial filters (minimum proven efficiency for high expiratory flow of 600 to 700 l/min) with the mouthpiece [97, 98] . when performing lung function testing in high-risk patients, the european respiratory society recommends that lung function testing should be limited to spirometry and diffusion capacity test. they also recommend the use of negative pressure rooms, when available [99] . currently, there is limited data available if spirometry is an aerosolproducing procedure; therefore, hcws should adhere to wearing full ppe [100] . the frontline hcws are at risk for contracting the covid-19 disease when caring for patients and providing aerosol-generating procedures. until further high-quality studies generate robust evidence, defining the precise nosocomial transmission risk associated with agmps, along with cdc's recommended ppe guidelines, we propose additional respiratory protective measures that could reduce the nosocomial transmission of covid-19 diseases to hcws providing respiratory interventions. world health organization. coronavirus disease 2019 (covid-19) situation report -1 world health organization. coronavirus disease 2019 (covid-19) situation report -141 world health organization. transmission of sars-cov-2: implications for infection 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for bronchology and interventional pulmonology (aabip) statement on the use of bronchoscopy and respiratory specimen collection in patients with suspected or confirmed covid-19 infection expert consensus on preventing nosocomial transmission during respiratory care for critically ill patients infected by 2019 novel coronavirus pneumonia protecting healthcare workers from sars-cov-2 infection: practical indications pulmonary function laboratories: advice regarding covid-19 italian pediatric respiratory society recommendations on pediatric pulmonary function testing during covid-19 pandemic task force of pulmonary function testing and clinical respiratory physiology, chinese association of chest physicians; pulmonary function testing group 1 (respiratory function technologists /scientists) lung function testing during covid-19 pandemic and beyond lung function testing in the covid-19 endemic publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank j. brady scott for his assistance with the final review of the manuscript. authors' contributions jl, rk, tw, and ap prepared the manuscript. jf, sm, rc, fl, and zl reviewed and edited the manuscript. the authors read and approved the final manuscript. availability of data and materials not applicable ethics approval and consent to participate not applicable consent for publication tyler weiss gives his consent to use his image in fig. 3a . key: cord-347833-b3yrxkt0 authors: ahlström, björn; larsson, ing-marie; strandberg, gunnar; lipcsey, miklos title: a nationwide study of the long-term prevalence of dementia and its risk factors in the swedish intensive care cohort date: 2020-09-04 journal: crit care doi: 10.1186/s13054-020-03203-y sha: doc_id: 347833 cord_uid: b3yrxkt0 background: developing dementia is feared by many for its detrimental effects on cognition and independence. experimental and clinical evidence suggests that sepsis is a risk factor for the later development of dementia. we aimed to investigate whether intensive care-treated sepsis is an independent risk factor for a later diagnosis of dementia in a large cohort of intensive care unit (icu) patients. methods: we identified adult patients admitted to an icu in 2005 to 2015 and who survived without a dementia diagnosis 1 year after intensive care admission using the swedish intensive care registry, collecting data from all swedish general icus. comorbidity, the diagnosis of dementia and mortality, was retrieved from the swedish national patient registry, the swedish dementia registry, and the cause of death registry. sepsis during intensive care served as a covariate in an extended cox model together with age, sex, and variables describing comorbidities and acute disease severity. results: one year after icu admission 210,334 patients were alive and without a diagnosis of dementia; of these, 16,115 (7.7%) had a diagnosis of sepsis during intensive care. the median age of the cohort was 61 years (interquartile range, iqr 43–72). the patients were followed for up to 11 years (median 3.9 years, iqr 1.7–6.6). during the follow-up, 6312 (3%) patients were diagnosed with dementia. dementia was more common in individuals diagnosed with sepsis during their icu stay (log-rank p < 0.001), however diagnosis of sepsis during critical care was not an independent risk factor for a later dementia diagnosis in an extended cox model: hazard ratio (hr) 1.01 (95% confidence interval 0.91–1.11, p = 0.873). renal replacement therapy and ventilator therapy during the icu stay were protective. high age was a strong risk factor for later dementia, as was increasing severity of acute illness, although to a lesser extent. however, the severity of comorbidities and the length of icu and hospital stay were not independent risk factors in the model. conclusion: although dementia is more common among patients treated with sepsis in the icu, sepsis was not an independent risk factor for later dementia in the swedish national critical care cohort. trial registration: this study was registered a priori with the australian and new zeeland clinical trials registry (registration no. actrn12618000533291). dementia is a common and often detrimental group of diseases with a sharply increasing incidence in the elderly [1, 2] . in general, the disease is characterized by memory loss, disturbances in language, altered perception, and other psychological and psychiatric changes. together, these symptoms cause impaired daily functioning [3] and may severely affect health-related quality of life [4] . in hospitalized patients, and especially in the intensive care population, sepsis is a common syndrome [5] defined by a dysregulated host response to an infection [6] . the systemic inflammation in sepsis has been suggested to have a long-term negative impact on the brain [7] . both short-and long-term effects of experimental sepsis on brain cells and behavior have been described in rodents [8] [9] [10] . septic encephalopathy and persisting cognitive disturbances have also been reported in human studies [11] [12] [13] . moreover, in patients with an assessment of cognitive function before and after hospitalization, a decline in cognitive function was more pronounced after hospitalization for severe sepsis than after admission for other reasons [14] . sepsis diagnosis has also been reported to be more common in the history of patients with dementia than age-and sex-matched controls from the health care system [15] . finally, sepsis is an independent risk factor for dementia in observational studies [16, 17] . based on these data, we hypothesized that dementia would develop more commonly in patients admitted for, or developing, sepsis in intensive care compared with other patient groups. however, the prevalence of dementia in the population is relatively low [1] . additionally, dementia is usually a slowly developing syndrome with a long subclinical period before diagnosis [18] . dementia also increases the risk of sepsis [19] , and several comorbidities are risk factors for both dementia and sepsis. we therefore set out to investigate our hypothesis in a large nationwide database with an extended follow-up and accounting for comorbidities. our primary endpoint was the hazard ratio (hr) of sepsis for a diagnosis of dementia adjusting for several potential risk factors. we also investigated the impact of these risk factors and crude dementia incidence in this cohort. this study was approved by the regional ethics committee of uppsala (approval no. 2016/421). since this is a registry-based study, informed consent was waived. the protocol of the study was registered a priori with the australian and new zeeland clinical trials registry (registration no. actrn12618000533291). reporting strictly follows the strobe statement [20] . the swedish intensive care registry (sir) is a national registry to which all general icus in sweden are reporting data on all admissions [21, 22] . the national patient register (npr) includes data from all in-patient hospital visits in sweden, and the cause of death registry includes deaths of all swedish residents, including all deaths abroad [23] . both registries are run by the swedish national board of health and welfare. the swedish dementia registry (svedem) is a national quality registry started in 2007, with primary care and specialized memory units reporting cases in sweden. the svedem had an estimated coverage ratio of 27-35% of dementia incidence in sweden in 2017, partly overlapping with the npr [24, 25] . all adult patients aged > 17 years who had at least one episode of intensive care in the sir in 2005 to 2016 were included. we excluded patients with a diagnosis of dementia at icu admission and patients who died or acquired a diagnosis of dementia during the first year after icu admission. patients in the sepsis diagnosis code cohort (henceforth referred to as the sepsis cohort) were identified by sepsis diagnosis codes registered in the sir. the diagnosis of severe sepsis and septic shock, represented as icd-10 a41.9 (2005-2010), r65.1 or r57.9 (2011-2016), has to be confirmed or negated when registering a patient in the sir. those without sepsis diagnosis codes in sir were included in the no sepsis diagnosis code cohort (hereafter referred to as the no sepsis cohort). during the entire study period, the sir defined the diagnosis of sepsis, severe sepsis, and septic shock according to the second international sepsis definitions conference of 2001 [26] . from the sir, we extracted data on the severity of illness at admission, invasive ventilator support, renal replacement therapy (rrt), icu length of stay (icu-los), and diagnoses relevant to the icu episode. for patients with repeated admissions, we used the first icu episode with a sepsis diagnosis code or, for patients without a sepsis diagnosis code, the first icu episode in the sir. we treated overlapping icu episodes as one episode. the severity of illness was initially reported as acute physiology, age, chronic health evaluation ii (apache ii) in the sir [27] and, during 2010, gradually substituted with the simplified acute physiology score 3 (saps3) [28] . death date was extracted from the cause of death registry. from the npr, we derived icd-10 [29] diagnosis codes for all inpatient care episodes from 5 years before the icu care episode to december 31, 2016. the revised charlson comorbidity index (cci) [30] was calculated using diagnoses from all health care contacts preceding or coinciding with the first icu episode. we defined dementia using the following icd-10 codes according to the cci [31] : f00x-f03x, f051, and g30x-31x. because the inpatient care diagnoses database only includes diagnoses from inpatient care, we incorporated data from the svedem to track down patients with dementia not admitted to the hospital. the date of dementia diagnosis was the first occurrence of the condition in the npr or the svedem. the swedish dementia centre, commissioned by the swedish national board of health and welfare, provides recommendations on the diagnostic process in suspected dementia. in both primary and specialist care, the recommendation is to use the diagnostic criteria of the icd-10, especially identifying the importance of symptom stability (6 months) and the exclusion of co-existing confusion [32] . for descriptive statistics, we used counts with percentages, means with standard deviations and medians and interquartile ranges (iqr) as appropriate. we assessed the crude incidence of dementia with kaplan-meier curves using the log-rank test. for the primary analysis, hrs for the risk of dementia were calculated in a cox regression model with mortality censored. the following covariates were chosen from available variables through directed acyclic graph analysis and a literature review: sepsis; age [1] and sex, all of which have been previously described as independent risk factors for dementia [33] ; cci; saps3 box 2+3; hospital length of stay (h-los); icu-los; invasive ventilator therapy; and rrt. missing data were substituted by redundancy between data sources where possible. missing saps3 box 2+3 was substituted by multiple imputations into five datasets using the multivariate imputation by chained equations (mice) package in r [34] . the results from the analyses on the imputation datasets were pooled using the harrel miscellaneous (hmisc) package in r. the proportional hazards assumption was deemed fulfilled after visual inspection of plots of scaled schoenfeld residuals against time and the covariates treated as continuous were evaluated for linearity by plots of martingale residuals against the covariate. because of nonlinearity for all continuous covariates, we used cubic splines in the cox model [35] . seven sensitivity analyses were performed according to the description in additional file 1. we defined statistical significance as p < 0.05. hrs for which cubic splines were applied were calculated between the 25th and 75th percentiles. data management and descriptive statistics were performed in spss for windows version 24 (microsoft inc., il, usa). for inference tests (i.e., regression analyses) and multiple imputations, we used r software version 3.5.3 (the r foundation for statistical computing, vienna, austria; https://www.r-project.org). of 315,155 patients, 210,334 (67%) were still alive and without dementia 1 year after icu admission (fig. 1) . of those 210,334 patients, 16,115 (8%) had a sepsis diagnosis code in icu care. the patients were followed for a median of 3.9 years (iqr 1.7-6.6). saps3 data were completely missing in 23.8% of the patients in the sepsis cohort and 45.2% in the no sepsis cohort. of patients with missing saps3, 46% had a registration of an apac he ii score in the sepsis cohort and 23% in the no sepsis cohort. missing saps3 data were imputed. of all patients admitted to the icu in 2005-2016, 8495 (4.0%) emigrated at least once from sweden, and of these, 5358 (63.1%) had at least one listing in the npr or the sve-dem > 1 year after icu admission. patients in the sepsis cohort were older, had higher saps3, and had more comorbidities, expressed as a higher cci score. they also had longer icu-los and h-los and were more commonly treated with invasive ventilation and rrt (table 1) . during follow-up, the sepsis cohort had a mean of 3.9 episodes of inpatient care, whereas 32% of these patients had no such episode. the no sepsis cohort had a mean of 3.4 episodes of inpatient care, and 38% of these patients were without any such episode. the 6312 patients ultimately developing dementia were older and predominantly female and had higher saps3 and longer icu-los and h-los than those without dementia ( table 2 ). in addition, those patients who developed dementia were less frequently treated with rrt and invasive ventilator therapy. finally, patients with dementia had a higher rate of acute surgical admissions, but a lower rate of planned surgical admissions. the size of these differences was generally small, however. dementia prevalence and 1-year mortality increased with age in patients admitted to the icu during the study and alive on the last day of follow-up (december 31, 2016) (fig. 2) . in the unadjusted analysis, dementia was more common in individuals diagnosed with sepsis during their icu stay (log-rank p < 0.001) as depicted in the kaplan-meier survival curve (fig. 3) . however, after adjusting for age, sex, cci score, saps3 box 2+3, h-los, icu-los, invasive ventilator therapy, and rrt, sepsis was no longer an independent risk factor for dementia (hr 1.01, 95% ci 0.91-1.11) (fig. 4) in any of the pre-specified sensitivity analyses, sepsis was not an independent risk factor for dementia (additional file 2). in our nationwide swedish cohort of 210,334 patients alive without dementia 1 year after icu admission, sepsis was found to be a crude risk factor for a later diagnosis of dementia. however, after adjusting for baseline characteristics of the patients in our cohort, sepsis was no longer an independent risk factor for dementia. this finding was consistent in all performed sensitivity analyses. in a previous study [36] , 516 patients having survived a sepsis episode were compared with 4517 patients having survived a hospitalization without sepsis. all included individuals underwent at least one prospective cognitive testing. when followed for up to 1 year, the sepsis patients performed worse on repeated cognitive testing. however, it is not clear whether this condition evolves into fulfilling the diagnostic criteria of dementia, and the authors did not control for age, comorbidities, or the degree of acute illness. in the present study, we controlled for several factors expressing both comorbidity and the degree of acute illness besides age. guerra et al. performed two studies on a 2005 medicare cohort. in their first study [16] , the findings seem to confirm the hypothesis that the higher rate of observed cognitive dysfunction after sepsis is evolving into a higher rate of clinically diagnosed dementia in patients treated in the icu with sepsis than in those treated in the icu without sepsis during their hospitalization. however, they were only able to adjust for comorbidities diagnosed in the year preceding the index hospitalization, thereby risking underestimating the comorbidities. in addition, the authors run the risk of overlooking the presence of dementia diagnoses in earlier years that was not registered in the year preceding hospital admission. furthermore, because dementia is a syndrome of a slowly evolving disease [18] , dementia diagnosed early after the index hospitalization might be an example of a clinically overt disease coming to the attention of the medical system in the convalescence period after hospitalization rather than a consequence of the sepsis episode or acute illness per se. dementia may also be a risk factor for sepsis [19] . we sought to lessen the effect of both over-diagnosis due to hospitalization and causality problems between sepsis and dementia by excluding dementia diagnoses registered during the first year after icu admission. in the second study by guerra et al. [17] , patients admitted to the icu with sepsis were compared with non-hospitalized patients matched on age group, sex, and race. sepsis was a significant risk factor for dementia. however, in a model adjusting for comorbid diagnoses associated with dementia during the index hospitalization, the effect of sepsis decreased compared with using the same comorbidities diagnosed before the index hospitalization. moreover, when using comorbidities diagnosed during the index quarter in the model, the effect of sepsis on the risk of dementia disappeared in line with our findings. in a casecontrol study [15] , the odds ratio for having had a sepsis diagnosis in 5955 patients with a dementia diagnosis was higher than in age-and sex-matched controls without dementia. in their design, the authors did not account for the amount of time elapsed from sepsis to the diagnosis of dementia, nor did they adjust for comorbidities diagnosed during the index hospitalization. despite that the patients in the sepsis and the no sepsis cohorts are from the same icu cohort, they were not comparable, i.e., sepsis cohort patients had more chronic illnesses, were older, and had a higher degree of acute illness. hence, it was essential to adjust to these specific factors. our study used the revised cci as a composite fig. 2 dementia prevalence by age interval in patients of the icu cohort alive at 31st of december 2016 and mortality 1 year from icu admission. line thickness represents the number of patients at risk. icu, intensive care unit; n_mort, number at risk of mortality; n_dem, number at risk of dementia measure of the comorbid burden of each patient. we also adjusted for the severity of acute illness, as we presumed that it might mediate the effect of sepsis on dementia development. saps3 box 2+3, i.e., acute illness severity, was an independent risk factor for dementia. however, in a sensitivity analysis in which saps3 box 2+3 was excluded from the model, sepsis was not a significant risk factor for dementia. this finding implies that saps3 box 2+3 does not modulate the effect of sepsis in the model. as expected, age was a strong risk factor for developing dementia during follow-up in our cohort of icufor variables treated as continuous: age, icu-los, hospital los, cci score, and saps3 box 2+3, the hr is of the difference between the 25th and 75th percentiles. hr, hazard ratio; ci, confidence interval; icu, intensive care unit; los, length of stay; cci, revised charlson comorbidity index; saps3, simplified acute physiology score 3; rrt, renal replacement therapy treated patients. intriguingly, in the oldest age category (> 90 years), we observed a lower prevalence of dementia compared with another study on a swedish cohort [33] . this lower prevalence may be related, in part, to the very high mortality rates in this elderly patient group that have been treated in the icu. surprisingly, the cci score was not an independent risk factor for dementia in the model. we speculate that this finding is due to the small difference between the 25th and 75th percentiles of the cci score. a wider range of cci might have yielded another result. for the variables in which cubic splines were applied, the hr was calculated for the difference between values at the 25th and 75th percentiles to reduce the risk of false conclusions from the hrs of these splined variables. still, despite this adjustment, results for the splined variables need to be interpreted cautiously. however, their validity as covariates of sepsisthe primary endpoint of the study-in the model is higher after cubic spline application than if we would have categorized these nonlinear variables [37] . a major strength of this study is that our sample contains virtually all intensive care patients in sweden over 11 years (2005 to 2015) , which represents the different socioeconomic groups of a high-income country. another strength is the possibility to follow the patients for an extended period before icu admission. such an approach allows for an accurate assessment of comorbidities in general and pre icu dementia in particular. we believe that the long mean follow-up of > 4 years from 1year post-icu admission is also an important asset of the study in that most types of dementia are gradually developing diseases [38] . our study also has by far the largest cohort of icu survivors to study the association between sepsis and dementia. finally, we were able to control for the severity of acute illness. our study has some limitations of note. the major limitation is that we define dementia as a dementia diagnosis at an inpatient visit at a hospital or a dementia diagnosis in the svedem. we thus expect to miss a proportion of patients despite using data from several registries to detect dementia in both hospital-admitted patients and outpatients. however, we have no reason to believe that dementia would be unreported to a larger extent in patients treated for sepsis in the icu as the sepsis cohort patients had more hospital inpatient visits than the no sepsis cohort patients during follow-up. this observation is possibly due to the higher comorbidity burden and higher age in the sepsis cohort patients. moreover, we choose not to include patients that did not live up to 1 year after icu admission, resulting in excluding almost one third of the patients in the analysis. however, we found in a sensitivity analysis that our results did not change after including those patients not surviving up to 1 year after icu admission. another potential shortcoming of the data is the possibility the patients die before they develop dementia, implying that the findings of this study could potentially need to be verified in cohorts with much lower mortality. in a sensitivity analysis, we included only patients with saps3 in the lowest quartile expecting a lower mortality and thus a smaller risk of dying acting as a competing event, but sepsis was not an independent risk factor in this analysis. finally, the present study is limited because 4% of the patients emigrated from sweden at some point during the study. however, 63% of these patients had at least one listing in our data sources during the follow-up, which also were the case in the complete cohort. thus, we chose not to exclude emigrated patients from the main analysis; however, doing so in a sensitivity analysis did not affect our results. because the effect of sepsis on the risk of later dementia development has been shown to be minimal in previous studies and not present at all in our study, we recommend that further research on outcome after sepsis be directed in other directions. in conclusion, although dementia was more common in the whole nation swedish icu cohort for 2005-2015 treatment for sepsis in the icu, sepsis was not a risk factor for later dementia after adjustment for pre-specified, relevant, baseline variables. in our sample, acute illness severity altered the risk of dementia, which might account for a fraction of the apparent causality between sepsis and dementia in icu patients. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03203-y. dementia in western europe: epidemiological evidence and implications for policy making the public's perceptions about cognitive health and alzheimer's disease among the u.s. population: a national review dementia: timely diagnosis and early intervention what do we know about quality of life in dementia? a review of the emerging evidence on the predictive and explanatory value of disease specific measures of health related quality of life in people with dementia epidemiology of severe sepsis the third international consensus definitions for sepsis and septic shock (sepsis-3) does infection-induced immune activation contribute to dementia? deterioration of spatial learning performances in lipopolysaccharide-treated mice sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism the additive effect of aging on sepsis-induced cognitive impairment and neuroinflammation septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and s-100b protein cognitive impairment in the septic brain persistent cognitive impairment, hippocampal atrophy and eeg changes in sepsis survivors long-term cognitive impairment and functional disability among survivors of severe sepsis association between sepsis and dementia risk factors for dementia after critical illness in elderly medicare beneficiaries risk of a diagnosis of dementia for elderly medicare beneficiaries after intensive care alzheimer' s disease dementia increases the risks of acute organ dysfunction, severe sepsis and mortality in hospitalized older patients: a national population-based study strengthening the reporting of observational studies in epidemiology (strobe) long-term mortality and cause of death for patients treated in intensive care units due to poisoning the swedish board of health and welfare. the national patient register. 1-2 no significant difference in cognitive decline and mortality between parkinson's disease dementia and dementia with lewy bodies: naturalistic longitudinal data from the swedish dementia registry sccm/esicm/accp/ats/sis international sepsis definitions conference apache ii: a severity of disease classification system.pdf saps 3-from evaluation of the patient to evaluation of the intensive care unit. part 1: objectives, methods and cohort description the swedish board of health and welfare available from: www. socialstyrelsen.se accessed 3 updating and validating the charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries coding algorithms for defining comorbidities in icd-9-cm and icd-10 administrative data the swedish dementia centre twenty-year changes in dementia occurrence suggest decreasing incidence in central mice: multivariate imputation by chained equations in r flexible smoothing with b -splines and penalties spurious inferences about longterm outcomes: the case of severe sepsis and geriatric conditions regression modelling strategies. 2. springer international publishing swizerland measuring cognition and function in the preclinical stage of alzheimer's disease. alzheimer's dement preferred reporting items for systematic reviews and meta-analyses: the prisma statement publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations henrik renlund, the statistician, is gratefully acknowledged for statistical support. authors' contributions ba, gs, iml, and ml conceived and designed the study; ba and ml acquired and analyzed the data; ba and ml drafted the manuscript; and ba, gs, iml, and ml finalized the manuscript. all authors approved the final manuscript as submitted. uppsala university hospital research fund and the centre for clinical research at region dalarna, sweden, funded this research. open access funding was provided by uppsala university. the data used in this study are available from the sir, the npr, and the svedem. however, privacy or ethical restrictions apply to the availability of these data, which were used under license for the current study. thus, these data are not publicly available. the data, however, are available from the authors upon reasonable request and with permission of the sir, the npr, and the svedem. this study was approved by the regional ethics committee of uppsala (approval no. 2016/421). because this is a registry-based study, informed consent was waived by the same ethics committee. not applicable. the authors declare that they have no competing interests. key: cord-351600-bqw9ks4a authors: zhang, shuai; guo, mengfei; duan, limin; wu, feng; hu, guorong; wang, zhihui; huang, qi; liao, tingting; xu, juanjuan; ma, yanling; lv, zhilei; xiao, wenjing; zhao, zilin; tan, xueyun; meng, daquan; zhang, shujing; zhou, e; yin, zhengrong; geng, wei; wang, xuan; zhang, jianchu; chen, jianguo; zhang, yu; jin, yang title: development and validation of a risk factor-based system to predict short-term survival in adult hospitalized patients with covid-19: a multicenter, retrospective, cohort study date: 2020-07-16 journal: crit care doi: 10.1186/s13054-020-03123-x sha: doc_id: 351600 cord_uid: bqw9ks4a background: coronavirus disease 2019 (covid-19) has become a public health emergency of global concern. we aimed to explore the risk factors of 14-day and 28-day mortality and develop a model for predicting 14-day and 28-day survival probability among adult hospitalized patients with covid-19. methods: in this multicenter, retrospective, cohort study, we examined 828 hospitalized patients with confirmed covid-19 hospitalized in wuhan union hospital and central hospital of wuhan between january 12 and february 9, 2020. among the 828 patients, 516 and 186 consecutive patients admitted in wuhan union hospital were enrolled in the training cohort and the validation cohort, respectively. a total of 126 patients hospitalized in central hospital of wuhan were enrolled in a second external validation cohort. demographic, clinical, radiographic, and laboratory measures; treatment; proximate causes of death; and 14-day and 28-day mortality are described. patients’ data were collected by reviewing the medical records, and their 14-day and 28-day outcomes were followed up. results: of the 828 patients, 146 deaths were recorded until may 18, 2020. in the training set, multivariate cox regression indicated that older age, lactate dehydrogenase level over 360 u/l, neutrophil-to-lymphocyte ratio higher than 8.0, and direct bilirubin higher than 5.0 μmol/l were independent predictors of 28-day mortality. nomogram scoring systems for predicting the 14-day and 28-day survival probability of patients with covid-19 were developed and exhibited strong discrimination and calibration power in the two external validation cohorts (c-index, 0.878 and 0.839). conclusion: older age, high lactate dehydrogenase level, evaluated neutrophil-to-lymphocyte ratio, and high direct bilirubin level were independent predictors of 28-day mortality in adult hospitalized patients with confirmed covid-19. the nomogram system based on the four factors revealed good discrimination and calibration, suggesting good clinical utility. since december 2019, an ongoing outbreak of coronavirus disease 2019 (covid-19) has struck wuhan, hubei province, china [1] [2] [3] [4] . human-to-human transmission has occurred through respiratory droplets or likely feces [5, 6] . epidemiological and clinical characteristics of patients with covid19 in china have been reported [2] [3] [4] 7] . the number of cases grew quickly since january 2020. as of june 9, 2020, 7,039,918 confirmed cases of covid-19 have occurred, resulting in 404,396 deaths [8] . outbreaks of covid-19 infection imposed a great burden on the healthcare system of many countries. to guide the allocation of limited healthcare resources, as well as the timely recognition and intervention of patients who were at high risk of mortality, efficient prognosis of the disease is needed. previous reports have shown age, sequential organ failure assessment (sofa) score, d-dimer, preexisting concurrent cardiovascular or cerebrovascular diseases, amounts of cd3 + cd8 + t cells, and cardiac troponin i to be risk factors for mortality of adult inpatients with covid-19 [9] [10] [11] . meanwhile, several prognostic models for predicting mortality risk have been developed [12, 13] . the most common predictors included in this prognostic model were age, sex, c-reactive protein (crp), lactate dehydrogenase (ldh), and lymphocyte count. however, most of these studies have relatively few outcome events, showed a high risk of model overfitting, and failed to clearly describe the intended use of these models. in this study, we investigated 828 patients with confirmed covid-19 who were admitted to wuhan union hospital west area and central hospital of wuhan between january 12 and february 9, 2020. since the median time to death from illness onset was reported to be 18.5 days, we believed 28-day could be an appropriate time point for the inclusion of mortality events and administrative censoring [10] . we aimed to explore the risk factors of 28-day mortality and develop a nomogram scoring system for predicting 28-day survival probability among patients with covid-19. this multicenter, retrospective, cohort study (clinical trial identifier chictr2000029770) was conducted at wuhan union hospital west area and central hospital of wuhan. the study was approved by the institutional ethics committee of union hospital, tongji medical college, huazhong university of science and technology (20200036); the requirement for informed consent was exempted by the ethics committee. the inclusion criterion was adult patients with confirmed covid-19. those who lacked laboratory findings and ct images or lost 28-day follow-up were excluded. besides, patients with hematological diseases had abnormal blood routine test due to their hematologic disorders, which made the analysis of blood routine test unfeasible, and were also excluded. in the training cohort, we retrospectively analyzed 604 consecutive patients with confirmed or suspected covid-19 who were admitted in wuhan union hospital west area between january 12, 2020, and february 7, 2020. eighty-eight of the 604 cases were excluded from the study; among them, 71 were suspected cases, 9 lacked laboratory findings and ct images due to their death or being transferred to other hospitals within 24 h after admission, and 8 patients were with hematological diseases. finally, a total of 516 patients were enrolled in the training cohort (union hospital training cohort, 420 survivors and 96 non-survivors, 87 patients died within 28 days of admission, fig. 1 ). next, another 194 consecutive patients were admitted in wuhan union hospital west area between february 8, 2020, and february 9, 2020. among them, 3 were suspected cases, 4 lacked laboratory findings and ct images due to their death within 24 h after admission, and one patient had hematological diseases; 8 patients were excluded from the study. finally, 186 patients with confirmed covid-19 were included as external validation cohort 1 (union hospital external validation cohort, 156 survivors and 30 non-survivors, 26 patients died within 28 days of admission). a total of 158 patients with confirmed or suspected covid-19 who were admitted in central hospital of wuhan between january 12, 2020, and february 6, 2020, were selected by simple random sampling. of the158 patients, 31 were suspected cases and one died within 24 h after admission, all of whom were excluded from the study, and the remaining 126 confirmed patients were included as the external validation cohort 2 (central hospital external validation cohort, 106 survivors and 20 non-survivors). a total of 46 deceased patients had been reported in a previous submission, and 18 patients participated in a phase 3 randomized, double-blind, placebo-controlled, multicenter study for evaluating the efficacy and safety of remdesivir in hospitalized adult patients with severe covid-19 [14, 15] . the diagnosis and clinical classification of covid-19 were based on the guidelines of the diagnosis and clinicians from the hospital identified patients who satisfied the study inclusion criteria through surveillance of all patients. we collected all available information from patients, their families, physicians, and the electronic medical records in the hospital, including the epidemiological history; clinical, laboratory, and ct findings; treatment (i.e., antiviral therapy, corticosteroid therapy, respiratory support, kidney replacement); and outcomes. all clinical data used in this study were collected from the first day of hospital admission unless indicated otherwise. electronic medical data were inputted onto a local server. a team of trained physicians searched the patient charts for all the information recorded. for patients discharged within 28 days after admission, patients or their families were followed up to obtain the information about their 14-day and 28-day outcomes by telephone interviews. the primary outcome of this study was mortality at 14 days and 28 days after admission. to avoid overfitting in our model, we calculated the numbers of variables allowed to enroll in our multivariable cox regression model based on a previous study for guidance on sample size requirements for prediction models [17] . in our multivariable model, by setting nagelkerke's r 2 = 0.18, we found that our sample size was sufficient to estimate the overall outcome risk and 6 variables could be enrolled in the multivariable analyses. considering a total number of 516 patients (with 96 decreased patients within 28 days after admission), the final nagelkerke's r 2 = 0.163, the cox-snell r squared statistic (r 2 cs ) = 0.099, and the candidate predictor parameter (epp) = 14.46, with 95% ci for overall risk = 0.138 and 0.203. among a dozen of indicators, which were associated with 28-day mortality in unavailable cox regression analyses (p < 0.001), variables included into the multivariable cox regression model were selected mainly based on the previous evidence, clinical significance, the correlation between predictors, and availability of data [18] . previous studies have shown older age, dyspnea, and higher levels of ldh, crp, and direct bilirubin (dbil) to be associated with severe disease at admission [19, 20] . elevated neutrophil-to-lymphocyte ratio (nlr) value was observed in patients who died of covid-19 and found to be able to predict severe cases of covid-19 at its early stage [20, 21] . meanwhile, these risk factors, including older age and higher ldh levels, have been reported to be associated with adverse clinical outcomes in adults with sars [22, 23] . other important indicators such as ct images, d-dimer, and ferritin might be unavailable in emergency circumstances. therefore, we chose age, nlr, ldh, crp, and dbil as the five variables for our multivariable cox regression model. all these variables included in the cox regression analyses were measured at admission. we converted these indicators including respiratory rate, breaths per minute, nlr, platelets count, alanine aminotransferase (alt), prothrombin time (pt), and ldh to binary variables and converted these indicators including total bilirubin, white blood cell count, dbil, urea nitrogen, d-dimer, and crp to trichotomous variables when performing univariable cox regression analyses in the training cohort. in addition, variables including ldh and nlr were dichotomized, and direct bilirubin was trichotomous when performing multivariate cox regression analyses to obtain risk factors for 28-day mortality in the training cohort. these predictors were eventually selected by forward stepwise regression. categorical variables were presented as frequency rates and percentages, and continuous variables were expressed as mean ± standard deviation (sd) if they were normally distributed or median (interquartile range [iqr]) if they were not. proportions for categorical variables were compared using the χ 2 test or fisher's exact test. means for continuous variables were compared using independent group t test when the data were normally distributed. otherwise, the wilcoxon rank-sum test was employed. 95% confidence interval (ci) of mortality was analyzed by wilson score ci. for the training cohort and the union hospital validation cohort, missing data have been mentioned in the relevant tables, and there was no other missing data, unless otherwise noted. and for the central hospital external validation cohort, 6 out of 126 missed ldh information, and these missing data were handled by multiple imputations [24] . the nomogram was used to visually score the patients' various parameters according to the results of multivariable cox regression analyses, and then to compute the probability of the event based on the patients' total score. c-index was calculated to evaluate the distinguishing power, and the calibration curve was used to evaluate the calibration of the nomogram. all statistics were two-tailed, and a p value less than 0.05 was considered as significant. all statistical analyses were performed by using the sas software package (version 9.4). the demographic and clinical characteristics at admission for the union hospital training cohort (n = 516), union hospital external validation cohort (n = 186), and central hospital of wuhan external validation cohort (n = 126) are listed in table 1 . among the 828 patients, 381 were females and 447 were males. on admission, 289 were mild and 539 were severely ill cases. the median age of non-survivors was older than that of survivors in both 3 cohorts. the median duration from illness onset to admission for all the patients was estimated to be 10 days (iqr, 7.0-13.0), and no difference was seen between the non-survivor and survivor groups (p = 0.484). the treatments, outcomes, and complications of the 828 cases were shown in table 2 . a total of 681 (82.25%) patients received oxygen therapy, 149 (18.00%) patients received mechanical ventilation, and 75 (9.06%) patients received invasive mechanical ventilation. antiviral therapies were used in 739 (89.25%) patients, systematic corticosteroids in 375 (45.29%) patients, and hydroxychloroquine in 57 (6.88%) patients. as of may 18, 2020, 682 (82.37%) patients have been discharged and 146 (17.63%) patients died. the median duration from illness onset to death in 146 deceased patients was estimated to be 20.0 days (iqr, 14.0-26.0). figure 2 shows the 28-day kaplan-meier survival curves for all patients and the two subgroups categorized by the severity of illness. of 146 non-survivors, 143 (97.95%) of the non-survivors developed ards; the most common complication was acute cardiac injury (40, 27.40%) followed by acute renal injury (32, 21.92%), septic shock (31, 21.23%), and acute liver injury (15, 10 .27%). next, we analyzed the risk factors for 28-day mortality in the training cohort by using cox regression model. eighty-seven decreased patients within 28 days were enrolled in the cox regression analyses. univariable cox regression analyses showed age, male, dyspnea, respiratory rate, curb-65 pneumonia severity score (curb-65 score), quick sepsis related organ failure assessment (qsofa) score, reticular patterns, and 15 laboratory factors were associated with 28-day mortality ( table 3 ). the comparison between survivors and non-survivors in laboratory and ct findings were also displayed in table s1 and figure 3 showed the temporal changes of the three independent laboratory risk factors from hospital admission in survivors and nonsurvivors. compared with survivors, non-survivors showed a significantly higher nlr, ldh, and dbil value at all time points. development and validation of nomogram for 14-day and 28-day mortality next, we worked out a nomogram scoring system for predicting the 14-day and 28-day survival probability of patients with covid-19 on the basis of the four independent predictors of mortality (fig. 4a) . to help physicians better understand the scoring system, we explained how to calculate the score in the legend of fig. 4 . figure 4b and c shows the calibration plot for the prediction model, in which the predicted probability of 14-day and 28-day survival is plotted against the observed data. the curves of predictive 14-day and 28-day survival probability were closely approximated to the observed probability, which means the nomogram scoring system exhibited good calibration. the discrimination of the constructed nomogram was evaluated with the c-index (0.886, 95% ci, 0.873-0.899), suggesting a favorable discriminative power. we also compared the nomogram score in our study with the curb-65 score and qsofa score. in the training cohort, the discrimination c-index of curb-65 and qsofa scores were 0.781 (95% ci, 0.757-0.805) and 0.672 (95% ci, 0.644-0.699), respectively. as indicated by the lack of overlap in the confidence intervals, the discrimination power of the nomogram score developed in the training categorical variables were presented as frequency rates and percentages continuous variables were expressed median (iqr) ci confidence interval cohort was significantly higher than that of the curb-65 and qsofa scores. to further verify the nomogram scoring system, two external cohorts were included. the external validation cohort 1 was performed by using the union hospital external validation set. in the union hospital external validation set, the final multivariable model for 28-day mortality showed strong external validity, with a discrimination c-index of 0.879 (95% ci, 0.856-0.900) indicating an 87.9% correct model identification of the 28-day survival probability across all possible pairs of patients. in the central hospital of wuhan validation set, the nomogram also exhibited a good discrimination power (c-index, 0.839, 95% ci [0.798-0.880]). calibration of the nomogram predicted 14-day and 28-day survival probability corresponding with the actual survival in both external validation cohorts (fig. 4d-g) . in this study, we employed the clinical and laboratory features of covid-19 patients to work out an effective and easy tool for predicting 28-day mortality. univariate analyses revealed that these factors including age, male sex, dyspnea, respiratory rate, curb-65 score, qsofa score, reticular patterns, leukocyte count, lymphocyte count, nlr, and several other biochemical parameters were associated with mortality. multivariate analyses found that older age, nlr over 8.0, dbil levels higher than 5.0 μmol/l, and ldh levels higher than 360 u/l at admission were four independent predictors of 28-day mortality in adult hospitalized patients with covid-19. many more patients developed fever and had comorbidities including hypertension and diabetes than those in guan et al.'s study with a relatively large sample size [7] . however, patients in our study were all from wuhan city, while patients in guan et al.'s study were from 30 provinces, autonomous regions, and municipalities in mainland china. since a great shortage of medical resources existed in wuhan city, the hardest-hit area of the covid-19 outbreak at the early stage of this pandemic, this regional difference should be noted. when compared with other studies, patients in which were also from wuhan, the proportions of patients with fever and comorbidities were comparable [4, 25] . the overall crude mortality rate in our series was higher than that in the previous report [26] . on the basis of a statistical model involving 72,314 patients, zhong and his colleagues estimated that the case mortality rate was 2.3% in patients with confirmed covid-19, 2.9% in hubei province, and 49% in severely ill patients. however, shang et al. reported that the mortality rate in severely ill patients with covid-19 was about 49% [27] . the discrepancies in the mortality rates might be ascribed to proportions of patients of different severities in different cohorts, given that all death events in our cohort were observed in severely ill patients. thus, the proportion of severe cases in our study should be taken into account. in fact, after a mandatory hierarchical management was introduced, more severe covid-19 patients were transferred to our hospitals, while mild cases were re-directed to the "mobile cabin hospitals." compared with survivors, more non-survivors were older, male, and were complicated with more chronic conditions. this result was coincident with the finding of a previous study focusing on critically ill covid-19 patients [27] . as aforementioned, all the non-survivors except two were those who were categorized as severely ill at admission in our study. this result suggested that mild patients could be treated by home quarantine or in our mobile cabin hospitals, given their satisfactory survival and the shortage of medical resources. of note, reticular patterns were more frequently found on ct images at presentation in non-survivors and were reportedly the predominant imaging finding on ct images 3 weeks after symptom onset [28] . previous studies have reported that older male patients were more subject to covid-19 infection, and severe patients were older than their non-severe counterparts [4, 7] . compared with survivors, non-survivors were reported to be older in two observational studies [9, 27] . in this study, we found that age was an independent risk factor for 28-day mortality in patients with covid-19. a higher level of ldh was suggested to indicate more extensive lung tissue injury and reported to be linked with poor outcomes in patients with severe acute respiratory syndrome (sars) [25, 29] . in patients with covid-19, plasma ldh level was reported to be higher in severe, icu, and deceased covid-19 patients than in mild, non-icu-patients, and survivors [27, 30] . our study showed that ldh could serve as a valuable predictor of mortality in covid-19 patients, with its hazard ratio being the highest. reminiscent of a previous mortality prediction model developed by yan et al., ldh higher than 365 u/l was also reported to be a risk factor for mortality in patients with covid-19 [31] . meanwhile, this previous model highlighted the crucial role of [20, 21] . this study confirmed that it could act as a predictor of mortality in covid patients. dbil was reported to be associated with severe covid-19 in a multicenter retrospective study [19] , now identified as one independent risk factor for 28-day mortality. although the presence of preexisting comorbidities seems to increase the odds of death, the association was not significant in our study. we also employed the four independent predictors to construct a predictive model which was shown in a form of nomogram scoring system. our prediction mode was constructed based on a reasonable size and consecutive cohort of adult patients with confirmed covid-19. this kind of sample selection minimized the selection bias. however, the proportion of severely ill patients was large in our hospital since wuhan union hospital was a designated hospital for severely ill covid-19 patient treatment. this made the cohort in our study less representative of adult hospitalized patients with confirmed covid-19 in wuhan. however, it should be highlighted that our model not only showed good discrimination and calibration in an external validation from the same hospital, but also performed well in an external validation cohort consisting of patients from another hospital, which was not a designated hospital for severely ill covid-19 patient treatment. therefore, our prediction models are based on and validated in wuhan hospitalized populations with covid-19 infection and should therefore be applicable to other sites within wuhan. compared with the curb-65 and qsofa scores, our scoring system displayed better discrimination ability in the training cohort. by employing our model, once the fig. 4 the nomogram scoring system for predicting patients' survival probability based on age, ldh level, dbil, and nlr. a nomogram for predicting the probability of 14-day and 28-day survival. the number of points for each factor is in the top row. for each factor, the absence is assigned 0 points. the presence of factors is associated with the number of points. the points for each factor are summed together to generate a total point score. the total points correspond to the respective 14-day and 28-day survival probabilities. the ability of this model to distinguish between low-risk and high-risk patients can be demonstrated by considering two hypothetical individuals who might be encountered in practice: patient a is 60 years old with nlr of 10, dbil of 4 μmol/l, and ldh of 400 u/l, getting a total score of 144.23; patient b is 40 years old with nlr of 3, dbil of 10 μmol/l, and ldh 100 u/l, getting a total score of 41.06. our model predicts that patient a's 14-day survival probability is 75%, and his 28-day survival probability is 63%. for patient b, his 14-day survival probability and 28-day survival probability are more than 95%. b-g the calibration plot of survival probabilities at 14 days and 28 days. nomogram-predicted survival probability is plotted on the x-axis, with observed survival probability on the y-axis. dashed lines along the 45°line through the origin point represent the perfect calibration models in which the predicted probabilities are identical to the actual probabilities. the training cohort calibration plot of survival probabilities at 14 days (b) and 28 days (c). d, e the external validation cohort 1 calibration plot of survival probabilities at 14 days (d) and 28 days (e). f, g the external validation cohort 2 calibration plot of survival probabilities at 14 days (f) and 28 days (g) target patients' data on the four risk factors were measured at admission, their risk of 14-day and 28-day mortality can be calculated by our model to guide the decision of clinical physicians. considering that the outcome events outside wuhan are different, when trying to apply this prediction mode into other provinces in china or other countries, this mode might need to be updated and adjusted to the local setting before it can safely be applied. our study had several limitations. first, it was of retrospective nature, and all data were collected from case records. therefore, important information might be missed and further prospective studies are needed. second, it is worth pointing out that the amount of missing data differed between the survivor and non-survivor groups, especially for ferritin and d-dimer. even though we believe these differences were attributed to different physicians' decisions in their clinical practice due to the absence of guideline recommendations, the resulting potential bias should be noted and further prospective studies can be also helpful to decrease this discrepancy in missing data. third, this study included a high population of patients who were severely ill; there may be a selection bias when identifying the risk factors of mortality. since physicians should evaluate the patients' condition at admission, we focused on the information of patients at admission, other important factors during hospitalization that might influence case mortality, such as the use of non-invasive assisted ventilation or other medications and timing, as well as longitudinal observations of clinical and laboratory variables, were not covered. more detailed analyses involving these factors should be undertaken. in conclusion, our study demonstrated that older age, high lactate dehydrogenase level, evaluated neutrophilto-lymphocyte ratio, and high direct bilirubin level were independent predictors of 28-day mortality in adult hospitalized patients with confirmed covid-19. the new nomogram scoring system for the prediction of 14-day and 28-day survival probability based on the four variables showed good discrimination and calibration in two independent validation cohorts, suggesting a potential to guide the medical practitioners in the monitoring and management of covid-19. a new coronavirus associated with human respiratory disease in china a novel coronavirus from patients with pneumonia in china clinical features of patients infected with 2019 novel coronavirus in wuhan epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster early 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remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all the patients who consented to donate their data for analysis and the medical staff members who are on the front line of caring for patients.authors' contributions yj, yz, and jc designed the study. fw, gh, jx, ym, zl, dm, xw, and jz collected the epidemiological and clinical data. sz, mg, ld, gh, zw, qh, tl, zz, xt, sz, ez, zy, and wg summarized all the data. sz, mg, and ld analyzed and drafted the manuscript. all authors revised the final manuscript. the authors read and approved the final manuscript. the data that support the findings of this study are available from the corresponding authors upon reasonable request. the study was approved by the institutional ethics committee of union hospital, tongji medical college, huazhong university of science and technology (20200036); the requirement for informed consent was exempted by the ethics committee. no individual participant data is reported that would require consent to publish from the participant. the authors declare no competing interests. supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-03123-x. key: cord-003532-lcgeingz authors: nan title: 39th international symposium on intensive care and emergency medicine: brussels, belgium, 19-22 march 2019 date: 2019-03-19 journal: crit care doi: 10.1186/s13054-019-2358-0 sha: doc_id: 3532 cord_uid: lcgeingz nan introduction: increasing evidence supports a central role for "immunosuppression" in sepsis. it is necessary to develop biomarkers of immune dysfunction that could help to identify patients at risk of poor outcomes [1] . the decreased expression of human leucocyte antigen (hla)-dra is proposed as a major feature of immunodepression and its persistent decrease is associated with mortality in sepsis [2] . in a previous study, we evidenced that fcer1a (fc fragment of ige receptor ia) is the gene showing the lowest expression levels of the entire transcriptome in sepsis [3] . here we studied the association between fcer1a expression and mortality in infected surgical patients. methods: fcer1a and hla-dra expression levels were quantified by droplet digital pcr in blood of 257 infected surgical patients. 26 patients died within 28 days (10.11%). spearman test was used to evaluate the association between gene expression and the sequential organ failure assessment (sofa) score. areas under receiver operating curves (auroc) were used to determine the gene expression cut-off values predicting mortality. kaplan-meier survival curves were obtained and differences in survival between groups were evaluated using the log rank test. cox regression was employed to assess mortality risk at 28 days. results: gene expression levels of fcer1a and hla-dra correlated inversely with patients' severity (r: -0.5 p<0.001; r: -0.3, p<0.001 respectively). both genes showed significant aurocs to predict survival, but fcer1a showed the best accuracy (fig. 1) . patients with introduction: severe pulmonary and renal conditions such as acute respiratory distress syndrome (ards), respiratory failure, and deterioration in kidney function often occur in patients with nosocomial pneumonia (np). the emergence and course of infection is genetically determined, hence host genetic landscape may influence an ability to resist infection. methods: variants for genotyping were selected using the phewas catalog which presents genotypic data for 13835 caucasian patients, 1358 phenotypes and 3144 single nucleotide polymorphisms (snps) with p < 0.05 [1] . snps with the lowest p-values for phenotypes with both, respiratory and renal manifestations were selected: intergenic variants rs7130588 and rs4980785, rs347344 (edil3) and rs2470893 (cyp1a1). cyp1a1 gene was associated with pneumonia and ards in our previous investigations, so we included in our analysis three sites of cyp1a1 gene (rs2606345, rs4646903 and rs1048943) studied on a smaller sample. genotyping was performed on 7 sites for a sample results: allele rs2606345-g of the cyp1a1 gene was protective against ards and an increase in creatinine level (fig. 1) . the rs7130588-g allele was associated with lung complications and with the development of severe respiratory insufficiency (fig. 2) . conclusions: the snps rs2606345 and rs7130588 can influence the aggravation of pulmonary and renal symptoms through genetically mediated response to infection. introduction: an uncontrolled inflammatory response plays a major role in the sepsis related organ dysfunction. mesenchymal stem cells(mscs) can improve survival of sepsis experimental models by modulating the inflammatory response. macrophages have been considered as important immune effector cells and their polarization imbalance aggravates the disordered inflammation reaction. the project aims to identify the effects of mscs on macrophages polarization against dysregulated inflammatory response. methods: raw264.7 cells were plated in the lower chambers of transwell system in the presence or absence of lipopolysaccharide (lps). then, mscs were seeded in the upper chambers and incubation for different time. finally, transforming growth factor beta (tgfβ) receptor (tgf-βr) inhibitor was added in transwell system. the phenotype of raw264.7 cells were analyzed by flow cytometry, the levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay (elisa). results: our data showed that lps increased the level of interleukin (il)-6 in raw264.7 cells (p<0.001) (fig. 1 ). in line with il-6 expression, lps induced the expression of m1 macrophage (p<0.001). moreover, lps stimulated raw264.7 cells co-culture with mscs in transwell system, mscs inhibited the expression of il-6 and m1 macrophages, while increased m2 macrophages (p<0.001). compared with lps group, the concentration of tgf-β was obviously increased in mscs treatment groups (p<0.001), furthermore, there were no significantly difference between mscs directed and indicted groups. more significantly, tgf-βr inhibitor abolished the impact of mscs on lps stimulated raw264.7 cells (p<0.001) (fig. 2) . conclusions: mscs polarized m1 macrophages into m2 macrophages and decreased pro-inflammatory cytokine levels by paracrining tgf-β. introduction: sepsis is dysregulated response to an infection, which can lead to progressive microcirculatory dysfunction, release of reactive oxygen intermediates (roi) and life-threatening organ dysfunction. our aim was to investigate the relationship between organ damage -characterized by the sequential organ failure assessment (sofa) scores, microcirculatory failure and roi production, in a large animal model of experimental sepsis. methods: fecal peritonitis was induced in anesthetized minipigs (n=28; 0.5g/kg autfeces containing 5-9 x10 6 cfu bacteria i.p.), control animals (n=9) received sterile saline i.p. invasive hemodynamic monitoring and blood gas analyses were performed between 16-24 hrs, the signs for failure of circulatory, respiratory and urinary systems were evaluated in accordance with the sofa score. the microcirculatory perfusion rate in the sublingual region was measured by orthogonal polarization spectral imaging technique (cytoscan a/r). the leukocyte-origin roi production was determined by lucigenine (mostly o 2 -. ) and luminol-based (h 2 o 2 ) chemiluminescence methods. results: between 16-24 hrs after induction the sofa score indicated moderate organ failure in 19 animals (m: 1.9; 25p: 1.5, 75p: 2.9) and the change was statistically significantly higher in 9 pigs, suggesting severe organ dysfunction (m: 4.1; 25p: 3.5, 75p: 5.2). the microcirculation was significantly deteriorated in all cases, independently of sofa score data. the h 2 o 2 production was significantly lower in septic animals as compared to controls, while the lucigenine enhanced roi production correlated with the sofa score-indicated moderate and severe organ dysfunction. conclusions: sublingual microcirculatory parameters are not correlating with the severity of sofa score-indicated organ dysfunction in abdominal sepsis. the measurement of roi production of the whole blood seems to be better biomarker for the detection of the progression of events from moderate to severe organ damages. introduction: the purpose of this study was to characterize differences in sepsis management in patients with and without left ventricular (lv) dysfunction. septic patients with lv dysfunction have higher mortality, and limited guidance exists for sepsis management of patients with lv dysfunction. the possibility exists that the cornerstones of sepsis management may contribute to these poor outcomes. methods: a retrospective chart review was conducted from may 2016 -january 2018 at two centers. adult patients who had a diagnosis of sepsis, were treated with vasopressors for > 3 hours, and had an echocardiogram within 12 months were included. patients were divided into two groups: reduced ejection fraction (ef) of < 40% and preserved ef defined as ef ≥40%. information about patient outcomes and sepsis management were collected. the primary outcome was the need for mechanical ventilation (mv). categorical and continuous data were analyzed using the chi-squared and mann-whitney u tests, respectively. the irb has approved this project. results: a total of 37 patients with ef < 40% and 42 patients with ef ≥40% were included. no significant differences in fluid management, vasoactive agent maximum rate or duration, or steroid use were observed. net fluid balance between low and preserved ef was positive 4.6 liters vs. 5.1 liters (p = 0.814), respectively. the number of patients that needed mv was higher in the low ef cohort (86% vs. 57%, p = 0.004), and this cohort had fewer mv-free days (20, iqr 0-25 vs. 24 (iqr 0 -28), p=0.064. conclusions: no significant differences were observed with regard to sepsis management, reflecting current guidelines. the significantly increased need for mv is a provocative result. a potential mechanism is the inability of a patient with reduced lv dysfunction to maintain appropriate cardiac and respiratory function in the face of fluid overload. prospective analysis of the role of fluid balance in septic patients with lv dysfunction is warranted. introduction: the relationship between myocardial injury and systemic inflammation in sepsis response is not well understood [1] . it´s proposed to evaluate the association between myocardial injury biomarkers, high-sensitive troponin t (hs-ctnt) and n-terminal pro-brain natriuretic peptide (nt-probnp), with inflammatory mediators (il-6, il-1β , il-8, il-10, il-12 / il-23p40, il17a, il-21 and tnf-α ) and biomarkers, c protein reactive (cpr) and procalcitonin (pct), in septic patients methods: this was a prospective cohort study performed in three intensive care units, from september 2007 to september 2010 enrolling patients with sepsis (infection associated with organ dysfunction), and septic shock (hypotension refractory by fluids infusion requiring vasopressor). blood samples were collected up to 48h after the development of first organ dysfunction (d0) and on the 7th day after inclusion in the study (d7) results: ninety-five patients were enrolled, with median age 64 years (interquatile?48-78), apache ii: median 19 (14-22), sofa: median 8 (5-10); 24.2% were admitted in icu with sepsis and 75.8% with septic shock. hospital mortality was 34.7%. in d0, nt-probnp correlated with il-8 (r = 0.495, p <0.001) and il-10 (r = 0.471, p <0.001). in d7, hs-ctnt and nt-probnp correlated with pct (r = 0.446, p < 0.001 and r = 0.495, p < 0.001; respectively). nt-probnp d0 was higher in nonsurvivors than in survivors on mortality in seventh day (p = 0.029) and in-hospital mortality (p = 0.030). hs-ctnt d7 (p = 0.030) and nt-probnp d7 (p <0.001) were significantly higher in non-survivors on in-hospital mortality. nt-probnp d7 (or 9.28; ic95% 2.05-41.94, p=0,004) and hs-ctnt d7 (or 10,93; ic95% 2.139 -55.795, p=0,04) were independently associated with in-hospital mortality conclusions: nt-probnp plasma levels at d0 correlated with il-8 and il-10, and both nt-probnp and hs-ctnt at d7 correlated with pct. in addition, nt-probnp has been shown to be an important predictor of mortality introduction: heparin-binding protein (hbp) acts proinflammatory on immune cells and induces vascular leakage through cytoskeletal rearrangement and cell contraction in the endothelium and is a promising novel prognostic biomarker in sepsis and septic shock. however, studies on repeated measures of hbp are lacking. our objective was to describe the kinetics of plasma hbp during septic shock and correlate it to hemodynamic parameters. methods: we included patients with septic shock (sepsis-3) on admission to helsingborg hospital's intensive care unit (icu) during september 2016 to february 2018. patients were sampled from icu admission and every 4 hours for 72 hours or until death or icu discharge. the plasma samples were analyzed for hbp and converted using the natural log (lnhbp) for normality. lnhbp was then evaluated against mean arterial pressure (map) as primary analysis and against systemic vascular resistance index (svri) as a secondary analysis, using mixed-effects linear regression models, treating patient id as a random intercept and adjusting for hemodynamic parameters. results: a total of 22 patients were included with median age 67 years, 9 females (41%), 7 surgical admissions (32%), median sofa-score 12 points on day one and 6 deaths from all causes within 90 days (27%). plasma hbp ranged from 0 to 932 ng/ml with a median of 47 ng/ml (lnhbp range 1.6 to 6.8, median: 3.9 ). an increase lnhbp was significantly associated with a decrease in map (coef. -2.58 mmhg, 95% ci: -0.62 to -4.55, p=0.010, n=22), when adjusting for heart rate (hr), noradrenaline (na), vasopressin (vp), dobutamine (dbt) and levosimendan (ls). in a secondary subgroup analysis, an increase in lnhbp was also significantly associated with a decrease in svri (coef. -94.2 dyne*s*cm-5*m-2, 95% ci: -1.3 to -187.1, p=0.047, n=13), when adjusting for map, hr, na, vp, dbt, ls and cardiac index. conclusions: repeated measures of plasma hbp during septic shock were correlated with important hemodynamic parameters in this small pilot study. introduction: mid-regional pro-adrenomedullin (mr-proadm) comes from the synthesis of the hormone adrenomedullin (adm), which is overexpressed during inflammation and progression from sepsis to septic shock. thus, mr-proadm can be a useful biomarker for the clinical management of septic patients [1] . the aim of our study was to understand the ability of mr-proadm to predict 30-day (30-d) mortality and to find a correlation between mr-proadm and sequential organ failure assessment (sofa) score in the first 24 hours from intensive care unit (icu) admission. methods: we evaluated 28 consecutive septic shock patients according to 2016 sepsis iii definitions. clinical data from the medical records included demographics, comorbidities, laboratories, microbiology and biomarker levels. whole blood samples for biomarker profiling were collected at 24, 72 and 120 hours from icu admission. mr-proadm measurement was detected in edta plasma using a sandwich immunoassay by trace® (time resolved amplified cryptate emission) technology (kryptor thermo fischer scientific brahms). results: overall 30-d mortality rate was 50.0%. mr-proadm [odds ratio (or) = 1.195], sofa score (or = 2.174) and lactate (lac) levels (or = 1.956) in the first 24 hours were associated with 30-d mortality in univariate logistic analysis (p value < 0.05, table 1 ). 30-d mortality rate was not associated with procalcitonin (pct) levels (or = 1.002). further linear regression analysis showed significant correlation between mr-proadm and sofa score at 24 hours from icu admission (p value<0.001, fig. 1 , table 2 ). conclusions: mr-proadm demonstrated superior accuracy to predict 30-d mortality compared to pct levels and is directly linked to sofa score at 24 hours from admission. mr-proadm may aid early identification of poor prognosis septic patients who could benefit a more intensive management. introduction: study of the expression of cell free dna (cfdna) in the search for new biomarkers for infection, sepsis and septic shock. methods: the population studied was all patients included in the sepsis protocol from march 2017 to january 2018, hospitalized patients of a federal public hospital. plasma samples were collected for quantification of cfdna, which after centrifugation were stored at -80°c and then thawed and analyzed by fluorescence using a varioskan flash fluorometer). cfdna values were expressed as ng/ml. the patients were divided into 2 groups: infection and sepsis/septic shock. we analyzed mortality, sequential organ failure assessment score (sofa score), qsofa (quick sofa), comorbidities, cfdna and laboratory parameters of 111 patients. results: among the 111 patients, 28% were classified as infection and 72% sepsis/septic shock. overall lethality was 33%, infection 9.7%, and sepsis/septic shock 42.5% (p<0.001). the mean of cfdna, sofa and lactate was higher according to the classification of infection and sepsis/septic shock: cfdna (159.4±117.3 and 282.7±358.6, p=0.006), sofa (1.9±2.1 and 6.6±4.3, p<0.001), qsofa (positive in 25% and 75%, lactate (1.6±0.8 and 3.8±3.5, p<0.001). we analyzed leukocytes, creatinine, crp (c reactive protein), inr (international normalized ratio), as predictors of severity and only crp showed no association with disease severity (p=0.84). levels of cfdna and qsofa showed worse prognostic utility as a predictor of sepsis / septic shock when compared to lactate and sofa: or 1.00 (95% ci 0.41-2.45), p=0.98 for cfdna, or 2.4 (95% ci 1.37-4.21), p=0.002 for sofa and or 2.00 (95% ci 0.94-4.28), p=0.072 for lactate. negelkerke r square was 0,633 for cfdna. in addition, area under the curve for cfdna mortality was 0.60 (95% ci 0.46-0.73) and sofa 0.81 ci 95% 0.19-0.91). conclusions: our study suggests that cfdna and qsofa have worse prognostic accuracy when compared to lactate and sofa, variables already used in clinical practice and easily measured. introduction: the aim of this study is to develop a "molecular equivalent" to sequential organ failure assessment (sofa) score, which could identify organ failure in an easier, faster and more objective manner, based on the evaluation of lipocalin-2 (lcn2/ngal) expression levels by using droplet digital pcr (ddpcr). sepsis has been classically defined as the exuberant, harmful, pro-inflammatory response to infection. this concept is changing [1] and the presence of a life-threatening organ dysfunction caused by a dysregulated host response to infection is now considered a central event in the pathogenesis of sepsis [2] . methods: lcn2 expression levels were quantified by ddpcr in blood of a total of 257 surgical patients with a diagnosis of infection. spearman analysis was used to evaluate if lcn2 correlated in a significant manner with sofa score. area under the receiver operating curve (auroc) analysis and multivariate regression analysis were employed to test the ability of lcn2 to identify organ failure and mortality risk. results: spearman analysis showed that there was a positive, significant correlation between lcn2 expression levels and sofa score (fig. 1) . aurocs analysis showed that lcn2 presents a good diagnostic accuracy to detect organ failure and mortality risk (fig 2) . in the multivariate regression analysis, patients showing lcn2 expression levels over the optimal operating points (oops) identified in the aurocs showed a higher risk of developing organ failure (table 1) and a higher mortality risk (table 2) . conclusions: quantifying lcn2 expression levels by ddpcr is a promising approach to improve organ failure detection and mortality risk in surgical patients with infection. introduction: sepsis is an inflammatory state due to an exacerbated immune response against infection. in cancer patients, sepsis presents a 10-fold higher mortality than in general population and leads to longer intensive care unit (icu) and hospital lengths of stay. it has been shown that reduced levels of circulating immunoglobulins (ig) might be a surrogate marker of unfavorable outcome in sepsis [1] . the aim of this study was to evaluate the association between ig levels in plasma and 60-day mortality rate in cancer patients with septic shock. methods: from december 2017 to november 2018, we conducted a prospective study in the intensive care unit (icu) of cancer institute of state of sao paulo, an 84-bed icu linked to university of sao paulo. patients ≥18 years old with cancer and septic shock were enrolled. descriptive statistics were computed for demographic and outcome variables. laboratory data and ig levels were collected at icu admission and at days 1, 2 and 3. a multivariate analysis was performed to evaluate predictors of 60-day mortality. results: a total of 190 patients were included in the study. the 30-day and 60-day mortality were 40.5% and 45.3%, respectively. no significant differences in igm and igg levels were observed between survivors and non-survivors. in both groups, the median igm levels were low and the median igg levels were normal. in the multivariate analysis for 60-day mortality, a favorable status performance measured by the eastern cooperative oncology group (ecog) was associated with better survival; metastatic disease, higher sequential organ failure assessment (sofa) score at admission and higher levels of initial lactate were associated with increased mortality. conclusions: low levels of serum endogenous immunoglobulins are not predictors of 60-day mortality in cancer patients with septic shock. introduction: cytovale has developed a rapid biophysical assay of the host immune response which can serve as a rapid and reliable indicator of sepsis. neutrophils and monocytes undergo characteristic structural and morphologic changes in response to infection. one type of response is the generation of neutrophil extracellular traps (nets), these have been proposed as potential mediators for widespread tissue damage. during netosis there is a fundamental reorganization of a cell's chromatin structurea signal that we have shown is sensitively measured by the cytovale cytometer. we hypothesized that quantification of plasticity (deformability) of leukocytes in the peripheral blood provides an early indicator of sepsis. the cytovale assay uses microfluidic cytometry to measure the plasticity of up to 100,000 white blood cells from edta-anticoagulated, peripherally-collected whole blood and provides a result in 5 minutes. methods: in two prospective studies conducted in two academic medical centers in baton rouge, la, the cytovale test was performed on peripheral blood samples obtained from 500 patients who presented to the emergency department with signs or symptoms suggestive of infection. the two studies included high acuity patients (400 patient study) and low acuity patients (100 patient study). an adjudicated reference diagnosis of sepsis or no sepsis was established for each subject, using consensus definitions, by review of the complete medical records. results: the receiver operator curve (roc) performance of the cytovale assay for both studies demonstrated an area under the curve (auc) greater than 0.85 (fig. 1) . conclusions: measurement of neutrophil and monocyte plasticity by a novel assay provides an accurate and rapid indication of sepsis in patients who present to an emergency room with signs or symptoms of infection. plasma hepatocyte growth factor in sepsis and its association with mortality: a prospective observational study introduction: sepsis and septic shock are commonly associated with endothelial cell injury. hepatocyte growth factor (hgf) is a multifunctional protein involved in endothelial cell injury and plays a pivotal role in sepsis. this study assesses its correlation with relevant endothelial cell injury parameters and prognostic value in patients with sepsis. methods: a prospective, observational cohort study was conducted in patients with sepsis admitted to the department of critical care medicine at the zhongda hospital from november 2017 to march 2018. the plasma hgf level was collected on the first 24h after admission (day 1) and day 3, then was measured by enzyme-linked immunosorbent assay. the primary endpoint was defined as all-cause 28-day mortality. furthermore, we analyzed the correlation of hgf with relevant endothelial cell injury markers. results: eighty-six patients admitted with sepsis were included. hgf levels of non-survivors were elevated upon day 1 (1940.62 ± 74.66pg/ml vs. 1635.61 ± 47.49pg/ml; p = 0.002) and day 3 (1824.82 ± 137.52pg/ml vs. 1309.77 ± 83.49pg/ml; p = 0.001) compared with that in survivors, and showed a strong correlation with von willebrand factor (r = 0.45, p <0.0001), lactate (r = 0.35, p = 0.0011), pulmonary vascular permeability index (r = 0.38, p = 0.0241), first 24 h fluid administration (r = 0.38, p <0.0001) and sequential organ failure assessment score (r = 0.40, p = 0.0001) (fig. 1) . plasma levels were able to discriminate prognostic significantly on day 1(auc: 0.72, 95%ci: 0.60-0.84) and day 3 (auc: 0.77, 95%ci: 0.63-0.91) (fig. 2) . conclusions: hgf levels are associated with sepsis and are correlated with established markers of endothelial cell injury. elevated hgf level in sepsis patients is a predictor of mortality. methods: adult patients with septic shock by the sepsis-3 classification due to lung infection or primary bacteremia or acute cholangitis are screened using two consecutive measurements of ferritin and of hla-dr/cd14 co-expression for mals (ferritin above 4,420 ng/ml) or immunosuppression (hla-dr/cd14 less than 30%) and randomized into immunotherapy with either anakinra (targeting mals) or recombinant ifnγ (targeting immunosuppression) and into placebo treatment. main exclusion criteria are primary and secondary immunodeficiencies and solid and hematologic malignancies. results: 101 patients have been screened so far. most common infections are community-acquired pneumonia (41.6%), hospitalacquired pneumonia (26.7%) and primary bacteremia (12.9%). mean +/-sd sofa score is 12.6 +/-2.9 and charlson's comorbidity index 5.21 +/-2.44; 25 patients have mals (24.8%); two immunosuppression (2%); the majority remain unclassified for immune state. conclusions: current screening suggests greater frequency of mals than recognized so far in a setting of septic shock due to lung infection or primary bacteremia or acute cholangitis. development of an algorithm to predict mortality in patients with sepsis and coagulopathy d hoppensteadt 1 , a walborn 2 , m rondina 3 , j fareed 1 study was to develop an equation incorporating biomarker levels at icu admission to predict mortality in patients with sepsis, to test the hypothesis that using a combination of biomarkers of multiple systems would improve predictive value. methods: plasma samples were collected from 103 patients with sepsis at the time of icu admission. biomarker levels were measured using commercially available, elisa methods. clinical data, including the isth dic score, sofa score, and apache ii score were also collected. 28-day mortality was used as the primary endpoint. stepwise linear regression modeling was performed to generate a predictive equation for mortality. results: differences in biomarker levels between survivors were quantified and using the mann-whitney test and the area under the receiver operating curve (auc) was used to describe predictive ability. significant differences (p<0.05) were observed between survivors and non-survivors for pai-1 (auc=0.70), procalcitonin (auc=0.77), hmgb-1 (auc=0.67), il-6 (auc=0.70), il-8 (auc=0.70), protein c (auc=0.71), angiopoietin-2 (auc=0.76), endocan (auc=0.58), and platelet factor 4 (auc=0.70). a predictive equation for mortality was generated using stepwise linear regression modeling. this model incorporated procalcitonin, vegf, the il-6:il-10 ratio, endocan, and pf4, and demonstrated a better predictive value for patient outcome than any individual biomarker (auc=0.87). conclusions: the use of a mathematical modeling approach resulted in the development of a predictive equation for sepsis-associated mortality with performance than any individual biomarker or clinical scoring system. furthermore, this equation incorporated biomarkers representative of multiple physiological systems that are involved in the pathogenesis of sepsis. the effects of biomarker clearances as markers of improvement of severity in abdominal septic shock during blood purification t taniguchi 1 , k sato 2 , m okajima 2 introduction: sepsis associated coagulopathy (sac) is commonly seen in patients which leads to dysfunctional hemostasis. the purpose of this study is to determine the thrombin generation potential of baseline blood samples obtained from sac patients and demonstrate their relevance to thrombin generation markers. methods: baseline citrated blood samples were prospectively collected from 49 patients with sac at the university of utah clinic. citrated normal controls (n=50) were obtained from george king biomedical (overland park, ks). thrombin generation studies were carried out using a flourogenic substrate method. tat and f1.2 were measured using elisa methods (seimens, indianapolis, in). functional antithrombin levels were measured using a chromogenic substrate method. results: the peak thrombin levels were lower (82 ± 40nm) in the dic patients in comparison to higher levels observed in the normal plasma (133 ± 10nm). the auc was lower (561 ± 280) in the dic group in comparison to the normals (624 ± 18). the dic group showed much longer lag time (4.1 ± 2.1) in comparison to the normal group (2.1 ± 2.2). wide variations in the results were observed in these parameters in the dic group. the f1.2 levels in the dic group were much higher (570±48 pmol) in comparison to the normal (210 ± 25 pmol). the tat levels also increased in the dic group (27.9 ± 5.1 ng/ml) in comparison to the normal (2.8 ± 0.8 ng/ml). the functional antithrombin levels were decreased in the dic group (64 ± 11%). conclusions: these results validate that thrombin generation such as f1.2 and tat are elevated in patients with dic. however thrombin generation parameters are significantly decreased in this group in comparison to normals. this may be due to the consumption of prothrombin due to the activation of the coagulation system. the decreased functional at levels observed in the dic group are due to the formation of the complex between generated thrombin and antithrombin. introduction: sepsis-associated disseminated intravascular coagulation (dic) is a complex clinical scenario involving derangement of many processes, including hemostasis. assessment of markers including inflammation, endothelial function, and endogenous anticoagulants may provide insight into dic pathophysiology and lead to improved methods for assessment of patient condition and response to treatment. methods: citrated plasma samples were collected from 102 patients with sepsis and suspected dic at icu admission and on days 4 and 8. dic score was determined using the isth scoring algorithm (e.g. platelet count, pt/inr, fibrinogen and d-dimer). cd 40 ligand (cd40l), plasminogen inhibitor 1 (pai-1), nucleosomes, procalcitonin (pct), microparticle tissue factor (mp-tf) and prothrombin 1.2 (f1. 2) were measured using commercially available elisa kits. protein c activity was measured using a clot-based assay. interleukin 6 (il-6), interleukin 8 (il-8), interleukin 10 (il-10), tumor necrosis factor alpha (tnfα), and monocyte chemoattractant protein (mcp-1) were measured using biochip technology. results: significant differences in levels of protein c (p=0.009), pct (p=0.0005), il-6 (p=0.019), il-8 (p=0.0149), pai-1 (p=0.015), were observed between survivors and non-survivors. significant variation of protein c (p=0.002), nucleosomes (p=0.05), pct (p<0.0001), il-6 (p=0.001), il-8 (p=0.003), il-10 (p=0.011), tnfα (p=0.021) and mcp-1 (p=0.021) were observed based on severity of dic score. conclusions: markers from multiple systems perturbed in dic were associated with mortality, suggesting that while these systems may not be routinely evaluated in the normal course of patient care, dysfunction of these systems contributes significantly to mortality. in addition, numerous inflammatory cytokines showed an association with dic score. this suggests that the measurement of additional markers in sepsis-associated dic may be of value in the prediction of mortality and may be helpful in guiding treatment for these patients. introduction: the endotoxin activity assay (eaa) is a rapid immunodiagnostic test based on chemiluminescence. it was approved by the fda in 2003 as a diagnostic reagent for risk assessment of severe sepsis in the icu. ascertaining endotoxin levels in the bloodstream is important in targeting patients and determining the appropriate timing for initiation of treatment. it has high sensitivity and specificity for endotoxin, and is considered to be useful in predicting clinical symptoms and determining prognosis. the usefulness of the eaa has yet to be fully clarified. methods: a total of 142 patients admitted to the icu between january 2014 and june 2018 with suspected sepsis or sepsis were enrolled. the eaa was conducted within 24 hr after admission. patient characteristics were determined, together with levels of il-6, procalcitonin, presepsin, and pao2/fio2. thereafter, the patients were classified into 5 groups depending on their eaa value: 1) < 0.2; 2) from ≤ 0.2 to < 0.4; 3) from ≤ 0.4 to < 0.6; 4) from ≤ 0.6 to < 0.9; and 5) ≤0.9). the transition of various markers was also examined. the spearman rank correlation, wilcoxon rank sum test, and a nonrepeated anova were used for the statistical analysis. a p-value of < 0.05 was considered statistically significant. the eaa values showed a positive correlation with both the apache ii (r=0.48) and sofa scores (r=0.56)(p<0.01), although that with the latter was stronger. a significant correlation was also observed with levels of procalcitonin (r=0.45) and presepsin (r=0.51 early diagnosis is important to allow early intervention. the current clinical methods are insufficient for early detection. we hypothesized that intraperitoneal microdialysis allows detection of peritonitis prior to changes in standard clinical parameters in a pig model. methods: bacterial peritonitis was induced in 5 pigs by bowel perforation and intraperitoneal fecal instillation, one pig underwent sham surgery. intraperitoneal microdialysis catheters were placed in each abdominal quadrant. the observation time was 10 hours. results: in peritonitis pigs the intraperitoneal lactate increased during the first two hours and remained elevated throughout the observation time (table 1) , whereas the arterial lactate remained within reference range (<1.6 mm). intraperitoneal glucose decreased significantly. hemodynamics were hardly influenced during the first two hours, and decreased thereafter. sham surgery did not influence in any of the parameters. conclusions: a rapid and pronounced increase in intraperitoneal lactate and decrease in intraperitoneal glucose was observed after instillation of intraabdominal feces. systemic lactate increase was absent, and the hemodynamic response was delayed. postoperative intraperitoneal microdialysis is applicable in detecting peritonitis earlier than standard clinical monitoring and should be evaluated in a clinical study in order to explore if early intervention based on md data will reduce icu length of stay, morbidity and mortality. introduction: procalcitonin (pct) is a serum biomarker suggested by the surviving sepsis campaign to aid in determination of the appropriate duration of therapy in septic patients. trauma patients have a high prevalence of septic complications, often difficult to distinguish from inflammatory response. pct values typically declined after 72h from trauma and increased only during secondary systemic bacterial infections. the aims of the study are to evaluate reliability and usefulness of pct serum concentration in trauma. methods: we retrospectively analyzed data from 40 trauma patients admitted to icu at bufalini hospital -cesena, from july 2017 to august 2018. we collected data about antimicrobial therapy, injury severity score (iss), first arterial lactate in emergency room, sofa score and sepsis severity. plasma pct concentration was measured using an automate analyzer (modular e-brahms) on 1st day of antimicrobial therapy and every 48h hours. antimicrobial therapy was stopped according to a local protocol; however medical judgment was considered the overriding point for therapeutic decision. results: median iss of patients was 33.5, inter quartile range (iqr) 13.5. pct mean concentration at the starting of antimicrobial treatment was 13.07 μg/l (d.s 40.1), median 0.72 (iqr 10.13). no significative correlation (spearman´s rho test) was found between pct at day 1 of antimicrobial therapy and iss (rho -0.186), between first arterial lactate in er and pct (rho 0.158). daily course of pct was not related to distance from trauma (rho -0.116). in 21 of 40 patients (52.2 %) pct measurement led physician to save days of antimicrobial therapy compared with standard clinical practice. we couldn´t find any cut off value. conclusions: our experience suggests that pct could help physician to optimize duration of antimicrobial therapy in trauma patients. no standard approach can be recommended at present. introduction: long duration of antimicrobial treatment may predispose to colonization and subsequent infections by multidrugresistant organisms (mdro) and clostridium difficile. progress (clinicaltrials.gov registration nct03333304) is an on-going trial aiming to use pct for the restraining of this calamity. methods: adult patients with sepsis by the sepsis-3 classification and any of five infections (pneumonia community-acquired; hospital-acquired or ventilator-associated; acute pyelonephritis; primary bacteremia) are randomized to pct-guided treatment or standard of care (soc) treatment. in the pct arm antibiotics are discontinued when pct on or after day 5 is decreased by more than 80% of the baseline or remains below 0.5 ng/ml; in the soc arm antibiotics are discontinued at the discretion of the attending physician. patients are followed for six months. primary endpoint is the rate of infections by mdro and/or c.difficile or death. serial stool samples are cultured for mdro and screened for glutamate dehydrogenase antigen and toxins of c.difficile. results: 201 patients have been enrolled so far. mean ± sd sofa score is 4.4 ± 2.4. most common diagnoses are community-acquired the progress trial is the first trial assessing the probable benefit from pct guidance to reduce ecological sequelae from long-term antibiotic exposure. analysis of baseline patient characteristics indicates that progress is a real-world trial so that results can have major clinical impact. prospective multi-site validation of 11-gene host response signature for influenza diagnosis s thair 1 , s schaffert 1 , m shojaei 2 , t sweeney 3 there are no blood-based diagnostics able to identify influenza infection and distinguish it from other infections. we have previously described a blood-based 11-gene influenza meta-signature (ims) score to differentiate influenza from bacterial and other viral respiratory infections. methods: we prospectively validated the ims in a multi-site validation study by recruiting 654 individuals (608 patients with suspected influenza, 46 healthy controls) in 10 community or hospital clinics across australia. we assayed the ims and 15 genes from viral genome of 3 influenza strains to generate the blood flu score (bfs) as a measure of viremia using nanostring from whole blood rna. results: using clinically determined phenotypes, the ims score distinguished patients with influenza from healthy (auc=0.95), non-infected (auc=0.83), bacterial (auc=0.88), other viruses (auc=0.77) ( figure 1a) . interestingly, probes of bfs were found in all phenotypic groups (non-infected, bacterial, and other viral infections) to varying degrees, and positively correlate with the ims score (r=0.53). ims aurocs improve when the bfs is used to inform the phenotypic groups: healthy (auc=0.92), non-infected (auc=0.90), bacterial (auc=0.93), other viruses (auc=0.88) ( figure 1b ). patients who were clinically influenza negative but had a high ims and bfs were admitted less often, yet had~4-fold higher mortality than those who were clinically influenza negative with low ims and no bfs (table 1) . conclusions: collectively, our prospective multi-center validation of the ims demonstrates its potential in diagnosis of influenza infections. introduction: previous findings of our group suggest that patients with gram-negative hospital-acquired severe sepsis have better prognosis when sepsis is developing after recent multiple trauma through stimulation of favorable interleukin (il)-10 responses [1] . under a similar rationale, we investigated if preceding osteomyelitis may affect experimental osteomyelitis. methods: sham or experimental osteomyelitis was induced in 32 male new zealand white rabbits after drilling a hole at the upper metaphysis of the left tibia and implementing diluent or 5log10 of staphylococcus aureus using foreign body. after three weeks, the foreign body was removed and experimental pyelonephritis or sham surgery was induced after ligation of the right pelvo-ureteral junction and instillation of 6log10 of escherichia coli in the renal pelvis. survival was recorded and circulating mononuclear cells were isolated and stimulated for the production of tumour necrosis factor-alpha (tnfa) and il-10. at death or sacrifice, tissue outgrowth and myeloperoxidase (mpo) were measured. results: four sham-operated rabbits (s), 16 rabbits subject to sham surgery and then pyelonephritis (sp) and 12 rabbits subject to osteomyelitis and then pyelonephritis (op) were studied. survival after 14 days of group sp was 56.3% and of group op 100% (log-rank 6.59; p: 0.010). lab findings are shown in figure 1 . il-10 production was blunted. negative correlation between e. coli outgrowth and tissue mpo was found at the right kidney of the op group (rs: -0.767, p: 0.016) but not of the sp group (rs: -0.318, p: 0.340). conclusions: preceding staphylococcal osteomyelitis provides survival benefit to subsequent experimental osteomyelitis through downregulation of innate immune responses leading to efficient phagocytosis. introduction: activation of neutrophils is a mandatory step and a sensitive marker of a systemic inflammatory response syndrome (sirs) which is closely related to development of multiple organ failure. the search for drugs that can prevent sirs and reduce mortality in critically ill patients remains significant. the aim of this study was to study the anti-inflammatory effect of the synthetic analogue of leu-enkephalin (dalargin) on human neutrophils. methods: the study was conducted on isolated from the blood of healthy donors neutrophils. their activation was assessed by fluorescent antibodies to markers of degranulation cd11b and cd66b (sd11b-fitc and cd66b-alexafluor647 (bd biosciences, usa). as inductors of inflammation lipopolysaccharide (lps) and the peptide formyl met-leu-pro (fmlp) were used. 100mkm fmlp and dalargin in concentrations of 50 and 100 μ g / ml were added to neutrophils at a concentration of 4 ppm / ml and incubated for 30 min at 37°c; then antibodies were added and incubated for 30 min on ice; then fluorescence was assessed by flow cyto flow meter beckman-coulter fc 500. non-parametric criteria were used; data were presented as a median and 25%-75% interquartile intervals. the statistical significance was estimated using mann-whitney test. the difference was considered statistically significant at p<0.05 results: synthetic analogue of leu-enkephalin in various concentrations has an anti-inflammatory effect on both intact and preactivated with bacterial components neutrophils, reducing their activation and degranulation in a dose-dependent manner (figs. 1, 2) . conclusions: synthetic analogue of leu-enkephalin prevents neutrophil activation by bacterial compounds. this has a potential of translation into clinical practice for sepsis treatment. introduction: the endothelin system plays important roles in circulatory regulation through vasoconstrictor et-a and et-b2 receptors and vasodilator et-b1 receptors (etar; etbr, respectively). tissue hypoxia during the progression of sepsis is associated with microcirculatory and mitochondrial disturbances. our aim was to investigate the possible influence of etar antagonist, etbr agonist or combined treatments on oxygen dynamics, microcirculatory and mitochondrial respiration parameters in experimental sepsis. methods: male sprague-dawley rats (n=8/group) were subjected to faecal peritonitis (0.6 g/kg faeces ip) or sham-operation. septic animals were treated with sterile saline solution, or received the etar antagonist etr-p1/fl peptide (100 nmol/kg iv), etbr agonist irl-1620 (0.55 nmol/kg iv) or same doses as combination therapy, 22 hr after sepsis induction. invasive hemodynamic monitoring and blood gas analyses were performed during a 90-min observational window. introduction: sepsis often induces immunosuppression, which is associated with high mortality rates. nivolumab is a human igg-4 antibody directed against the programmed cell death 1 (pd-1) immunecheckpoint inhibitor, which disrupts pd-1-mediated signaling and restores antitumor immunity. nivolumab is an approved anti-cancer drug that may have the potential to improve sepsis-induced immunosuppression. methods: this multicenter, open-label study investigated the safety, pharmacokinetics and pharmacodynamics of a single intravenous infusion of 480 or 960 mg nivolumab in japanese patients with immunosuppressive sepsis (lymphocytes ≤ 1100 /μl). the dosing of nivolumab was set using the predicted steady state concentration of nivolumab at 3 mg/kg every 2 weeks (q2w), which was the approved dosage for cancer patients at the time of planning. results: five and eight patients were assigned to the 480 and 960 mg groups, respectively. the mean (standard deviation) peak serum drug concentration in the 480 mg group was comparable to the predicted median concentration (90% pi [prediction (figures 1 and 2 ). adverse events (aes) were observed in four patients in each group. drug related-aes were observed in only one patient in the 480 mg group (table 2) . no deaths related to nivolumab occurred. conclusions: a single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentration in patients with sepsis. results suggest both 480 and 960 mg nivolumab therapy could improve relevant immune indices. introduction: the systemic inflammatory response syndrome (sirs) accompanies tissue trauma and infection and, when severe or dysregulated, contributes to multiple organ failure and critical illness. observational studies in man and animal have shown that low-dose acetyl-salicylic acid promotes resolution of inflammation and might attenuate excessive inflammation by increasing the synthesis of specialised pro-resolving lipid mediators (spms). methods: we randomly assigned patients with sirs who were expected to stay in icu for more than 48 hours to receive enteral aspirin (200 mg per day) or placebo for 7 days or until death or discharge from the icu, whichever came first. the primary outcome was il-6 serum concentration at 48h after randomisation. the secondary outcomes included safety and feasibility outcomes. in one center, additional blood samples were taken during the first three days for exploratory analysis of spms using reversed-phase highperformance liquid chromatography -tandem mass spectrometry (rp-hplc-ms/ms). results: from march 2015 through december 2017 a total of 48 patients across four general icus in australia underwent randomization (table 1) . compared to placebo patients, il-6 serum concentration after 48h in aspirin-treated patients was not significantly lower (40 [16-166] pg/ml vs 44 [7.4-85] pg/ml; p=0.66). there were no significant differences for control vs. aspirin-treated patients in the change of pro-resolving/anti-inflammatory lipids between the time points (figure 1, 2 ). there were no between-group differences with respect to icu or hospital mortality, number of bleeding episodes or requirements for red cell transfusions (table 2) . conclusions: in patients admitted to the icu with sirs, low-dose aspirin did not result in a decreased concentration of inflammatory biomarkers compared with placebo. introduction: sepsis is associated with excessive ros production, nf-kb, inos and inflammatory mediators overexpression. vitamin c is a cellular antioxidant, it increases enos and decreases nf-kb; it has several immune-enhancing effects and is crucial for endogenous vasopressors synthesis. vitamin c reserves in sepsis are often as poor as in scurvy [1] . in recent studies, intravenous high vitamin c dose seems to reduce organ failure and improve outcome in septic shock. methods: we treated all septic shock patients admitted to our icu in 7 months (from 3/2018 to 9/2018) with intravenous vitamin c 1.5g/ 6h and thiamine 200 mg/12h (for its synergistic effects) [2] as adjunctive therapy for 4 consecutive days and we compared data to septic shock patients admitted in the previous 7 months period. we enrolled 24 patients: 13 received vitamins supplementation, 11 standard of care. we analysed 28-days mortality, sofa at 48 and 96 hours, pct variation from baseline in first 5 days, vasoactive therapy length and daf 28 (days alive and free from vasopressors, mechanical ventilation and rrt in 28 days follow up). patients with end stage kidney disease were ruled out. we analysed data with mann-whitney and wilcoxon tests. results: vit c group showed lower 28-days mortality (23% vs 54.5%: ns); sofa improvement at 48 (-2.4±1.5 vs -0.9±1.9: p=0.01) and 96 hours (-4.2±2 vs -1.9±2: p<0.01) was higher in vit c group; vit c patients had faster pct reduction without statistical significance. mean vasoactive therapy length was quite similar. daf was 16.5 (±9.1) days in vit c group and 9.3 (±8.9) in controls (p=0.03). 3 control patients needed rrt, none in vit c group. conclusions: despite small study size, we found that vit c has positive effects on survival and improves sofa score (fig.1) and daf (fig.2 ) in septic shock. no vit c patient developed oxalate nephropathy nor worsened renal function. introduction: toxin-producing gram-positive organisms cause some of the most severe forms of septic shock [1, 2] . adjunctive therapies such as intravenous immunoglobulins (ivig) have been proposed for these patients [3, 4] . however, at patient presentation, the presence of a toxin-producing organism is most often unknown. methods: we reviewed the use of ivig in our patients requiring extracorporeal membrane oxygenation (ecmo) in a 2-year period between february 2016 and march 2018. results: in 44% (15/34) of the patients that received ivig for presumed toxin-mediated shock, group a streptococcus or panton-valentine leukocidin producing s. aureus was isolated, but the clinical characteristics of these 15 patients were not significantly different from the ones with other final diagnoses, except for a predisposing influenza infection and the presence of an often very high procalcitonin level. these 34 patients were extremely unwell at presentation with a sofa score of 15 ± 3, high lactate levels (8.6 ± 5.8 mmol/l) and need for vasopressors (equivalent norepinephrine dose of 0.93 ± 0.62 μ g/kg/min). they had very high inflammatory parameters with a procalcitonin ≥ 100 ng/ml in more than half of patients (18/34). ivig use in these patients was generally safe, with only 1 possible transfusion reaction. the mortality of 35% (12/34) was lower than predicted based on the sofa scores. conclusions: ivig administration can be considered in a selected group of patients presenting with acute and very severe septic shock, as part of a multimodal approach [5] . introduction: extra corporeal treatments are used in septic patients to decrease the inflammatory mediators, but definitive conclusions are lacking . more over in many studies the effect of aki isn't evaluated and this may be an important bias. . the aim of this study is to evaluate in septic patients with aki: 1the effect of the adsorbing membrane oxiris on the immunological response 2-the different response in survivors and non survivors methods: from our local data base we analyzed retrospectively 50 septic shock patients with aki (kdigo classification) submitted to crrt with the adsorbing membrane oxiris (baxter, usa ) . at basal time ( t0 ) and at the end of the treatment ( t1 ) we evaluated the following variables: il 6 il 10 procalcitonin endotoxin (eaa). all data are expressed as mean ±sd or median and iqr. student t test or mann-whitney was used to compare values changes. p < 0.05 was considered statistically significant. results: thirty patients with sepsis /septic shock and aki were enrolled in this study. 10 patients had aki 3, 15 patients aki 2, 5 patients aki 1. the duration of treatment was 38± 10 hours. 20 patients had citrate as anticoagulation and 10 heparine continous ev. at table 1 are shown the main results of this study in all the patients. survivors vs non survivors had a significant decrease of il 6, procalcitonin and eaa. conclusions: data of this study confirm on clinical ground previous study "in vitro" [1] that the adsorbing membrane oxiris has important immunological effect during septic shock with aki. this must be confirmed in a rct. introduction: sepsis is common and often fatal, representing a major public health problem. hemoadsorption (cytosorb) therapy aims to reduce cytokines and stabilise the overall immune response in septic shock patients. methods: a prospective, multi-centre, investigator initiated study to evaluate hemoadsorption (cytosorb) therapy in septic shock patients admitted to a tertiary icu's in india during 2016 to 2018. all centres followed a common protocol and received ethics committee approval. results: a total of 45 patients were administered cytosorb in addition to standard of care. a total of 26 patients (62%) survived out of 45 patients. among survival group, 17 patients (71%) were administered cytosorb within 48 hours of icu admission resulting in significant reduction in sepsis scores, apache ii (24.42 vs 19.33) and sofa (12.46 vs 8.71) post cytosorb therapy. also there was reduction in inflammatory markers like cytokines il6 in most of the patients. all patients in survivor group showed a significant improvement in map (69.2 vs 76.8) and reduction in vasopressors (epinephrine 0.3 to 0.03 mcg/kg/min, nor-epinephrine 0.34 to 0.04 mcg/kg/min) after cytosorb therapy. no device related adverse effect was observed in any of the patients. among the non-survivor group, (16 patients, 38%) we observed that cytosorb was administered after 48 hours of icu admission. although a few patients showed improvement in sofa score, majority did not show a significant improvement with map (68.05 vs 60.4 mm of hg) and required increased demand in vasopressors. conclusions: in this multi-centered prospective iis study, we could observe clinical benefits of hemoadsorption (cytosorb) therapy in septic shock patients if the therapy was initiated early. larger randomised study are required to establish the above clinical benefits in larger patient population. a single centre experience with hemoadsorption (cytosorb) in varied causes of sepsis and mods y mehta 1 , c mehta 1 , a kumar 1 , j george 2 , a gupta 3 , s nanda 1 , g kochar 1 , a raizada 3 introduction: sepsis and the multiorgan failure is a leading cause of mortality in the intensive care unit. promising new therapies continue to be investigated for the management of septic shock. we tried to evaluate a novel hemoadsorption therapy (cytosorb) through a retrospective evaluation of patient's data in our centre. we used it as an adjuvant therapy in our patients with sepsis due to varied causes. methods: we retrospectively analysed data of 100 introduction: septic shock is a life-threatening multiple organ dysfunction that has high morbidity and mortality in critically ill patients, due to a dysregulated host response to infection. the aim of this study was to evaluate the efficacy of therapeutic cytokine removal (cytosorb®) in the management of patients with septic shock. methods: we retrospectively analyzed patients admitted to icu with septic shock between june 2015 and november 2017. patients included in the study were diagnosed according to the third international consensus definitions for sepsis and septic shock (sepsis-3), received maximal supportive care including continuous veno-venous hemodiafiltration (cvvhdf) for acute kidney injury and cytosorb® haemoadsorption column was added to return limb of the cvvhdf circuit. demographic data, procalcitonin and leukocyte levels before and after therapeutic cytokine removal and duration of cytosorb® haemoadsorption column application and apache ii scores were recorded. results: the mean age of 48 patients included in the study was 54 ±16.4 years (74% male) and the mean body mass index was 23.1 ±5.9. the mean apache ii score was 21.5 with an expected and actual mortality rates of 40% and 25%, respectively. 18% of the patients were admitted with sepsis and 82% of them with septic shock. 37.5% (n=18) of the cases were solid organ transplant recipients. cvvhdf was applied in all patients during therapeutic cytokine removal. treatment was combined with ecmo in 8 patients. while the mean duration of cvvhdf was 102.1 hours, the duration of cytosorb® haemoadsorption column application was 24.1±13.4 hours. procalcitonin (16.5 ± 25ng/ml vs 25±34ng/ml) and leucocyte levels (14048±10490/ mm3 vs 9278±8693 mm3) after therapeutic cytokine removal were found significantly lower than the pretreatment values (respectively p=0.0013, p=0.006). conclusions: therapeutic cytokine removal applied with cvvhdf in septic shock patients have positive contributions to biochemical parameters and provide survival advantage. introduction: recent studies have focused on demonstrating the potential benefits of immunomodulation in the management of septic patients. the aim of our study was to assess the effects of a hemoadsorption column (cytosorb®) in critical ill septic patients. methods: after ethical approval was obtained, we prospectively included 39 patients admitted to the general icu of fundeni clinical institute. three consecutive sessions of renal replacement therapy (continuous venovenous hemodiafiltration) in combination with cytosorb® were applied after icu admission. clinical (heart rate, arterial pressure, temperature, glasgow coma scale) and paraclinical data (pao2, serum bilirubin and creatinine, platelet count, white blood cell count, ph, c-reactive protein and procalcitonine), vasopressor support and need for mechanical ventilation were recorded before and after the three sessions. results: the mean age in the study group was 57±15 years. median number of organ dysfunction at the time of icu admission was 4 [1] [2] [3] [4] [5] and the mean sofa score was 10.0±3.7. the use of cytosorb® was associated with a non-significant increase in pao2/fio2 ratio from 216±80 to 248±94 (p=0,278) and creatinine levels from 1.8±1.3 to 1.6 ±1.2 mg/dl (p=0.685). although we observed a non-significant increase in c-reactive protein levels from 136±66 mg/l to 144±72 mg/ l (p=0.577), we noted a significant decrease in procalcitonine levels from a median of 20.0 [2.2, 100 .0] ng/dl to a median of 9.1 [0.7, 55.2] ng/dl (p=0.041). a significant decrease in platelet count was also noted from 135384±99263 /mm3 to 78470±61624 /mm3 (p=0.002). mean sofa score decreased non-significantly from 10.0±3.7 to 9.1 ±4.1 (p=0.533). conclusions: the use of cytosorb was associated with a slight nonsignificant improvement in organ function and a decrease of procalcitonine levels. thrombocytopenia remains one of the most important complications of renal replacement therapy. introduction: circulating cell-free neutrophil extracellular traps (nets) would induce a microcirculatory disturbance of sepsis. the removal of nets remnants from the circulation could reduce nets-dependent tissue injury. to address this issue, we evaluated the effect of hemoperfusion with a polymyxin b cartridge (pmx-dhp; toray, japan), which was originally developed for the treatment in patients with gram-negative bacterial infection, on circulating cell-free nets in patients with septic shock and in phorbol myristate acetate (pma)-stimulated neutrophils obtained from healthy volunteer. methods: ex vivo closed loop hemoperfusion was performed through a circuit formed by connecting the small pmx module to a tube and a peristalsis pump. whole blood from healthy volunteers incubated with or without pma or from septic shock patients were applied to circuit and perfused. blood was collected at 0, 1 and 2 hr after perfusion. circulating cell-free nets were assessed by myeloperoxidase (mpo)-, neutrophil elastase (ne)-, and cell free (cf)-dna. results: plasma mpo-dna, ne-dna and cf-dna levels were significantly increased at 2 hr after pma stimulation when compared with plasma levels without pma. when either blood from septic shock patients or pma-stimulated neutrophils obtained from volunteers were applied to circuit, circulating mpo-dna, ne-dna and cf-dna were significantly reduced in perfusion with pmx filter than in perfusion without pmx filter at times 1 and 2 hr. conclusions: in the ex vivo experiments, mpo-dna, ne-dna and cf-dna were found to decrease after ex vivo perfusion through pmx filters. selective removal of circulating components of nets may improve the remote organ damage in patients with septic shock. a retrospective study of septic shock patients who were treated with direct hemoperfusion with polymyxin b-immobilized fibers based on the levels of endotoxin activity assay s sekine, h imaizumi, i saiki, a okita, h uchino tokyo medical university, anesthesiology/icu, tokyo, japan critical care 2019, 23(suppl 2):p047 introduction: the purpose of this study was to evaluate the outcomes for septic shock patients with direct hemoperfusion with polymyxin b-immobilized fibers (pmx-dhp) and endotoxin activity assay (eaa). methods: according to the levels of eaa, 41patients were classified for three groups (low group (gl); eaa <0.4, intermediate group (gm); eaa >0.4 or eaa <0.6, high group (gh); eaa >0.6). in order to evaluate the severity of illness, acute physiology and chronic health eva-luationii (apache ii) score, the sequential organ failure assessment (sofa) score, catecholamine index (cai) were recorded. and the presence of pmx-dhp treatments were also recorded. blood samples were obtained to measure eaa levels, inflammatory markers (procalcitonin (pct), c-reactive protein (crp), and white blood cell count (wbc)), serum lactate level as an indicator of tissue hypoxia, and for blood culture. apache ii score, sofa score, cai, inflammatory markers, serum lactate levels (lac) and blood culture results were examined for diagnosis of septic shock and prognosis of 30-days mortality. each values were also compared to eaa levels. results: 41 septic shock patients were included (gl/ gm/ gh: 12/ 13/ 16). in gh, apache ii and sofa score was significantly higher than that in gl (p< 0.05). eaa levels were significantly increased in gramnegative bacteremia patients compared to the patients with grampositive bacteremia or fungemia. there was no relationship between eaa levels and other inflammation markers, cai, and lac. in gm, 30days mortality in patient with pmx-dhp treatments was lower than that of without pmx-dhp treatments (0.14 (1/7) vs 0.5 (3/6), p=0.27). in gh, 30-days mortality in patient with pmx-dhp treatments was same as that of without pmx-dhp treatments (0.5 (3/6) vs 0.5 (5/10), p=1.0). conclusions: these results of this study suggest pmx-dhp treatment may improve the outcome of septic shock patients with intermediate eaa levels. introduction: numerous inconclusive randomized clinical trials (rcts) in sepsis in the past years suggest a need to re-think trial design to improve resource allocation and facilitate policy adoption decisions. the inclass study (clinicaltrials.gov nct: 03345992) is an ongoing rct evaluating clarithromycin as an immune modulator in high-risk septic patients with clinical and cost-effectiveness outcomes. we aim to compare the original one-shot trial with an alternative sequential design that balances trial costs and value of information. methods: adult patients with sepsis, respiratory failure and total sofa score of at least 7, are randomized to receive intravenous clarithromycin or placebo adjunctive to standard-of-care therapy. for the cost-effectiveness study, efficacy is measured in quality-adjusted life years (qalys) by eq-5d-3l questionnaire at 90 days. the endpoint is the incremental net monetary benefit (inmb) of clarithromycin compared to placebo, defined as wtp x (increment in qaly) -(increment in costs), where wtp is willingness to pay per qaly gained. fixed and variable costs of trial execution (including administrative, insurance, supplies, tests) are calculated; hospitalization cost is extracted from patient records; medical care beyond day 28 is recorded; cost of adoption in the general population is estimated. previous data from rcts using clarithromycin are used to form a prior belief about the inmb. known incidence of sepsis with respiratory failure allows estimation of the population to benefit from trial decision. a bayesian model is used to determine the sequential design that maximizes trial value. results: we will compare the performance of the sequential trial design with the one-shot design of inclass trial in terms of sample size, cost, social-welfare, and probability of correctly identifying the best treatment. conclusions: in this protocol we validate a bayesian model for sequential clinical trials and assess the benefits for the patient population and health care system. the effect on the outcome of critically ill patients with catecholamine resistant septic shock and acute renal failure through implementation of adsorption therapy g schittek 1 introduction: cytosorb-adsorption has been described as an effective way for hemodynamic stabilisation in septic shock [1] . aim of this study was to examine whether the adsorption-therapy could influence patient-outcome with catecholamine resistant septic shock (crss) and acute renal failure(arv). furhtermore we tried to identify clinical constellations that would predict an effective use of adsorbers [ 7, 34] . initial il-6 in patients with catecholamine-reduction through adsorption was non-significantly different to those with no reduction (2376 ng/l [838, 5000] vs. 5000 ng/l [3488, 5000]). mortality did not differ significantly between the groups (71% vs 79%). length of intensive care unit stay (los) did differ significantly (13 days [4, 24] vs 22 days [19, 29] ). conclusions: il-6 can be reduced with adsorption. patients with catecholamine-reduction did not differ in regard to their initial il-6. los was shorter for patients treated with adsorption. according to our experience adsorption can be taken into consideration when crss is beginning. introduction: in our intensive care unit (icu), we have already started expanded application to the contact precautions. applied patients are; 1) emergency admission, 2) patients who had already had bacteria* that are required to contact precautions, 3) scheduled surgical patients with prolonged icu stay, although we have not yet decided the started period of expanded application exactly. *detected bacteria(db);mrsa, cd, mdrp, esbl, pseudomonas a, pisp, prsp, vrsa. the aim of this study was to determine the adequate starting period of expanded application to the contact precautions in the scheduled surgical patients in the mixed icu. methods: we performed retrospective observational study on 4221 patients who were admitted to our icu after planed surgery from may 2013 to dec. 2017. we detected the patients who acquired bd newly and investigated the relation to the length of icu stay. the relationship between detection rate and categorized date was also analyzed using logistic regression adjusted for age, gender, apache2, and sofa score. using youden´s index and roc curve, we also calculated cutoff point of the duration of icu stay related to detection rate. finally, we made the logistic regression model of each cutoff day(day1 to 7) and compared odds ratio(or) and auc of each models using stata. results: category day 2 or more, especially day 4 or more had significantly higher detection rate of db compared to day 1 ( results: pao2/fio2 was lower than 240 mmhg in 171 (67%) patients. compared to patients in group 2, patients in group 1 were less severely ill at admission but presented a higher sofa and cpis score and a greater incidence of ards and shock at pneumonia onset (fig 1) . 117 (69%) patients in group 1 had a microbiological diagnosis of pneumonia, compared to 71 patients (85%) in group 2 (p=0.007). pao2/fio2 ≤240 mmhg was associated with less probability of having microbiological diagnosis of pneumonia (or 0.40, 95% ci 0.21 to 0.79, p=0.008). when adjusted for other variables significantly associated with positive microbiology, pao2/fio2 ≤240 mmhg remained significantly associated with less probability of a microbiological diagnosis (adjusted or 0.34, 95% ci 0.12 to 0.94, p=0.038). hospital mortality was significantly higher in patients in group 1 compared to group 2 (42% vs 29%, p=0.044). however, no difference was found in non-response to treatment, icu and hospital stay, icu mortality (table 1) and 90-days survival (fig 2) . conclusions: a significant higher number of patients with vap didn't have a definitive etiological diagnosis when using the proposed threshold criteria of pao2/fio2 ≤240 mmhg. pao2/fio2 ratio does not seem a good predictor of etiology in patients with vap. introduction: immunological dysfunction is common in critically ill patients but the optimal method to measure it and its clinical significance are unknown. levels of tumor necrosis factor alpha (tnf-α) after ex-vivo whole blood stimulation with lipopolysaccharide has been proposed as a possible method to quantitate immunological function. we hypothesized that patients with a lower post-stimulation tnf-α level would have increased rates of nosocomial infections (nis) and worse clinical outcomes. methods: a secondary analysis of a phase 2 randomized, multicentre, double-blinded placebo controlled trial [1] . there were no differences in allocation groups; all the patients were analyzed as one cohort. on enrolment, whole blood was incubated with lps ex-vivo and tnf-α level was measured. patients were grouped in tertiles according to delta and peak tnf-α level. the primary outcome was the development of nis; secondary outcomes included 90-day mortality. results: data was available for 201 patients. baseline characteristics and outcomes are reported in tables 1 and 2 . patients in the highest tertile for post lps stimulation delta tnf-α compared to the lowest tertile were younger, had a lower acuity of illness and had lower baseline tnf-α. when grouped according to peak post-stimulation tnf-α levels, patients in the highest tertile had higher serum tnf-α at baseline. both comparisons showed no difference between nis and clinical outcomes between tertiles. in multi-variate analysis peak or delta tnf-α were not associated with the occurrence of nis. conclusions: admission ex-vivo stimulated tnf-a level is not associated with the occurrence of nis or clinical outcomes. further study is required to evaluate the ability of this assay to quantify immune function over the course of critical illness. results: sanitary and epidemiological examination revealed the connection between infection and intravenous infusion of dexamethasone performed concurrently with chemotherapy. in 5 patients fever with chills and hypertension developed within 2 hours after infusion of the infected drug; empirical intravenous antibiotic therapy started immediately after collecting blood culture. in 6 patients fever appeared after 2-4 days outpatiently, so they received antibiotics per os. all these patients had permanent vascular access, and bsi was detected either the next chemotherapy course when fever reappeared (3 pts) while using vascular access, or as a result of a specific examination (3 pts). in all cases empirical antibiotic therapy started on the first day of fever, drug correction was performed in 6 patients according to results of bacteriological research. septic shock developed in 1 patient, pneumonia in 3 patients. permanent vascular access was preserved only in 1 case. all patients were cured and continued to receive antitumor treatment. conclusions: detection of more than 1 case of b. cenocepacia bsi should be the reason for sanitary and epidemiological examination. a favorable outcome of bsi treatment is associated with the early start of antibiotic therapy and its correction after microbiological examination. emerging conclusions: implementation of asp in hospital allows to decrease incidence of eskape-bacteremia and candidemia, which may lead to improved clinical outcomes in icu's patients (fig 1) . association of multi-drug resistant (mdr), extended-drug resistant (xdr) and pan-drug resistant (pdr) gram negative bacteria and mortality in an intensive care unit(icu) s chatterjee 1 , s sinha 1 , a bhakta 2 , t bera 3 , t chatterjee 3 , s introduction: colistin-resistant klebsiella pneumoniae (cr-kp) is increasingly reported around the world. it is worrying to note emergence of resistance to last line of defence against mdr gram negative infections in regions endemic to carbapenem resistance. we report the first outbreak of cr-kp co-producing carbapenemases in an adult intensive care unit (icu) from south india. methods: retrospective analysis of all patients with carbapenem resistant klebsiella pneumoniae blood stream infection (bsi) was done between january 2017 and december 2017. microbiological and clinical variables along with outcomes were analysed. results: seven patients had cr-kp with no prior exposure to colistin. all seven were modified hodge test (mht) negative making probability of blakpc unlikely. in resource limited setting, analysis beyond mht could only be performed for cr-kp samples. 2/7 samples belonging to cr-kp isolates produced the blandm-1 whilst 5/7 cr-kp isolates did not produce either blakpc or blandm carbapenemases prompting hypothesis of blaoxa-48 or blavim as the causative factor. compared to carbapenem resistance only group, cr-kp group had higher apache ii, icu length of stay and mechanical ventilation duration. 28 day mortality was noted to be 56.3% for carbapenem resistant and 43% for cr-kp groups. aggressive infection control measures were undertaken with successful containment of cr-kp strains along with reduction in overall bsi. conclusions: infection control measures form the backbone of patient care in centres showing endemicity for carbapenem resistant klebsiella to prevent colistin resistance and also to reduce occurrence of overall blood stream infections. rapid diagnosis of carbapenem resistance: experience of a tertiary care cancer center with multiplex pcr s mukherjee tata medical center, critical care medicine, kolkata, india critical care 2019, 23(suppl 2):p074 introduction: sepsis due to carbapenem resistant organisms has high mortality; inappropriate empirical antibiotic is one of the main causes of this poor outcome. on the contrary, "too much" broad spectrum empiric antibiotics will increase drug resistance, even in community, because of selection pressure. so, early diagnosis of resistance pattern (carbapenemase genes) is crucial. aim of this study is to compare rapid diagnostic test like polymerase chain reaction (pcr) with conventional culture sensitivity (c/s) to identify carbapenem resistance. methods: this is a prospective observational study done in tata medical center, kolkata, india. real time multiplex pcr technique has been developed "in house" in our microbiology lab and can identify ndm, ndm1, kpc, oxa -23, oxa -48, oxa -58 & vim carbapenemase genes. blood cultures were sent as per clinical & laboratory diagnosis of sepsis in icu patients. culture positive samples had been used for conventional c/s by vitek 2 system along with pcr study to identify carbapenemase genes. result of pcr technique was been compared with conventional c/s method. results: multiplex pcr results were available within 3-4 hours of positive blood culture compared to conventional c/s method that takes 2 -3 days. among 392 positive blood cultures, 146 samples were positive for carbapenemase genes. most common gene identified was oxa -48 (43%), followed by ndm1 (25%). our pcr technique has very high sensitivity, specificity, positive & negative predictive value (99.35%, 94.65%, 93.1% & 99.43% respectively) while comparing with final c/s report by vitek 2 system (table 1) . there was only one false negative diagnosis for carbapenem resistance. conclusions: real time multiplex pcr for carbapenemase gene can be helpful for early diagnosis of carbapenem resistance and can help us to choose / modify antibiotics or to use 'targeted therapy'. it is more practical to "rule -in" infection rather than "rule -out" by this technique. carbapenemase producing enterobacteriaceae colonization in an icu: risk factors and clinical outcomes m miranda, jp baptista, j janeiro, p martins centro hospitalar e universitário de coimbra, intensive care unit, coimbra, portugal critical care 2019, 23(suppl 2):p075 introduction: carbapenemase-producing enterobacteriaceae (cpe) colonization has been increasingly reported in intensive care units (icus) since their first identification more than 20 years ago. colonization with cpe seems to constitute a risk factor for mortality. the aim of our study was to identify associated risk factors and clinical outcomes among patients with fecal colonization by cpe admitted to a portuguese tertiary hospital icu. methods: a 2-year retrospective study was performed in patients with previous unknown cpe status (colonization or infection), admitted to our icu. rectal swabs were performed and analyzed using real-time polymerase chain reaction testing. clinical records were reviewed to obtain demographic and clinical data. results: of 903 patients admitted, 38 (4.2%) harbored cpe, 15 (39.5%) were colonized at admission and 23 (60.5%) acquired cpe colonization during icu stay. the most frequent carbapenemase genes detected were kpc (87.5%) and vim (12.5%). cpe carriers had high rates of hospitalization (previous or ongoing), invasive procedures (mainly intraabdominal surgery), malignancy (hematopoietic or solid tumor), introduction: gram-negative pathogens-particularly pseudomonas aeruginosa and enterobacteriaceae-predominate in nosocomial pneumonia (np) and ciai both. these infections are becoming difficult to treat with available treatment options due to growing antimicrobial resistance in india. ceftazidimeavibactam has in-vitro activity against gram-negative organisms producing class a, class c and some class d beta-lactamases. we carried out a qualitative analysis to assess the safety and efficacy outcomes of the indian population cohorts involved in the re-prove and reclaim trials. methods: in line with the global reprove protocol, indian patients enrolled in the study with np, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam or 1000 mg meropenem. in the reclaim study, indian patients with a diagnosis of ciai were enrolled in the study and were randomly assigned (1:1) to receive either ceftazidime-avibactam (2000 mg of ceftazidime and 500 mg of avibactam) followed by metronidazole (500 mg); or meropenem (1000 mg). the primary efficacy outcome measure in the reprove and reclaim studies was clinical cure rate of caz-avi compared with that of meropenem at toc (test-of-cure) visit in pre-defined analysis sets. in both studies, non-inferiority was concluded if the lower limit of the twosided 95% ci for the treatment difference was greater than -12·5% in the primary analysis sets. as the indian subset study was not statistically powered to detect a difference in the subgroup, we descriptively analysed the efficacy results in the indian population and compared them with the overall results in the global trial. in addition, the study also analysed the safety of caz-avi in the indian patients by monitoring the number and severity of adverse events. introduction: early administration of effective intravenous antimicrobials is recommended for the management of the patients with sepsis. although meropenem (mepm) is one of the first-line drugs in patients with sepsis because of its broad spectrum, the optimal dose in the critical care settings especially during continuous renal replacement therapy (crrt) has not been established since therapeutic drug monitoring of mepm has not been popular. methods: eighteen critically ill patients who received crrt were enrolled in this study. one gram of mepm was administered over 1 hour, every 12 hours, and blood samples at 1, 2, 6, 9 and 12 hours after administration were collected on day 1, 2 and 5. all samples were stored at -80°c until analysis. the measurement of the blood concentration of mepm was performed using high performance liquid chromatography with ultraviolet detection (hplc-uv introduction: meningitis is one of the complications of severe traumatic brain injury, and it is often associated with encephalitis (incidence from 1.3-4.8% to 10-20%). the aim of the investigation was to study the dynamics of the concentration of meropenem in serum and cerebrospinal fluid (csf) with intravenous and intrathecal administration of meropenem. methods: in eight patients with bacterial meningoencephalitis blood serum and csf were studied prior to the administration of meropenem and 5-10 min, 1, 2.5 and 5 hrs after it. antibiotic regimen: 2000 mg of vancomycin (1000 mg bid) and meropenem (2000 mg tid diluted in 100 ml of saline iv + 20 mg bid diluted in 5 ml of saline bolus slowly intrathecally). meropenem infusion was carried out for 30 minutes, 5 mins after it 5 ml of blood and 1 ml of csf were sampled. prior to antibiotics administration blood and csf were taken for microbiological examination. to determine the concentration of antibiotics iquid chromatography/mass spectrometry was used. the samples were analyzed on an agilent 1260 infinity liquid chromatograph coupled to a sciex qtrap 6500 mass detector (sciex, us introduction: the prophylactic use of probiotics has emerged as a promising alternative to current strategies viewing to control nosocomial infections in a critically-ill setting. however, their beneficial role in vap prevention remains inconclusive. our aim was to delineate the efficacy of probiotics for both vap prophylaxis and restriction of icu-acquired infections in multi-trauma patients. methods: randomized, placebo-controlled study enrolling 58 multitrauma patients, requiring mechanical ventilation for >10 days. participants were randomly assigned to receive either probiotic (n=28) or placebo (n=30) treatment. a four-probiotic formula was applied and each patient received two capsules per day from day1 to day15 post icu admission. the content of one capsule was given as an aqueous suspension by nasogastric tube, while the other one was spread to the oropharynx after being mixed up with water-based lubricant. the follow-up period was 30 days, while icu stay and mortality were also assessed. ], while no difference in 30-day mortality rate was identified between groups (10.7% probiotics vs 6.7% placebo). conclusions: the prophylactic administration of probiotics exerted a positive effect on the incidence of vap or other icu-acquired infections and icu stay in a critically-ill subpopulation being notorious for its high susceptibility to infections, namely multi-trauma patients. use of a c-reactive protein-based protocol to guide the duration of antibiotic therapy in critically ill patients: a randomized controlled trial i borges 1 introduction: the rational use of antibiotics is one of the main strategies to limit the development of bacterial resistance. in this study we aimed to evaluate the effectiveness of a c reactive protein (crp) based protocol in reducing antibiotic treatment time in critically ill patients. methods: an open randomized clinical trial was conducted in two adult intensive care units of a university hospital in brazil (clini-caltrials.gov: nct02987790). patients were randomly allocated to: i) intervention -duration of antibiotic therapy guided by crp levels, and ii) control -duration of therapy based on best in the intention to treat analysis, the median (q1-q3) duration of antibiotic therapy for the index infection episode was 7.0 (5.0-8.8) days in the crp group and 7.0 (7.0-11.3) days in the control group (p=0.011). in the cumulative suspension curve of antibiotics, a significant difference in the exposure time between the two groups was identified, with less exposure in the crp group (p=0.007). in the pre-specified per protocol analysis, with 59 patients allocated in each group, the median duration of antibiotics was 6.0 (5.0-8.0) days in the crp group and 7.0 (7.0-10.0) days in the control group (p=0.011). mortality and relapse rates were similar between groups. conclusions: daily levels of crp may aid in reducing the time of antibiotic therapy in critically ill patients, even in a scenario of judicious use of these drugs. introduction: the macrophage activation syndrome (mas) or hemophagocytic lymphohistiocytosis(hlh) is a life threatening complication characterized by pancytopenia, liver failure, coagulopathy and neurologic symptoms and is thought to be caused by the activation and uncontrolled proliferation of t lymphocytes and well differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction [1, 2] .the etiology is unknown, but is considered to have an infectious trigger.the aim of our study is to evaluate the impact of hlh in our 9 beds infectious diseases icu, during 83 months period (2012-2018). methods: a retrospective study based on electronic databases, including all patients admitted in our icu, that have matched at least 5 out of 8 criteria for hlh diagnosis (1):fever; hepatosplenomegaly; >2 cytopenia (hb <9 g/dl, plt</dl, pmn -n<1000/mmc); hypertriglyceridemia>265mg/dl, fibrinogen<150mg/dl; hemophagocytosis-bone marrow, spleen, and/or lymphnodes; nk activity reduced/ absent; ferritin level>500ui/l; cd 25>2400. we have evaluated the etiology established with cultures, serology, and molecular methods, treatment with corticosteroids, iv immunoglobuline, cyclosporine, etoposide and outcome (2) . results: 2112 patients were admitted to icu, 15 patients(0.71%) met the criteria for hlh. the average length of stay in icu was 15 days; 6 patients died (40%) without relation with the followed treatment. conclusions: hlh is not a rare condition in infectious diseases icu. the etiology is more frequent established compared with literature data. treatment (corticosteroids, immunoglobuline, cyclosporine, etoposide) is not associated with increased survival forecasting hemorrhagic shock using patterns of physiologic response to routine pre-operative blood draws introduction: irreversible hemorrhagic shock (ihs), a critical condition associated with significant blood loss and poor response to fluid resuscitation, can induce multiple organ failures and rapid death [1] . determining the patients who are likely to develop ihs in surgeries could greatly help preoperative assessment of patient outcomes and allocation of clinical resources. methods: machine learning model of ihs is developed and validated via porcine induced bleed experiment. 36 healthy sedated yorkshire pigs first had one 20ml rapid blood draw during a stable period, and then were bled at 20ml/min to mean arterial pressure (map) of 30 mmhg. 10 subjects had ihs defined as map<20mmhg. arterial, central venous and airway pressures collected at 250 hz during the blood draw [ fig 1] were used to extract characteristic sequential patterns using graphs of temporal constraints (gtc) methodology [2] , and a decision forest (df) model was trained on these patterns to determine subjects at high risk of impending ihs. results: in a leave-one-subject-out cross-validation, our method confidently identifies 30% (95% ci [15.6%, 44.4%]) of the subjects who are likely to experience ihs when subject to substantial bleeding, while only giving on average 1 false alarm in 10,000 such predictions. this method outperforms logistic regression and random forest models trained on statistically featurized data [tab 1, fig 2] . conclusions: our results suggest that by leveraging sequential patterns in hemodynamic waveform data observed in preoperative blood draws, it is possible to predict who are prone to develop ihs resulting from blood loss in the course of surgery. future work includes validating the proposed method on data collected from human subjects, and developing a clinically useful screening tool with our investigations. work partially funded by nih gm117622. introduction: the h 2 s and oxytocin(oxy) systems are reported to interact with one another [1] . h 2 s plays a major role in the hypothalamic control of oxy release during hemorrhage [2] . there is scarce information about oxy receptor(oxyr) expression in the brain in general and what is there is ambivalent. oxyr has been immunohistochemically(ihc) detected in the human hypothalamus but not in the hippocampus, in contrast to rodents [3] , which underscores the need for additional characterization in relevant animal models. thus the aim of this study is to map the expression of the oxy and h 2 s systems in the porcine brain in a clinically relevant model of hemorrhagic shock (hs). methods: anesthesized atherosclerotic pigs (n=9) underwent 3h of hs (map 40+/-5mmhg) [4] , followed by 72h resuscitation. ihc detection of oxy, oxyr, the h2s producing enzymes cystathionine-γ -lyase (cse) and cystathionine-β -synthase(cbs) was performed on formalin fixed brain paraffin sections. results: oxy, oxyr, cse and cbs were localized in the porcine brain. proteins were differentially expressed in the hypothalamus (fig 2) , parietal cortex and cerebellum (fig 1) . cell types positively identified were: magnocellular neurons of the hypothalamus, cerebellar purkinje cells and granular neurons, and hippocampal pyramidal and granular neurons of the dentate fascia. arteries and microvasculature were also positive for oxyr and cse. conclusions: our results confirm the presence of oxy and oxyr in the hypothalamus similarly to the human brain. novel findings were: oxyr in the cerebellum and cse expression in the hypothalamus and cerebellum. the coexpression of oxyr and cse may link and help better understand neurochemical systems and physiological coping in hemorrhagic shock. funding: crc1149 introduction: septic shock is one of the main causes of intensive care unit (icu) admission, leading to mortality up to 50% of patients. acute kidney injury (aki) frequently occurs and is associated to great morbidity and mortality. hemodynamic optimization may reduce the incidence of aki, but the use of vasopressors to increase mean arterial pressure (map) could have deleterious effect on renal perfusion. we aimed at investigating the effect of map and norepinephrine (ne) on the incidence of aki in septic shock patients methods: retrospective study based on prospectively collected data on digital medical records (digistat) at our icu. introduction: in patients with distributive shock, increasing mean arterial pressure (map) to a target of >65 mmhg can improve tissue perfusion. patients unable to achieve the target map of >65 mmhg despite adequate fluid resuscitation as well as catecholamines and vasopressin standard care (sc), may benefit from the noncatecholamine vasopressor angiotensin ii to increase map. this posthoc analysis examined whether patients from the athos-3 study with a baseline (bl) map <65 mmhg and treated with sc plus either angiotensin ii (ang ii) or placebo achieved a map of >65 mmhg for 3 consecutive hours, without increasing the dose of sc therapy. methods: patients were assigned in a 1:1 ratio to receive ang ii or placebo, plus sc. randomization was stratified according to map (<65 or >65 mmhg) at screening. in patients with bl map <65 mmhg, we evaluated whether patients achieved a map of >65 mmhg for the first 3 hours after initiation (map measurements taken at hours 1, 2, and 3), without an increase in the dose of sc. results: among 321 treated patients, 102 had bl map <65 mmhg (ang ii, 52; placebo, 50). median bl map (iqr) was 61 (57-63) and 62 (59-64) mmhg for placebo and ang ii groups, respectively. patients with bl map <65 mmhg who were treated with ang ii were more likely to achieve map ≥65 mmhg for 3 consecutive hours after initiation without an increase in sc dose (67%, 95%ci 53-80), compared with placebo-treated patients (24%, 95%ci 13-38, or=6.52, p<0.0001). conclusions: in this post-hoc analysis of patients with bl map <65 mmhg, patients receiving ang ii plus sc were significantly more likely to achieve a map >65 mmhg for the first 3 consecutive hours after initiation than patients receiving sc only. this suggests that administering ang ii may help patients with catecholamine-resistant distributive shock to achieve the consensus standard target map. norepinephrine synergistically increases the efficacy of volume expansion on venous return in septic shock i adda, c lai, jl teboul, l guerin, f gavelli, c richard, x monnet hôpitaux universitaires paris-sud, hôpital de bicêtre, aphp, service de médecine intensive-réanimation, le kremlin-bicêtre, france critical care 2019, 23(suppl 2):p093 introduction: through reduction in venous capacitance, norepinephrine (ne) increases the mean systemic pressure (psm) and increases cardiac preload. this effect may be added to the ones of fluids when both are administered in septic shock. nevertheless, it could be imagined that ne potentiates in a synergetic way the efficacy of volume expansion on venous return by reducing venous capacitance, reducing the distribution volume of fluids and enhancing the induced increase in stressed blood volume. the purpose of this study was to test if the increase in psm induced by a preload challenge were enhanced by ne. methods: this prospective study had included 30 septic shock adults. to reversibly reproduce a volume expansion and preload increase at different doses of ne, we mimicked fluid infusion through a passive leg raising (plr). in patients in which the decrease of ne was planned, we estimated psm (using respiratory occlusions) at baseline and during a plr test (plr high ). the dose of ne was then decreased and psm was estimated again before and during a second plr (plr low ). . the increase in cardiac index induced by plr low was significantly greater than that induced by plr high (p<0.001). δ psmhigh -δ psmlow was moderately correlated with the diastolic arterial pressure at baseline-high (p=0.03, r=0.41) and with the ne-induced change in mean arterial pressure (p=0.004, r=0.57). conclusions: ne enhances the increase in psm induced by a plr, which mimics a fluid infusion. this suggests that it may potentiate the effects of fluid in a synergetic way in septic shock patients. this may decrease the amount of administered fluids and contribute to decrease the cumulative fluid balance. introduction: arginine vasopressin (avp) can be used in addition to norepinephrine (ne) for ne-resistant septic shock. however, a subgroup who will response to avp is unknown. the purpose of this study was to determine factors which could predict the response to avp in patients with ne-resistant hypotension. methods: this was a single-center, retrospective analysis of patients who administered avp for ne-resistant hypotension in our intensive care units (icus). eligible patients were adult patients who administered avp in addition to ne due to hypotension (mean arterial pressure (map) < 65) in our icus between august 2014 and december 2017. we divided all patients into two groups by response to avp; responders and non-responders. the responders were defined as an increase of map ≥ 10 mmhg at 1h after avp initiation. we conducted univariate and multivariate logistic regression analysis to evaluate the effect of variables on avp response. results: a total of 163 patients were included; 107 responders (66%), 56 non-responders (34%). there was no significant difference for map at the time of avp initiation (51 vs 52 mmhg; p = 0.40), initiation dose of avp (0.028 vs 0.031 u/min; p = 0.67), and dose of ne at the time of avp initiation (0.18 vs 0.18 μ g/kg/min; p = 0.95). map at 1h after avp initiation was significantly higher in responders than non-responders (74 vs 55 mmhg; p < 0.01). responders were older (69 vs 66; p = 0.02) and had lower heart rate (hr) (99 vs. 108; p = 0.01) and lactate (3.2 vs. 4.8 mmol/l; p = 0.02) at the time of avp initiation. the multivariate logistic analysis revealed that hr ≤ 103 (or 2.56, 95% ci 1.29-5.10, p < 0.01), lactate ≤ 3 (or 3.11, 95% ci 1.56-6.19, p < 0.01) and age ≥ 63 (or 2.16, 95% ci 1.05-4.45, p = 0.04) were significantly associated with the response to avp. conclusions: hr, lactate levels and age before avp initiation can predict the response to avp in icu patients with ne-resistant hypotension. the maximum norepinephrine dosage of initial 24 hours predicts early death in septic shock d kasugai 1 , a hirakawa 2 , n jinguji 3 , k uenishi 3 1 nagoya university gtaduate school of medicine, department of emergency and critical care, nagoya, aichi, japan; 2 fujita health university, department of disaster and traumatology, fujita health university, toyoake, japan; 3 fujita health university hospital, department of emergency and general internal medicine, fujita health university hospital, toyoake, japan critical care 2019, 23(suppl 2):p095 introduction: the mortality of septic shock refractory to norepinephrine remains high. to improve the management of this subgroup, the knowledge of early indicator is needed. we hypothesize that maximum norepinephrine dosage on the initial day of treatment is useful to predict early death in septic shock. methods: in this retrospective single-center observational study, septic shock patients admitted to the emergency intensive care unit (icu) of an academic medical center between april 2011 and march 2017 were included. cardiac arrest before icu admission and those with do-not-resuscitate orders before admission were excluded. the maximum dosage of norepinephrine initial 24 hours of icu admission (md24) was used to assess 7-day mortality. results: one-hundred-fifty-two patients were included in this study. median sofa score was 11 (9-13), and median md 24 was 0.24 (0.16-0.38) mcg/kg/min. vasopressin and steroid were administered in 58 (38 %) and 67 (44 %) cases. nineteen patients (13 %) died within a week. non-survivors had higher md24, higher sofa score, and higher rate of vasopressin use. the higher md24 predicted 7-day mortality (area under curve 0.797, threshold 0.60 mcg/kg/min, sensitivity 50 %, specificity 91%). after adjustment of inverse probability of treatment weighing method using propensity scoring, md24 higher than 0.6 mcg/kg/min was independently associated with 7-day mortality (or: 9.96, 95 %ci: 2.56-38.8, p < 0.001). conclusions: the maximum dosage of norepinephrine higher than 0.6 mcg/kg/min initial 24 hours was significantly associated with 7day mortality in septic shock, and may be useful in the selection of higher severity subgroup. the impact of norepinephrine on right ventricular function and pulmonary haemodynamics in patients with septic shock -a strain echocardiography study k dalla sahlgrenska university hospital mölndal, göteborg, sweden critical care 2019, 23(suppl 2):p096 introduction: septic shock is characterized by myocardial depression and severe vasoplegia. right ventricle performance could be impaired in sepsis. the effects of norepinephrine on rv performance and afterload in septic shock are not immediately evident. the aim of the present study was to investigate the effects of norepinephrine on rv systolic function, rv afterload and pulmonary haemodynamics. methods: eleven, volume-resuscitated and mechanically ventilated patients with norepinephrine-dependent septic shock were included. infusion of norepinephrine was randomly and sequentially titrated to target mean arterial pressures (map) of 60, 75 and 90 mmhg. at each target map, strain-and conventional echocardiographic were performed. the pulmonary haemodynamic variables were measured by using a pulmonary artery thermodilution catheter. the rv afterload was assessed by calculating the effective pulmonary arterial elastance (epa) and pulmonary vascular resistance index (pvri). results: the norepinephrine-induced elevation of map increased central venous pressure (38%, p<0.001), stroke volume index (7%, p<001), mean pulmonary artery pressure (19%, p<0.001) and rv stroke work (20%, p=0.045), while neither pulmonary vascular resistance index nor epa was affected. increasing doses of norepinephrine improved rv free wall strain from -19% to -25% (32%, p=0.003), tricuspid annular plane systolic excursion (22%, p=0.010) and tricuspid annular systolic velocity (17%, p=0.029). there was a trend for an increase in cardiac index assessed by both thermodilution (p=0.079) and echocardiography (p=0.054). conclusions: the rv function was improved by increasing doses of norepinephrine, as assessed both by strain-and conventional echocardiography. this is explained by an increase of rv preload. pulmonary vascular resistance is not affected by increased doses of norepinephrine. peripheral perfusion versus lactate-targeted fluid resuscitation in septic shock: the andromeda shock physiology study. preliminary report g hernandez 1 , r castro 1 , l alegría 1 , s bravo 1 , d soto 1 , e valenzuela 1 , m vera 1 , v oviedo 1 , c santis 2 , g ferri 2 , m cid 2 , b astudillo 2 , p riquelme 2 , r pairumani 2 , g ospinatascón table 1 . conclusions: this preliminary results suggest that using crt as a target for fr in septic shock appears to be feasible, and not associated with impairment of tissue perfusion-related parameters as compared to lactate-targeted fr. grant fondecyt chile 1170043 introduction: shock patients often become resistant to catecholamines which often require the addition of a non-catecholamine vasopressor. preclinical studies suggest that in the presence of aadrenoceptor antagonism, the renin-angiotensin aldosterone system exerts the major vasopressor influence. we sought to determine the effects of angii or lypressin (lyp [porcine vasopressin]) on blood pressure in a norepinephrine (ne)-resistant hypotension pig model. methods: phentolamine (phn), a reversible α-blocker that antagonizes the vasoconstriction by ne, was continuously infused to induce hypotension. after ne-resistant hypotension was established, lyp or angii was then co-infused with phn. mean arterial pressure (map) and heart rate were continuously recorded (fig. 1) . results: as shown in fig. 2 conclusions: in a background of α-adrenoceptor blockade, at clinically comparable doses, the vasopressor effect of ang ii was maintained while those of ne and lyp were attenuated. these data suggest that the blood pressure effect of vasopressin-like peptides may require a functioning α-adrenoceptor. patients with shock who are resistant to increasing doses of catecholamines may also have vasopressin resistance potentially making angiotensin ii a preferred vasopressor for these patients. introduction: resuscitative endovascular balloon occlusion of the aorta (reboa) has been increasingly used for the management of both traumatic and non-traumatic hemorrhagic shock. however, there is limited evidence for its use in gastrointestinal bleeding (gib), especially in the icu setting. we successfully treated a patient with massive gib using reboa in the icu. we will discuss the difficulty performing the procedure and its countermeasure. methods: a case report. results: an 83-year-old woman was transferred to our hospital with shock. coffee grounds material was found in a nasogastric aspirate after intubation and upper gastrointestinal endoscopy identified a pulsating large duodenum ulcer without active bleeding, for which an elective procedure was planned. she was admitted to our icu, responded to initial resuscitation, and thereafter extubated. her systolic blood pressure (sbp) suddenly dropped to 40mmhg with massive hematochezia at that night, and did not increase despite resuscitation with blood products, crystalloid and norepinephrine. to buy time until measures for stop bleeding, we planned to place reboa in the icu. following the placement of a sheath in the left femoral artery, we tried to place a 7 fr intra-aortic balloon occlusion catheter, which unintentionally and repeatedly went into the right common iliac artery because her left femoral artery was tortuous. after compressing the right lower abdomen, we managed to introduce reboa in zone 1. it took approximately 60 minutes to successfully place the catheter. the patient's sbp increased immediately after the balloon inflation and bleeding was endoscopically controlled. introduction: the natural components of the pomegranate fruit may provide additional benefits for endothelial function and microcirculation. we hypothesized that chronic supplementation with pomegranate extract might improve glycocalyx properties and microcirculation during anaerobic condition. methods: eighteen healthy and physically active male volunteers aged 22-28 years were recruited randomly to the pomegranate and control groups (9 in each group). the pomegranate group was supplemented with pomegranate extract for two weeks. at the beginning and end of the experiment, the participants completed a high intensity sprint interval cycling-exercise (anaerobic exercise) protocol. the systemic hemodynamics, microcirculation flow and density parameters, glycocalyx markers, and lactate and glucose levels were evaluated before and after the two exercise bouts. results: no significant differences in the microcirculation or glycocalyx were found over the course of the study. the lactate levels were significantly higher in both groups after the first and repeated exercise bouts, and were significantly higher in the pomegranate group relative to the control group after the repeated bout: 13.2 (11.9-14.8) vs. 10.3 (9.3-12.7) mmol/l, p = 0.017. conclusions: chronic supplementation with pomegranate extract has no impact on changes to the microcirculation and glycocalyx during anaerobic exercise, although an unexplained increase in blood lactate concentration was observed. introduction: extracorporeal membrane oxygenation in adults in accompanied by high mortality. our ability to predict who will benefit from ecmo based on currently available clinical and laboratory measures is limited. the advent of single cell sequencing approaches has created the opportunity to identify cell populations and pathophysiological pathways that are associated with mortality without bias from a priori cell type classifications. identification of such cell populations would provide both an important prognostic markers and key insight into immune response mechanisms and therefore a possibility for advanced drug matching that may impact clinical response to ecmo in these patients. methods: whole genome transcriptomic profiles were generated from a total of 40,935 peripheral blood monocytes obtained from 37 patients at the time of cannulation for ecmo (fig 1) . differential gene expression analysis was performed with the monocle package for the r statistical analysis framework. time-to-event data were analyzed in a survival analysis with a log-rank test for differences. results: genes encoding several members of the heat shock family of proteins were up-regulated in cells from non-survivors. notably, these genes were expressed by a small fraction of cells (2.4% on average). nevertheless, the proportion of cells expressing these genes was a significant predictor of survival to 30 days (p = 0.02 by log rank test), with a particularly pronounced effect in the first 5 days after initiation of ecmo support (fig 2) . conclusions: the proportion of cells expressing genes encoding members of the heat shock proteins is predictive of survival on ecmo. majority of pt (43%) had no known predisposing conditions, followed by immobility (21%) and cancer (15%). in ecg analysis tachycardia and v1-v3 t wave inversion were the most common findings whereas hypoxemia± hypocapnia were the most prominent features in abg analysis. 8 pt (10%) had bleeding complications (none intracranial), 3 (3.7%) during rtpa, 5 (6.3%) in the first 36h and only 3 pt required transfusion. mortality rate was 12%: 6% directly due to pe (all during cpr) and 6% due to late complications (newly diagnosed cancer and infections). conclusions: in our experience, fibrinolytic therapy is safe and effective but in submassive pe should be applied after thorough assessment of risks and benefits on individual basis aiming to patient tailored precision medicine. [2] trials evaluated the role of levosimendan in preventing low cardiac output syndrome in patients undergoing cardiac surgery. the studies were similar in their design and recruited patients with preoperatively low lvef undergoing either isolated cabg or valve surgery combined with cabg (table 1 ). in both, a 24-hour levosimendan infusion was started at induction of anesthesia. neither study met the primary efficacy composite enpoints, but both showed a clear tendency for better outcome in patients undergoing a cabg compared to a valve procedure. we are currently evaluating the solidity of a co-analysis based on shared end-points. we are planning a shared analysed of the data related to the cabg settings and analyze the aggregated mortality data for both studies at 1 and 3 months by cochran-mantel-haenszel odds ratio. data from individual studies would be analysed as fixed effect and breslow-day test was used to evaluate homogeneity of the odds ratios results: in the placebo groups of the two studies, the mortality is similar; 7.9% (22/279) in levo-cts and 7.3% (9/123) in licorn, corroborating the working hypothesis that the two studies can be coanalysed. in a preliminary combined analysis (fig 1) , 90-day mortality was 7.7% (31/402) in the placebo group and 2.9% (12/407) in the levosimendan group. odds ratio was significantly in favor of levosimendan (0.36; 95% confidence interval 0.18-0.72; p=0.0026, fig. 1 ) conclusions: the levo-cts and licorn trials can be co-analysed in their sub-setting of patients requiring isolated cabg surgery for mortality at 1 and 3 months. a preliminary analysis on mortality reinforce the hypothesis that, in isolated cabg surgery, levosimendan lowers post-operative mortality significantly both at 1 and 3 months, when started at the induction of anesthesia introduction: emergency medical system (ems) -based st elevation myocardial infarction (stemi) networks allows not only stemi diagnosis in the pre-hospital phase but also reduces treatment delays; treat your fatal complications and the immediate activation of the catheterization laboratory. the aim of study was to investigate the effect of out-of-hospital by mobile intensive care (micu) versus hospital beginning treatment in hospitalization length and survival of patients with stemi diagnosis introduction: contrast induced nephropathy (cin) is a complex acute renal failure syndrome, which can occur after primary percutaneous coronary intervention (pci) and is an important cause of morbidity and mortality in this subgroup of patients. the aim of our study was to establish the incidence and predictors of cin after primary pci. we performed a retrospective analysis of stemi patients treated with primary pci in the period from january until september of 2017. cin was defined as an absolute increase in baseline serum creatinine of ≥0.5 mg/dl (44 μmol/l) or >25% relative rise within 72 hours after primary pci. we analyzed demographic characteristics, risk factors, clinical status at hospital admission, laboratory parameters, left ventricle ejection fraction and data regarding pci procedure. results: the study included 729 patients, with an average age of 62.33 ± 11.78 years, 66.1% of the patients were males. an average of 175.67 ± 91.77ml of contrast medium per patient was utilized. cin developed in 11(1.5%) patients and overall intra-hospital mortality was 8.4 %. in multivariate analysis, the independent predictors of cin were age>75 years ( introduction: left main coronary artery (lmca) disease is a disease of the main coronary branch that gives more than 80% of blood supply to the left ventricle, it carries high mortality without surgical intervention; [1] however the influence of lmca surgery on morbidity icu measures needs to be explored. we aim to determine whether lmca is definitive risk factor for prolonged icu stay as a primary outcome and whether lmca is definitive risk factor for early morbidity methods: retrospective descriptive study with purposive sampling analyzing 398 patients underwent isolated coronary artery bypass surgeries (cabg). patients were divided into 2 groups those with lmca disease as group 1 (75 patients) and those with coronary arty disease requiring surgery but without lmca disease as group 2 (324 patients) then we will correlate with icu outcome parameters including icu stay length, postoperative atrial fibrillation, acute kidney injury, re-exploration, perioperative myocardial infarction, post operative bleeding and early mortality. results: patients with lms had significantly higher diabetes prevalence (43.3% vs 29%, p=0.001). however, we did not find a statistical significant difference regarding icu stay, or other morbidity and mortality outcome measures conclusions: diabetes was more prevalent in patients with lms. the latter group showed similar outcome as those without lms in this study these findings may help in guiding decision making for future practice and stratifying the patients care. introduction: multimorbidity in patients admitted for acute myocardial infarction [ami] is associated with higher risk for in-hospital mortality and adverse clinical outcomes. we investigated to what extent an increasing number of comorbidities affects the age-stratified excess risk of death and other clinical outcomes among patients with myocardial infarction. methods: we analyzed nationwide administrative data of 174`803 admissions for an acute myocardial infarction between 2006 and 2016. we calculated multivariate regression models to study the association of four comorbidities (chronic kidney disease [ckd], diabetes mellitus, heart failure [hf], and atrial fibrillation) and excess risk of in-hospital mortality, length of hospital stay [los] , and 30-day readmission and stratified the analysis for different age categories. results: the incidence of admissions for ami increased continuously during the observed decade without an increase in in-hospital mortality, los, and 30-day readmission. among admitted patients with ami, there was a stepwise increase in risk for adverse outcomes for each comorbidity. compared to patients with no comorbidity, patients with 4 comorbidities had 6-fold increased risk for mortality (adjusted odds ratio [or] 6.6, 95% confidence interval [ci] 5.6 to 7.7) and a similar risk for readmission (or 1.0, ci 0.9 to 1.2). the los was 5.3 days (ci 5.1 to 5.5) in patients with no comorbidity and increased by 2.5 days (ci 2.4 to 2.5) with each additional comorbidity. these associations were stronger in younger compared to older patients. ckd was the strongest predictor of in-hospital mortality and los, while hf was the strongest predictor of 30-day readmission. conclusions: this study of nationwide admitted patients with ami found a stepwise increase in the risk for adverse outcome with increasing number of comorbidities, particularly in the younger patient population. younger, multimorbid patients may thus have the largest benefits from multidisciplinary treatments. introduction: certified cardiac arrest centers, sophisticated post cardiac arrest care and prehospital ecls teams aim to increase survivor rates with a preferable neurological outcome after cardiac arrest. centers also provide emergency ecls and ecls pick ups for cardiogenic shock patients before arresting. few data answer the question of the long-term quality of life after ecls therapy. methods: in a retrospective single center register we included patients after emergency ecls (ecpr and cardiogenic shock) between 10/2010 and 10/2017 discharged alive and performed a follow-up after 2 years on average at 6/2018. in our center criteria to initiate ecls therapy in cardiogenic shock or under cardiac arrest are an observed collaps, shockable rhythm, absence of frailty and severe comorbidities. all patients were requested to take part in a telephone interview. thus, we analyzed survival, cpc scores and sf36 scores. results: 97 patients with hospital survival after ecls were screened. 44% (n=43) had survived until 6/2018; 38 patients were not accessible; 16 had ceased. 33 survivors (mean±sd; min-max; 53±17; 19-78 years, 8 women) answered sf36 questionaires 29±15; 7-64 months after ecls (45% cardiogenic shock, 55% ecpr with shockable rhythm in 89%). the participantsć pc scores were in median 1. the results of the sf36 were physical functioning 84±21, physical role functioning 84±28, bodily pain 92±17, general health 68±23, vitality 65±26, social role functioning 83±28, emotional role functioning 96±14 and mental health 81±22. survivors who did not take part at the sf36 had a cpc score of in median 2 (n=10, 5 personally signed refusals, 3 language barriers, 2 vegetative states). conclusions: after emergency ecls therapy and hospital survival 44% of our patients survived the following 2 years up to over 5 years with a preferable neurological outcome and a general mentally and physically satisfactory quality of life. a vague outcome in 39% limits the results of our study. introduction: successful weaning from va-ecmo requires the restoration of a sufficient cardiac function to ensure an adequate tissue perfusion. skin blood flow (sbf) is among the first to deteriorate during circulatory shock and the last to be restored after resuscitation. sbf would be a good predictor of successful weaning from va-ecmo. methods: patients with va-ecmo, who required a first weaning attempt, were included. weaning procedure (wp) was performed by a reduction of va-ecmo blood flow to 1 l/min for 10 minutes. the weaning criterion was an aortic velocity-time integral (vti) > 10 cm. successful weaning from va-ecmo was defined as hemodynamic stabilization and without the need to increase the vasopressor dose during the next 24 hours. sbf, assessed by skin laser doppler (peri-flux5000, perimed, right index finger); perfusion unit: pu), together with global hemodynamic parameters were obtained before and after 3 min of weaning. receiver operating characteristic curves (roc) were generated to assess the ability and reliability of baseline parameters to predict a successful weaning. results: we studied 22 wps in patients with va-ecmo for pulmonary embolism (n = 2), post cardiotomy (n = 3), acute coronary syndrome (n = 14), myocarditis (n = 3). these were successful (sw) in 12 and unsuccessful (nsw) in 10. at baseline, hemodynamic variables, lactate, ecmo blood flow were similar in both groups (table1). sbf was greater in sw than nsw patients (table1). during wp, ci rose from baseline and was similar in sw and nsw (p=0.1) ( table 2 ). vtis were higher in sw than nsw (13 (12-14) vs 8 (6-8), respectively, p=0.03). sbf decreased in sw and remained low in nsw (table 2) . from the roc curves analyses, baseline sbf had the highest area under the roc curve with a cut off ≥ 34 pu (sensitivity 83%, specificity 92%) (figure1). conclusions: sbf is a good predictor of successful weaning from va-ecmo introduction: postoperative cognitive dysfunction (pocd) is defined as a temporarily decline in cognition associated with surgery. long-term pocd (3 months after surgery) occurs in 10-30% of cardiac patients and is associated with a higher morbidity and mortality. endo-cabg is a new minimally invasive endoscopic coronary artery bypass grafting (cabg) technique that requires retrograde arterial perfusion which may be associated with a higher incidence of neurological complications. the aim of this study is to assess the incidence of pocd after endo-cabg. methods: sixty consecutive patients undergoing an endo-cabg were enrolled. pocd was assessed following the recommendations of the "1995 statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery". a comparative group of 60 patients undergoing percutaneous coronary intervention (pci) and a control group of 60 healthy volunteers were also enrolled. additional tests included the digit span test and digit symbol-coding test. patients were tested at baseline and at 3month follow-up. pocd is defined as a reliable change index (rci) ≤ -1.645 (significance level 5%), or z-score ≤ -1.645 in at least two different tests. results: after enrolling 60 patients in each group, respectively 46 in the endo-cabg-group, 44 in the pci-group and 48 healthy controls were analysed. patients suffering from a cva within three months after their procedure were automatically classified as having pocd (pci: n= 1; endo-cabg: n= 1). the total incidence of pocd was not different between groups (pci: n= 7; endo-cabg: n= 6, p=0.732). conclusions: our results suggest that the risk of pocd after endo-cabg is low and comparable with the risk of pocd after pci. introduction: rhabdomyolysis ( rml) post aortic surgery probably affects the renal outcome adversely [1, 2] . there is no robust data regarding the same in literature. methods: retrospective single center data review; prior approval from institutional review board. patients were divided to two groups group 1-with rml ( ck above cut off levels 1050 u/litre) and group 2 without rml. the determinants of rml and the impact of the same on outcome; predominantly renal function was evaluated. chi-square tests are performed for categorical variables whereas, student t tests (un-paired ) are performed with continuous variables. correlation is performed between creatine kinase and creatinine rise. p value 0.05 (two tailed) is considered for statistical significant level. results: out of 33 patients, 21 patients (63.64%) developed rhabdomyolysis ( group rml) and 12 did not( group non rml). demographic and intraoperative factors had no significant impact on the incidence of rml. there was a significantly higher incidence of renal complications including new postoperative dialysis in the rml group. other morbidity parameters were also higher in the rml group. conclusions: there is high prevalence of rml after aortic dissection surgery -identification of risk factor and early intervention might help to mitigate the severity of renal failure introduction: we investigate whether central venous pressure (cvp) pressure waveform signal can be informative in detection of slow bleeding in post-surgical patients. we apply a novel machine learning method to analyze cvp datasets to characterize bleeding in a porcine model of fixed rate blood loss. methods: thirty-eight pigs were anesthetized, instrumented with catheters, kept stable for 30 minutes, and bled at a constant rate of 20ml/min to mean arterial pressure of 30 mmhg. cvp waveforms were extracted from inspiration and expiration phases of respiration and statistically featurized. the proposed machine learning method, canonical least squares (cls) clustering, identifies correlation structures that differ between subsets of observations. we extend it to supervised classification. both clustering and classification methods yield human-interpretable models that reflect distinctive patterns of correlations within cvp waveforms. results: we conducted three experiments to discover structure in the physiological response to bleeding. first, we clustered respiration cycles with full knowledge of blood loss. the color-coded cluster assignments are shown in the figure 1 . they are consistent with escalation of bleeding. second, we deployed clustering on only cvp features without blood loss. temporal structure was complemented with some subject-specific clusters (fig 2) . third, we ran cls classification to decide whether an observation came from before or after the onset of bleeding (performance shown in the results: over the last decade, the number of patients with hlhs who underwent norwood 1 has increased. interstage mortality has decreased, and is currently 30-40%. significant morbidity was not seen at a rate higher than in the international literature. discharge planning, and community access to allied health professional services remained a concern. conclusions: the paediatric congenital cardiac surgical service in the united arab emirates is relatively new (compared to some services around the world). interstage mortality in hlhs is improving as a result of programme development, surgical progress and postoperative care. in the interstage period, there is currently no home monitoring programme in place. some patients were found to have had very extended hospital admissions. improved community support may reduce interstage mortality further, as well as improve the social situation of many of these patients. postoperative complications were observed in 112(10.9%) patients. we lined out the prevalence of cardiac complications, such as heart failure and rhythm disturbances, observed in 87 (8.5%) and 53 (5.1%) patients respectively. hospital mortality rate was 2.8% (29/1020). the cause of mortality in all cases was acute heart failure, due to the initial severity of the disease, and in 11(1.07%) cases an acute myocardial infarction was diagnosed. duration of postoperative period was 7.8 ± 0.9 days. conclusions: off-pump coronary artery bypass grafting can be safely performed with relatively low incidence of mortality and postoperative morbidity. prognostic value of mid-regional pro-adrenomedullin and midregional pro-atrial natriuretic peptide as predictors of multiple organ dysfunction development and icu length of stay after cardiac surgery with cardiopulmonary bypass in adults introduction: one of the most harmful complications after cardiac surgery with cardiopulmonary bypass is a syndrome of multiple organ dysfunction (mods). we consider that mid-regional proadrenomedullin (mr-proadm) and mid-regional pro-atrial natriuretic peptide (mr-proanp) plasma concentrations can be used as predictors of mods development and los in icu. methods: thirty six adult patients (mean age 60 years, 27 male) with cardiovascular diseases undervent cardiac surgery with cardiopulmonary bypass (heart valve(s) replacement -20 (55.6%) patients, aorta and it`s branch surgery -14 (38.9%) patients, valvular surgery and coronary artery grafting -2 (5.5%) patients). nyha heart failure class ii was in 3 (8.3%) patients, iiiin 27 (75%) patients, ivin 6 (16.7%) patients. in the dynamics levels of mr-proadm and mr-proanp were measured in the venous blood with the kryptor compact plus analyzer (thermo fisher scientific, germany) before 1 day and on the 1st and 6th days after surgery. all patients were divided into subgroups according to the lengths of stay in the icu and the development of mod in the postoperative period. the data are shown as median and 25th and 75th percentiles. the data were compared by mann-whitney u-test, pvalue of <0.05 was considered statistically significant. results: levels of mr-proanp did not significantly change at the study stages and did not have a significant difference between subgroups. the levels of mr-proadm increased in the first postoperative day and remained elevated for 6 days. this increase was significantly higher in subgroups of increased los in icu and with mods. the data are shown in the table 1 . conclusions: mr-proadm can be used as predictor of mods and los in the icu for adult patients underwent cardiac surgery with cardiopulmonary bypass. introduction: prolonged intensive care unit (icu) stay after cardiac surgery is associated with increased mortality and cost .the aim of this study was to investigate factors influencing prolonged icu stay. methods: consecutive patients who underwent cardiac surgery from june 2012 to october 2018 in our cardiothoracic department, were retrospectively investigated. group a consisted of pts with prolonged stay defined as more than 3 days and group b the rest of the cohort. the following characteristics and perioperative factors were compared between the groups: smoking, diabetes, copd, redo(re-operation), ejection fraction (ef)<50%, emergent procedure, cardiopulmonary bypass time (cpb)>120 min, low cardiac output syndrome (lcos), acute kidney injury(kdigo) and mortalitychi square test was used for the statistical analysis. introduction: hemorrhagic complications of extracorporeal membrane oxygenation (ecmo) pose a major morbidity and mortality. optimal anticoagulation strategies balancing risks of bleeding and thrombosis in children are poorly understood. we aimed to identify factors associated with non-surgical bleeding in the first 12 ecmo hours. methods: we evaluated all pediatric (<18 yrs) post-cardiotomy patients requiring ecmo between dec 2002-july 2017 stratifying them by presence/absence of surgical bleeding. non-surgical bleeding was defined as chest tube output >3cc/kg/hr during the first 12-hours not requiring reoperation. patient characteristics and coagulation parameters at various time points after ecmo initiation were compared between groups, and receiver operator characteristic (roc) curves were constructed to identify models and thresholds with optimal predictive performance. figure 1 . conclusions: deranged coagulation parameters, particularly kaolin rtime may predict non-operative bleeding in pediatric ecmo patients. these findings may guide therapeutic anticoagulation while avoiding hemorrhagic sequelae in at risk patients. introduction: elevated cardiac troponin (ctn) level in patients (pts) admitted in the intensive care unit (icu) is multifactorial and has been associated with a worse prognosis. the aim of the study was to review the frequency and the main cause of ctn elevation and to calculate a discriminating index. methods: we retrospectively assessed all pts admitted in our eightbed general icu during a 6-month period with at least one measurement of ctn during their icu stay. we recorded clinical characteristics, the level of ctn on admission, the maximum ctn during icu stay and the possible causes of elevation. variables are expressed as mean ± sd or as median and interquartile ratio (ir), according to the normality of their distribution. student´s ô test or the mann whitney u tests were used to compare the group of elevated ctn with the group of normal ctn. the prognostic performance of elevated ctn was evaluated by the receiver operating characteristics (roc) curve. statistical analysis was performed using spss version 21.0 (spss, inc., chicago, illinois). results: in 84 out of 92 pts that ctn was measured at least once, abnormal levels (>15.6 pg/ml) were found in 58 (69%) of them, and the maximum ctn value was 633 (1718.25) pg/ml. the clinical characteristics of the pts are depicted in table 1 . sepsis was the main cause of troponin elevation, which complicated by acute kidney injury (aki) in 20 pts (34%). maximum ctn, aki and the difference of maximum -admission ctn (äctn) differed significantly between pts who survived and pts who died (p=0.029 and 0.001, respectively). the area under the curve (auc) was 0.753 and the optimal prognostic cut-off value of äctn was 57 pg/ml with a sensitivity of 0.656 and a specificity of 0.833 conclusions: raised cardiac troponin values is a frequent finding in icu pts and sepsis is the driving cause. aki and the difference between maximum and admission ctn measurements differ significantly between pts who survive and pts who die. an elevation of ctn during icu hospitalization >57 pg/ml seems to be a threshold indicating poor prognosis regarding both mortality and aki. the prognostic role of nt-pro-bnp in septic patients with elevated troponin t level introduction: sepsis is frequently accompanied with release of cardiac troponin t (tnt) and nt-pro-bnp, but the clinical significance of this myocardial injury and cardiac dysfunction remains unclear [1] . tnt is known to be an independent predictor of mortality, whereas the prognostic role of nt-pro-bnp is uncertain. methods: here, we report data of va-ecmo-patients, treated with dobutamine, levosimendan, suprarenin or no inotropic agens, in respect of 30-day survival. all data were collected retrospectively (10/ 2010 to 10/2018) at a single center, all patients with a survival below 24 hours were excluded. while treatment of va-ecmo patients is strongly guided by standard operation procedures at our institution, no recommendation on positive inotropic therapy could be made. results: a total of 232 va-ecmo patients were evaluated, of which 47 patients were treated with levosimendan within 48 hours after cannulation. 30day survival in the whole cohort was 41.9%. a total of 99 patients did not receive any positive inotropic therapy at 24 hours after implantation (survival 48.0%). survival was best in the levosimendan plus dobutamine group 50%, followed by dobutamine mono-therapy 46.2% and levosimendan mono 41.2%. survival with suprarenin mono was 33.3%, suprarenin plus levosimendan 25.0% and suprarenin plus dobutamine 18,8%. pooling data, we found no evidence that levosimendan and/or dobutamine (survival 45.8%, n=83, p=0.882) improves survival over no inotropic therapy (fig 1) . therapy with any combination including suprarenin however resulted in poor survival (27.7%, n=65, p=0.009). adjustment for lactate levels or ecpr did not change the results. conclusions: this retrospective analysis of 232 va-ecmo patients shows no evidence that early inotropic therapy improves outcomes in va-ecmo patients. this conclusion is obviously biased by retrospective design. until randomized data are available, suprarenin however should be avoided. survey of non-resuscitation fluids in septic shock a linden-sonderso 1 introduction: positive fluid balance is associated with poor outcome in septic shock. the objective of the present study was to characterize non-resuscitation fluids in early septic shock. methods: consecutive patients >18 years of age were screened for inclusion criteria during a 4-month period in 8 icus in sweden and in canada. inclusion criteria were septic shock per sepsis-3 definition within 24 hrs of icu admission. a maximum of 30 patients per center were included. type, indication and volume of non-resuscitation fluids were recorded during the first 5 days of admission. fluids other than colloids, blood products and crystalloids given at rate > 5ml/kg/h were considered to be non-resuscitation fluids. the study was registered on clini-caltrials.gov (nct03438097). data are presented as median (interquartile range). results: a total of 201 patients were included between march 1st and june 30th 2018 (see table 1 for demographics). patients received 7886 (4051-12670) milliliters (ml) of non-resuscitation fluids introduction: we aimed to ascertain the extent and make-up of fluid overload in critically ill patients and to identify whether delivery of more concentrated medications could reduce this. positive fluid balance is associated with increased mortality [1] . a recent study has shown that the predominant component of fluid overload was from iv medications and maintenance fluid [2] . methods: we reviewed 20 sequential patients admitted to our icu with an apache ii score of greater than 15 and a length of stay (los) greater than 72 hours. the patients' electronic admission summary was interrogated to establish: length of stay (los) fluid balance at 72 hours, total volume administered as iv medications, total volume administered as maintenance fluid and total fluid administered introduction: in children less than 30 kilograms, maintenance fluids are routinely added to the resuscitation requirements calculated using parkland's or other formulae. the contribution of this component for fluid resuscitation in children can add a significant quantity to total estimated fluid requirements. for example, in a child who is 10 kilograms with a 25% burn, the maintenance fluid requirement is 1000 mls per 24 hours and the resuscitation component per parkland's will be 4 x 10 x 25%=1000 mls. hence, the maintenance requirement can exceed the resuscitation requirement in this child if the burn surface area is less than a 25 % burn. the contribution of maintenance fluids to the total fluid requirements in small children with thermal injuries is under-recognised and not frequently studied. methods: to understand the contribution of maintenance fluids to the total fluid requirements in children less than 30 kilograms who need resuscitation for thermal injuries of different sizes, we numerically simulated 1. children who had similar weights but different burn sizes and 2. children with similar burn size but different weights. the results are as shown in fig introduction: accurate quantification of fluid in resuscitation of thermal injuries is important for benchmarking, comparing and improving outcomes. in adults, it is usually expressed as mls/kg/%tbsa. in children, maintenance fluids are added to the resuscitation requirements. this is kept constant and the resuscitation component is titrated to meet pre-defined end points-usually urine output. maintenance fluids are not uniformly stratified across the weight ranges. we propose that quantification of fluids in mls/ kg/%tbsa in children does not accurately capture fluid needs for resuscitation due to the maintenance component of the fluid requirement. methods: we conducted this retrospective study in children admitted to a single-center burns intensive care unit (bicu) between january 2010 and december 2014. children ≤30 kilograms with tbsa ≥15% admitted within 8 hours of their injury were included. oe (observed to expected ratio) and fluid in mls/kg/% tbsa were calculated as shown in figure 1 . results: there were 33 children in the cohort with half requiring invasive mechanical ventilation in the bitu and nearly a quarter requiring inotropic support. the demographic details are as shown in table 1 . the oe ratio at the end of 24 hours in the cohort was 1.01 (0.68-1.36). the total fluid given was 6.9 (6.1, 8) mls/kg/ % tbsa. the titrated resuscitation component was 4.2 (3.7, 5.6) mls/kg/tbsa. total fluid (which included the maintenance fluid) had a poor correlation with oe ratio r2=0.34 (fig 2) . exclusion of the maintenance fluid had a better correlation with the oe ratio r2=0.75 conclusions: to capture differences in the titratable resuscitation component rather than differences in the maintenance requirements, fluid should be quantified in children by excluding the maintenance component when expressed as mls/kg/%tbsa. dynamic arterial elastance for predicting mean arterial pressure responsiveness after fluid challenges in acute respiratory distress syndrome patients p luetrakool 1 , s morakul 1 , v tangsujaritvijit introduction: dynamic arterial elastance (eadyn; pulse pressure variation/stroke volume variation; ppv/svv) is a dynamic parameter of arterial load that can be continuously monitored. previous study proposed that eadyn was able to predict mean arterial pressure (map) responsiveness after fluid challenge [1] [2] [3] [4] [5] . the objective of this study was to assess whether the eadyn was able to predict map responsiveness in acute respiratory distress syndrome (ards) patients ventilated with low tidal volume. methods: we performed a prospective study of diagnostic test accuracy in adult ards patients with acute circulatory failure and fluid responsiveness. all patients are continuously monitored blood pressure via arterial line connected with flotrac® transducer and vigileo® monitor. once the attending physicians decided to load intravenous fluid, we recorded ppv/svv and also other hemodynamic parameters before and after fluid bolus. map responsiveness was defined as an increase in map ≥ 10% from baseline after fluid challenge. results: twenty-three events were included. nine events (39.13%) were map-responsive. cardiac output, heart rate and stroke volume were similar in both map-responder and map-nonresponder group. baseline map, diastolic blood pressure (dbp) and pulse pressure (pp) were significantly different after fluid challenge in map-responder group. eadyn of preinfusion phase was failed to predict map conclusions: one of the arterial load parameters such as eadyn derived from non-calibrated pulse contour analysis method was unable to predict map responsiveness in ards patients with low tidal volume ventilation. the our aim is to test the hypothesis that in fr septic shock patients, fluid load will determine a significant increase in pmsf but not in cvp. we prospectively included all mechanically ventilated patients with diagnosis of septic shock with invasive hemodynamic monitoring (transpulmonary thermodilution volumeview-ev1000 ed-wards©). we collected hemodynamic and metabolic data and pmsf with the inspiratory holds technique, before and after a fluid challenge (fc) of 500 ml of ringer lactate in 10 minutes). fr was defined as an increase in cardiac output (co)>15%. results: 13 measures were obtained in 11 patients. in 8 case we observed fr. we found a significant increase in pmsf after a fc (mean difference(md) 16.9±21.5 mmhg, p=.015). cvp increased significantly (md 2.5±2.4 mmhg, p=.002). pmsf increased significantly in non-fr (md 27±10mmhg, p=.013) but not in fr while cvp was higher after fc only in fr (md 2.4±2.1mmhg, p=.008). venous return gradient (pmsf-cvp) globally increased after fc (md 14±22 mmhg, p=.03), but only in non-fr such increase was significant (md 24±12 mmhg, p=.03). no correlation was found between the variation co and venous return gradient. we did not find any improvement in metabolic parameters after the fluid challenge. conclusions: pmsf and combined cvp variations do not correlate with fr in our cohort of septic shock patients. inspiratory holds may not be adequate to infer pmsf in such context. further studies are warranted to investigate the effect of fc on pmsf in this field. evaluation of pre-load dependence over time in patients with septic shock i douglas 1 , p alapat 2 , k corl 3 , m exline 4 , l forni 5 , a holder 6 , d kaufman 7 , a khan 8 , m levy 3 , g martin 9 , j sahatjian 10 , w self 9 , e seeley 9 , j weingarten 9 , m williams 9 , c winterbottom 11 , d hansell 12 is an effective method to predict fluid responsiveness (fr) or cardiac response to preload expansion. we have previously shown that fluid responsiveness is a dynamic state, changing frequently over a 72 hour monitoring period. methods: fresh is a currently enrolling prospective randomized controlled study, evaluating the incidence of fr and patient centered outcomes in critically ill patients with sepsis or septic shock (nct02837731). patients randomized to plr guided resuscitation were evaluated every 6-12 hours over the first 72 hours of care and classified as fr if the sv increased > 10% when measured with non-invasive bioreactance (starling sv, cheetah medical). the time of first fr was noted. results: a total of 608 plr assessments were performed in 86 patients over a 72 hour monitoring period. 56 % were female, and the average age was 61 years. plrs were evaluated over time, with time 0 representing initial fluid resuscitation ( figure 1 ). when individual subjects were evaluated over time, 100% of subjects who became fr only after 24 hours showed evidence of lv/rv dysfunction ( figure 2 ). conclusions: fluid responsiveness or preload dependence frequently changes for septic shock patients over the first 72 hours of care. evidence suggests it is beneficial to periodically perform an assessment of preload responsiveness to guide fluid administration, as preload dependence is a dynamic and changing state. preload dependence provides additional information beyond fluid responsiveness. those patients who remain primarily fluid non-responsive (preload independent) are more likely to demonstrate echo confirmed lv/rv dysfunction, as the delay in return to cardiac function may be related to underlying cardiac deficits. further evaluation may be indicated in preload independent patients. introduction: hydroxyethyl starch (hes), a synthetic colloid, has been used as a volume expander, and is associated with renal impairment in patients with sepsis. however, a small dose of hes (6%, 130/0.4) has sometimes been used in acute ischemic stroke. therefore, we investigated whether a small dose of hes was linked with renal deterioration in patients with acute ischemic stroke. methods: a consecutive 524 patients with acute ischemic stroke within 7 days from onset were included between january 2012 and may 2016 (fig 1) . we collected admission serum creatinine (scr), estimated glomerular filtration rate (egfr), and renal function was assessed using kdigo definition of acute kidney injury on hospital days 5 to 9 as to patient's hospitalization period. is crucial for venous return and volaemic status, and as such it is a useful parameter in physiology and clinical settings alike. we tested whether: near infra-red spectroscopy (nirs) could be effective at measuring msfp both in healthy individuals and in conditions with a rise in interstitial pressures; after an occlusion pressure is relieved, the decrease in venular blood volume could allow calculation of τ (time constant) and thus venous resistances (rv). in order to verify these hypotheses we used a forearm nirs probe on healthy individuals at rest and during different degrees of maximal voluntary contraction (mvc). methods: 10 healthy subjects volunteered in the study that took place at sant'andrea hospital in rome (italy). all subjects had venular pressures and volumes assessed via a nirs probe positioned on the forearm using a pressure-cuff in steps of 5 mmhg from 0 to 50 mmhg, at rest and at 10% and 20% mvc. for each patient msfp, unstressed volume (vu) and stressed volume (vs) were measured. a temporary 30 mmhg occlusion was obtained and volume time course was calculated upon release, to derive τ . results: p-v relationship was found to have a 3-slopes shape reflecting venular network changes. we measured vu, vs, and obtained msfp values of 6.74 ± 1.83 mmhg, p<0.001; during exercise no changes in vu and vs were noted but msfp values rose; value was found to be 2.9 ± 0.1 sec at rest and 0.9 ± 0.03 sec after exercise, reflecting a reduction in rv. conclusions: nirs measurements on healthy subject may have implications in the clinical assessment of critical care patients where changes in interstitial pressure are possible. introduction: in the pathogenesis of multiple organ dysfunction syndrome (mods) important role plays the development of hepatic dysfunction. a known method for assessing hepatic blood flow is reohepatography (rhg). however, it requires the analysis of a large number of parameters of the rheogram curve. the aim of this study was to develop a method for assessing arterial hepatic blood flow based on the rhg in patients with mods after abdominal surgery. methods: 55 patients in the department of anesthesiology and intensive care unit were included in a prospective study (36 men and 19 women, age 60.1 ± 16.1 years, weight 78.5 ± 13.9 kg.). all patients were divided into two groups: group 1 -patients after orthopedic and trauma surgery (n = 28), group 2 -patients after abdominal surgery with mods (n = 27). patients in the groups did not have statistical differences by sex, age, body weight, height. rhg was carried out using the "reo-spectr" (russian federation). we have compared the rhg indicators between the groups ( table 1) . we have developed a method for assessing hepatic arterial blood flow, which consists in determining the area under the arterial part of rhg curve using the simpson's rule. its normal values range from 43.2 mω *s to 49.0 mω *s. the method is non-invasive, can be applied at the patient´s bed. its advantage is simplicity, it can be used for rapid diagnosis and monitoring the effectiveness of treatment. area under the rhg curve in the group 1 were 46.1 ± 8.1 mω *s and 20.0 ± 16.8 mω *s in the group 2 (p <0.05). conclusions: patients after abdominal surgery with mods have impaired hepatic blood flow, which may be associated with liver pathology caused by main surgical disease (obstructive jaundice) and hemodynamic disorders caused by acute cardiovascular failure. the method we developed allows us to determine disorders of hepatic arterial blood flow in the early stages before signs of liver dysfunction appear. comparison of pulse oximetry hemoglobin with laboratory measurement of arterial and centralresults: 80 patients: 54% male, median 68years (59-73); p:f ratio 174 (132-208); peep 10 (7-12); apache iii 80.5 (26); median ventilation time 6 days (3-9). fair agreement was seen in subjective assessment vs objective measures with binary assessment of rv size and function. ordinal data analysis showed poor agreement with rvfws ( figure 1 ) and rv dimensions. if onestep disagreement was allowed the agreement was good ( table 1 , 2). significant overestimation of severity of abnormalities was seen comparing subjective assessment with rv eda and tapse, s' and fac. there was no difference in agreement values when accounting for clinician echo experience, perceived expertise (at level of cardiologist) or type of qualifications. conclusions: relatively low levels of agreement were seen with subjective assessment vs objective measures of rv size and function assessed by echo. it seems prudent to avoid subjective rv assessment in isolation and a combination of objective and subjective measures should be used. introduction: even short periods of hypotension are associated with increased morbidity and mortality. using high-density numerical physiologic data, we developed a machine learning (ml) model to predict hypotension episodes, and further characterized risk trajectories leading to hypotension. methods: a subset of subjects with 1/60hz physiological data was extracted from mimic2, a richly annotated multigranular database. hypotension was defined as >5 measurements of systolic blood pressure ≤ 90 mmhg and mean arterial pressure ≤ 60 mmhg, within a 10-minute window. derived features using raw measurements of heart rate, respiratory rate, oxygen saturation, and blood pressure were computed. random forest (rf), k-nearest neighbors (knn), and logistic regression models were trained with 10-fold cross validation to predict instantaneous risk of hypotension using features extracted from the data leading to the first episode of hypotension (cases) or icu discharge in subjects never experiencing hypotension (controls). for a given subject, risk trajectory was computed from the collation of instantaneous risks. results: from a source population of 2808 subjects, 442 subjects met our definition of hypotension, and 724 subjects without hypotension comprised the control group. 204 features were generated from the four vital signs. the area under the curve (auc) for random forest classifier was 0.829, out-performing logistic regression (auc 0.826) or k-nearest neighbors (auc 0.783) (fig 1) . risk trajectories analysis showed average controls risk scores <0.3 (<30% risk of future hypotension), while the hypotension group had a rising risk score (0.45 to 0.7) in the 8 hours leading to the first hypotension episode, and significantly higher scores leading into subsequent episodes (fig 2) . conclusions: hypotension episodes can be predicted from vital sign time series using supervised ml. subjects developed hypotension have an increased risk compared to controls at least 8 hours prior to the episode. introduction: in critically ill patients or in patients undergoing major surgery, monitoring of co is recommended [1] [2] [3] . less-invasive advanced hemodynamic monitoring with pwa is increasingly used in perioperative and critical care medicine. in this study, we evaluate the measurement performance of an uncalibrated pulse wave analysis (pwa) device (mostcareup, vygon, ecouen, france) compared with cardiac output (co) assessment by pulmonary artery thermodilution (patd) in patients after cardiac surgery. methods: in patients after cardiac surgery, we performed seven sets of patd measurements to assess patd-co. simultaneously, we recorded the pwa-co and compared it to the corresponding patd-co. to describe the agreement between pwa-co and patd-co we used bland-altman analysis showing the mean of the differences and 95%-limits of agreement and calculated the percentage error. results: we included 17 patients in the analysis. the bias between pwa-co and patd-co was 0.01 l*min-1. upper and lower 95% limits of agreement were +1.40 l*min-1 and -1.38 l*min-1. the percentage error was 28.1%. conclusions: pwa-co estimated with using the mostcareup device shows good agreement with pulmonary artery thermodilutionderived co in patients after cardiac surgery. introduction: non-invasive continuous blood pressure monitoring devices have been investigated, however, these devices did not have sufficient accuracy and precision. we developed a continuous monitor using the photoplethysmographic technique and tested the accuracy and precision of this system to ensure it was comparable to conventional continuous monitoring methods used for critically ill patients. methods: the study device was developed to measure blood pressure, pulse rate, respiratory rate, and oxygen saturation, continuously with a single sensor using the photoplethysmographic technique. patients who were monitored with arterial pressure lines in the icu were enrolled. the physiological parameters were measured continuously for 30 minutes at 5-minute intervals using the study device and the conventional methods. the primary outcome variable was blood pressure. results: pearson fs correlation coefficient between the conventional method and photoplethysmography device were 0.993 for systolic blood pressure, 0.985 for diastolic blood pressure, 0.998 for mean blood pressure, 0.996 for pulse rate, 0.995 for respiratory rate, and 0.963 for oxygen saturation. percent errors for systolic, diastolic and mean blood pressures were 2.4% and 6.7% and 6.5%, respectively. percent errors for pulse rate, respiratory rate and oxygen saturation were 3.4%, 5.6% and 1.4%, respectively. conclusions: the non-invasive, continuous, multi-parameter monitoring device presented high level of agreement with the invasive arterial blood pressure monitoring, along with sufficient accuracy and precision in the measurements of pulse rate, respiratory rate, and oxygen saturation. conclusions: stroke volume measurement using bioreactance technique had strong correlation with odm while pwtt had moderate correlation. both devices had small bias with wide limits of agreement and percentage error compared with odm. therefore, these devices are not interchangeable with odm. however, using trends in stroke volume to guide treatment might still be acceptable. introduction: hemorrhage is the most common cause of trauma deaths and the most frequent complication of major surgery. it is difficult to identify until profound blood loss has already occurred. we aim at detecting hemorrhage early and reliably using waveform vital sign data routinely collected before, during, and after surgery. methods: we use waveform vital sign data collected at 250 hz during a controlled transition from a stable (non-bleeding) to a fixed bleeding state of 93 pigs. these vital signs include airway, arterial, central venous and pulmonary arterial pressures, venous oxygen saturation (svo2), pulse oximetry pleth and ecg heartrate, continuous co, and stroke volume variation (lidco). we used gated recurrent units (gru), long short-term memory (lstm) and dilated, causal, one-dimensional convolutional neural (table 1) . however, outside of the very low fpr range (cf. rocs in fig. 1 and 2), our models appear inferior to a referenced random forest (rf) classifier. conclusions: our work demonstrates the applicability of deep learning models to diagnose hemorrhage based on raw, waveform vital signs. future work will address why the rf classifier can address the greater homogeneity of subjects when they bleed compared to an apparently wide dispersion of their statuses when being stable. this work is partially supported by nih gm117622. can myocardial perfusion imaging with echo contrast help recognise type 1 acute myocardial infarction in the critically ill? introduction: many instances of significant bleeding may not occur in highly monitored environment, contribution in the delay in recognition and intervention. we therefore proposed a noninvasive monitoring for early bleeding detection using photoplethysmography (ppg). methods: fifty-two yorkshire pigs were anesthetized, stabilized and bled to hemorrhagic shock, and their invasive arterial blood pressure (abp), and ppg data were collected [1] . time series of vital signs were divided into data frames of 1 minute updated every 30 seconds and beat to beat features were computed. the final feature matrix contained 18 abp features and 85 ppg features. a supervised machine-learning framework using least absolute shrinkage and selection operator regularized logistic regression model was constructed to score the probabilities for hemorrhage of each data frame. data in stabilization was set as negative and data in bleeding was set as positive. model performance was evaluated by receiver operating characteristic (roc) area under the curve (auc) with leave-one-out cross validation, and its precision was assessed with activity monitoring operative characteristic (amoc). results: two different models were proposed using abp and ppg features separately. figure 1 showed the ppg model could classify the hemorrhage with auc = 0.89, where the auc of abp model was 0.91. figure 2 showed the ppg model could detect the hemorrhage on average 15.5 minutes (equals to 320 ml blood loss) if the false alarm rate of 1/100 was tolerated, whereas the average detection time of abp model were 12.5 minutes at same threshold of false alarm rate. conclusions: we proposed a novel non-invasive bleeding detection approach using ppg signals only. this method potentially can improve the identification of hemorrhage with in patients and environments where invasive monitoring is unavailable. table 1 , catheter and procedure characteristics are shown in table 2 . the median angle of bed position was 26°. no patients were positioned in neutral or tp. all procedures were successful with a mean of 1.3 punctures per patient, and a maximum of 3. the median procedure time was 12.5 minutes. no major complications occurred in any of our patients. conclusions: central venous catheterisation in moderate upright position is feasible and can be done safely when using realtime ultrasound by well-trained physicians. we recommend performing clinical assessment and pre-procedural ultrasound to choose the optimal puncture site and position in order to attain an optimal ultrasound visualisation of the vessel and patient comfort. methods: a retrospective analysis of 10 patients presenting to tertiary-care emergency department who required cvc for vasopressor administration was carried out. all central venous cannulation into the right brachiocephalic vein was performed with ultrasound guidance using the high frequency linear probe. right brachiocephalic vein was visualised in its long axis. the needle was positioned just beside the centre of ultrasound probe 15 degrees below the coronal plane and 10 degrees angle to the ultrasound probe and advanced just behind the clavicle. results: the mean puncture time taken to perform this procedure, calculated from the needle piercing the skin until to the aspiration of blood from the brachiocephalic vein through the needle, was 23 ± 6.8s. no procedure-related complications were detected. conclusions: the oblique needle trajectory of right brachiocephalic vein cvc in adult is feasible and able to visualised well the anatomical structure, hence avoid complications. introduction: central venous cannulation, a routine procedure on intensive care units, is associated with a low complication rate. as a consequence, the routine use of chest x-ray (cxr) or ultrasound (us) to assess these complications is under discussion. our aim was to identify risk factors for central venous catheter (cvc) placement associated complications that can help decide whether or not follow-up using cxr and/or us is indicated. methods: multicenter prospective, observational study. consecutive critically ill adult patients who underwent cvc placement. either the internal jugular vein or subclavian vein was cannulated. complication rates were determined. predicting factors were obtained through a questionnaire filled in by physicians after placing a cvc. if the questionnaire was incomplete or data was missing, analyses were performed using the available data. patient characteristics were duplicated if a patient recieved more than one cvc. outcomes were iatrogenic pneumothorax and malposition. pneumothorax was detected using us, whereas cxr was used to determine cvc malposition. table 1 . usguidance, insertion site, and setting were predictive for complications. the overall cvc placement associated complication rate is low and multiple risk factors associated with the occurrence complications were identified. a complication rate this low, strongly suggests that routine post-procedural diagnostics is superfluous. therefore, we suggest, provided that uneventful execution of the procedure is assured, post-procedural diagnostics are only necessary in selected cases with (multiple) risk factors. introduction: the use of ultrasound for subclavian vein cannulation (scv) has developed poorly due to the difficulty of visualizing this vein via the classical infraclavicular approach. we explored the feasibility of ultrasound-guided subclavian vein catheterization via a supraclavicular approach methods: prospective study conducted over six-month period in intensive care unit. after approval of the ethics committee, we included patients over 18 years of age and requiring central venous access. exclusion criteria were: hemostasis disorders, puncture area infections and cervico-thoracic vascular malformations the procedure consisted of catheterization of the vsc with a supraclavicular approach under ultrasound guidance using an ultrasound in plane approach (fig 1 and 2 ). data collection included clinical and ultrasound data: scv depth, diameter and length, catheterization time, number of needle redirection, cannulation success and complications. results: thirty four patients were included. age: 57 ± 15 (mean ± sd), 60% of whom were male. the success rate of scv catheterization was 97% (one failure). the depth of the scv was 11 ± 4.5 mm and its diameter was 11 ± 3.5 mm. the puncturable length of the scv was 33 ± 7mm and the puncture angle was 36 ± 15°. the time required to obtain an adequate ultrasound image was 25 ± 9 seconds. the interval between the beginning of the puncture and the insertion of the guidewire into the vein was 42 ± 29 sec. the total catheterization time was 69 ± 33 seconds. the number of needle redirection 0.8 +/-1.2 redirects. the quality of the ultrasound image was excellent or good in 87.5% of cases. an arterial puncture was observed in two patients conclusions: this preliminary study demonstrated the feasibility of the subclavian vein cannulation via the supraclavicular approach. more study are required to confirm its safety and to compare this approach to the infraclavicular acces using ultrasound. introduction: lung ultrasound b-lines, a comet-like reverberation artefacts arising from water-thickened interlobular septa, indicate extravascular lung water which is a key variable in heart failure management and prognosis. aim of this study is to measure the correlation between lung ultrasound b-lines and nyha functional classification. methods: this is a 6 months prospective study on congestive heart failure patients conducted in 2 urban emergency departments in malaysia. following enrolment, patients had their functional capacity categorised based on nyha classification, followed by point of care ultrasound (pocus) lung scan using a 12mhz linear probe. the scanning was performed by trained emergency physicians. the longitudinal scan done at the recommended 6 zones of both left and right lungs and the total number of b-lines identified were summed up as the comet score. comet score of 0, 1, 2 and 3 were categorised based on amount of blines of less than 5, 5-15, 15-30 and more than 30 b-lines respectively. results: hundred and twenty-two patients were analysed (69 males(56.6%) and 53 females(43.4%)) ranging from 24 to 88 years old. comet score of 1,2 and 3 were found to be statistically significant with presence of paroxysmal nocturnal dyspnoea, elevated jugular venous pressure, lung crackles, bilateral pitting oedema and chest radiographic findings. a moderate correlation between nyha classes with comet score 1,2 and 3 (rs= 0.77 (p<0.01)) was documented. conclusions: our study demonstrated a moderate correlation between nyha classes and lung ultrasound b-lines. lung ultrasound may be a potential tool to objectively determine the functional capacity in patients with congestive heart failure and monitor its changes in response to treatment and disease progression. the introduction: point of care ultrasound (pocus) is a tool of increasing utility in the management of the critically ill patient. guidelines exist for training and accreditation in pocus [1, 2] however the widespread use of pocus has been hampered by a lack of mentors. online communication with end-to-end security, such as whatsapp ™ are increasingly used in medicine as a communication aid [3] . some individuals are using such communications to share pocus images for review-the overall sentiment around these tools is unknown. methods: an online survey of pocus users was conducted via twitter ™. the question was "in situations where an expert opinion on an ultrasound is not immediately available, is it acceptable to get an expert review via an online medium such as whatsapp, and would you be happy to be that expert?" results: 304 votes were received. voters were a mix of pocus users from the usa, europe, and australia. 58% said the medium was acceptable, and that they would be happy to provide expertise. 34% voted "no", with 8% voting "other" (fig 1) . conclusions: in this international survey of pocus users, 58% were happy to provide and receive mentorship using remote software such as whatsapp. distance mentorship for pocus training should be explored. [2] . a description of the development and refinement of insight -a feasibility and clinical effectiveness randomized controlled trial. methods: a modified delphi exercise was used to select the most beneficial ultrasound windows and imaging questions to ask for each window in scheduled inter-professional ultrasound. 260 nurses, 46 doctors and 6 physiotherapists from critical care were given the same information regarding potential utility of each window. the windows and associated questions were individually ranked; each window and question tested against three further criteria; and filtered by ease of training to level 1 standard; clinical usefulness; time of practical delivery and applicability across an inter-professional group. results: the modified delphi exercises and prioritization exercise ranked ease of adoption by training; feasibility within the time frame and clinical usefulness to develop a core insight scan of 5 domains, each with set binary questions (tables 1 and 2 ) conclusions: we have developed a research intervention that will allow us to test the effectiveness of inter-professional scheduled whole body assessment of critically ill patients by ultrasound. we now plan to conduct a clinical effectiveness trial with an internal pilot to confirm feasibility. to search for optimal pressing time, the plots from the color sensor during nail bed compression were analyzed. we found two phases in the color sensor plots. in the initial part of compression, the plots changes rapidly (rapid phase) and then the slope of plots reduces (slow phase). the pressure release during the rapid phase could destabilize the measurement. the longest period of the rapid phase was 1.9999 s among all the study subjects. thus, a pressing time of 2 s seems to be needed to obtain stable crt measurements. conclusions: on our study for the investigation of standard pressing time and strength for crt measurements, pressing the nail bed with 3-7 n and 2 s appears to be optimal. detection of pancreas ischemia with microdialysis and co2sensors in a porcine model introduction: pancreas transplantation is associated with a high rate of early graft thrombosis. current postoperative monitoring lack tools for early detection of ischemia, which could precipitate a graft-saving intervention. we are currently exploring the possibility of ischemia detection with microdialysis and co 2 -sensors in the organ tissue or on the surface in a porcine model. methods: in anesthetized pigs, co 2 -sensors and microdialysis catheters are inserted into the parenchyma or attached to the surface of the pancreas. pco 2 is measured continuously and lactate is sampled with microdialysis every 15 min. ischemia is induced by sequential arterial and venous occlusions for 45 minutes, with 120 minutes of reperfusion in between. results: pco 2 increased and decreased in response to ischemia and reperfusion within minutes. lactate increased and decreased with the same pattern, but with a considerable delay as compared to pco 2 . an example is depicted in figure 1 . the values are presented in introduction: reliable automated handheld vital microscopy (hvm) image sequence analysis is a prerequisite for use of sublingual microcirculation measurements at the point-of care according to the current consensus statement. we aim to validate a recently developed advanced computer vision algorithm [1] versus manual analysis in a wide spectrum of populations and contexts. methods: our collaborators were invited to contribute raw data of published or ongoing institutional review board approved work. inclusion criteria were use of the cytocam hvm device, manual analysis with the ava software, and image quality as independently assessed by massey score of <10 in >50% of recordings in a random subset of each study. 233 subjects from 11 studies were included, covering clinical and experimental populations, major shock forms and interventions to recruit the microcirculation (table 1) . results: 2,599,710 red blood cells were tracked by the algorithm across 150,163 frames in 1462 measurements in real time. a good to excellent correlation was found between algorithm-determined and manual capillary density (p<0.0001, r 0.6-0.9, figure 1 ). capillary perfusion was classified using space-time diagram derived red blood cell velocity (rbcv), yielding good correlation with manual analysis for functional capillary density und proportion of perfused vessels. microcirculatory alterations during disease and interventions were equally detected by the algorithm and manual analysis. change in flow short of severe abnormality was reflected in absolute rbcv but not microcirculatory flow index. conclusions: we demonstrate the validity of automated software for hvm image sequence analysis across broad populations, disease conditions and interventions. thus, microcirculatory assessment at the bedside may finally complement point-of-care evaluation of disease severity and treatment response in critically ill patients and during surgery. introduction: in 2016, naumann et al introduced the poem score as a real-time, point-of-care score to assess sublingual microcirculation [1] . our study aimed to determine the reproducibility of the poem score. methods: two expert operators used a sidestream darkfield (sdf) videomicroscope (cytocam, braedius, netherlands) to separately acquire four high-quality video clips and assign a poem score to each image in 20 adult mechanically ventilated patients. each operator was blinded to the other's images and analysis. video clip scores and acquisition times were recorded. results: of the 20 patients enrolled in this study, 45% (n=9) required vasopressors. we categorized poem scores 4-5 as "normal" and poem scores 1-3 as "impaired." (fig 1) . with only one instance of interrater disagreement (i.e., a single image scored as 3 versus 4), cohen's kappa (0.86) confirmed a strong correlation between interpreters. the mean time to complete a study session was 9 minutes. conclusions: the present inability to quickly characterize the quality of sublingual microcirculation as either normal or impaired at the point of care limits real-world clinical application of this resuscitative endpoint. the rapidly obtained poem score appears to be reproducible between bedside interpreters. future studies should assess the effect of poem score-guided resuscitation. . sublingual microcirculatory images were obtained using a cytocam-idf device (braedius medical, huizen, the netherlands) and analyzed using standardized published recommendations. results: the median age of participants was 32 years. we found no significant difference in proportions of hemodynamic responders before and after marathon (64% vs 55%, p=0.819). also we did not find differences between plr induced changes of total vessel density (tvd) and proportion of perfused vessels (ppv) of small vessels before and after marathon. correlations between changes of sroke volume and changes of tvd or ppv of small vessels during plr were not significant. conclusions: marathon running did not change microcirculatory responsiveness. introduction: clinical measurement of mitochondrial oxygen tension (mitopo 2 ) has become available with the comet system [1] . a question with any novel technique is whether it is feasible to use in clinical practice and provides additional information. in elective cardiac surgery patients we measured cutaneous mitopo 2 and tissue oxygenation (sto 2 ). methods: institutional research board approved observational study in patients undergoing cardiopulmonary bypass (cpb). mitopo 2 measurements were performed on the left upper arm (comet, photonics healthcare b.v.) by oxygen-dependent delayed fluorescence of 5aminolevulinic acid (ala)-induced protoporphyrin ix [2] . priming of the skin was done with ala (alacare, photonamic gmbh) applied the evening before surgery. sto 2 measurements (invos, medtronic) were done in close proximity to the comet sensor. results: at the time of writing 28 of 40 patients were enrolled and mitopo 2 measurements were feasible in this clinical setting. mitopo 2 appeared sensitive with a high dynamic range. for example, highdose vasopressor therapy decreased mitopo 2 and blood transfusion increased a low mitopo 2 but not a high mitopo 2 . in the example in figure 1 , mitopo 2 is clearly dependent on cpb flow and the restored cardiac circulation is able to maintain good cutaneous oxygenation after cpb even before returning of cellsaver blood. sto 2 had the tendency to provide relatively stable values within a small bandwidth and little response to even major hemodynamic changes. conclusions: mitopo 2 shows the effect of interventions on mitochondrial oxygenation and provides additional information compared to standard monitoring and sto 2 . introduction: traumatic asphyxia is a rare condition in which breathing and venous return is impaired due to a strong compression to the upper abdomen or chest region, and induces swelling, purplish red appearance, and petechiae around the face and neck. to our knowledge, there are no reports describing details of traumatic asphyxia including the clinical course and the therapeutic reactivity from cardiac arrest. we focused on cardiac arrest among all traumatic asphyxia patients treated at our hospital, and investigated their clinical features and therapeutic reactivity. methods: sixteen cases of traumatic asphyxia involved with our hospital between april 2007 and march 2018 were reviewed by using the pre-hospital activity record, medical record, and hyogo prefectural inspection record. these patients were divided into three groups. the first group had already cardiac arrest at the time of rescue from the trapped place (group a; 6 cases). the second group became cardiac arrest after the rescue (group b; 5 cases). the third group did not experience cardiac arrest (group c; 5 cases). results: all cases had abnormal findings in skin or conjunctiva (table 1) . total mortality rate reached 56%, but among 11 cases of group a and b who resulted in cardiac arrest, there were 10 cases with injury severity score 16 or more and abbreviated injury scale in the chest 3 or more. they had pneumothorax, flail chest, pericardial hematoma. seven of them restored spontaneous circulation, and two cases achieved neurologically full recovery. conclusions: there are some cases of traumatic asphyxia whose therapeutic reactivity is very good even after cardiac arrest, so it is important not to spare efforts for life support in such cases. rhythm and 75% witnessed arrest, five hundred ten (25%) patients had a good functional outcome at 6-months. physiological derangements were each negatively associated with outcome in bivariate analysis at the p <0.001 level. a summary score of physiological derangements was included with potential confounders in the final regression model, and was independently associated with outcome with the chance of a good outcome decreasing by 46% for each increase of one physiologic derangement (95% ci 0.46-0.63). conclusions: uncorrected physiological derangements are independently and cumulatively associated with worse outcome after cardiac arrest. although causality cannot be established, it is reasonable to consider that the correction of physiological parameters may be an important step in the chain of survival after resuscitation. characteristics introduction: glan clwyd hospital (gch) was recently designated one of three cardiac arrest centres for wales. it has offered a 24/7 percutaneous coronary angiography (pci) service to a geographically dispersed north wales population of approximately 690,000 since june 2017. prior to this, urgent coronary angiography was available on a more limited basis to patients requiring pci. the aim of this study was to investigate factors associated with hospital mortality after critical care admission following cardiac arrest. methods: retrospective review of the ward watcher critical care database at gch to identify patients who had undergone cpr in the 24 hours prior to critical care admission in 2013-18. patients likely to have sustained ooha of cardiac aetiology (ooha-c) were identified from primary and secondary diagnoses and free text entry. data were subsequently analysed using excel and spss. the project was registered as a service evaluation with gch audit department. results: there were 190 cardiac arrest admissions over this period, increasing from 25 in 2013-14 to 69 in 2017-18. of these 122 were ooha, of which 103 were considered ooha-c. although ooha-c hospital mortality appeared to decrease over the time period (89%% to 56%), this was not statistically significant (p=0.149). factors associated with survival to hospital discharge are presented in the tables below. on logistic regression, only pci and low ph within the first 24 hours of critical care remained statistically significant (p=0.027 and p<0.001 respectively). conclusions: although we have been unable to make a distinction between patients presenting following stemi and nstemi, and appreciating a potential influence of selection bias, the significant association between pci and survival to hospital discharge supports the introduction of clinical pathways enabling pci access following ooha-c [1] . chest radiography. [1] here, we aimed to derive and validate rules to estimate p_max.lv using anteroposterior chest radiography (ches-t_ap), which is performed for critically-ill patients urgently needing determination of personalised p_max.lv. methods: a retrospective, cross-sectional study was performed with non-cardiac arrest adults who underwent chest_ap and computed tomography (ct) within 1 h (derivation:validation=3:2). on chest_ap, we defined cd (cardiac diameter), rb (distance from right cardiac border to midline) and ch (cardiac height, from carina to uppermost point of left hemi-diaphragm) (fig 1, 2) . [1] setting p_zero (0, 0) at the midpoint of xiphisternal joint and designating leftward and upward directions as positive on x and y axes, we located p_max.lv (x_max.lv, y_max.lv). the coefficients of the following mathematically-inferred rules were sought: x_max.lv=a0*cd-rb; y_max.lv=ß0*ch+γ . (a0: mean of (x_max.lv+rb)/cd; ß0, γ : representative coefficient and constant of linear regression model, respectively 1) . conclusions: evaluable echocardiographic records were reached in most of the patients. etco2 positively correlated with all parameters under consideration, while the strongest correlation was found between cimax and etco2. therefore, cimax is a candidate parameter for real-time monitoring of haemodynamic efficacy of chest compressions during cpr. introduction: the uk resuscitation council has set out guidelines for management of patients post cardiac arrest [1] . this is in line with european resuscitation council guideline. we set out to find if we are following the guideline. methods: we did a retrospective audit over the course of 2 years looking at the data of 24 patients who had in hospital and/or out of hospital cardiac arrest and after the return of spontaneous circulation were admitted to the intensive care unit (icu). we focused on whether the care they received was as per the standards set by the uk resuscitation council. results: we had 11 in the hospital and 13 out of hospital cardiac arrests; 11 patients had less than 10 minutes of cpr, 9 had more than 10 minutes cpr and 4 patients the data was not recorded; 16 patients needed more than 61 minutes to reach from the site of arrest to the icu. the partial pressure of carbon dioxide was >5.5 kpa in 11 patients at two or more occasions. target map was not documented in 9 patients; blood sugar target was not documented in 15 patients and was not maintained within limits in 5 patients. target temperature was not documented in 10 patients. the withdrawal of treatment was not delayed for 72 hours in 1 patient out of 24. in 4 patients neurological tests were not documented. multimodal assessment tools were not used in 1 patient. electroencephalography and serum neuron specific enolase were not used to diagnose brain deaths as they were not available at our trust. 11 patients were discharged, 12 died in the icu and 1 died in hospital after discharge from icu. conclusions: the audit reflected our local practice and showed that our mortality was in line with the acceptable limits; poor documentation of plan of care which posed problems in analyzing the care that these patients received; some of the parameters were not being maintained as set by uk resuscitation guideline. introduction: high-quality chest compressions (cc) with minimized interruptions are one of the most essential prerequisites for an optimal outcome of resuscitation. therapy of reversible causes of cardiac arrest often requires intra-hospital transportation (iht) during ongoing cpr. the present study investigated cc quality during transportation depending on the position of the provider. methods: 20 paramedics were enrolled into a manikin study with four groups: a reference group with the provider kneeling beside manikin on the floor (group 1), and 3 groups performing cc during a simulated iht of 100 meters: walking next to the bed (group 2), kneeling beside the patient in bed (group 3, fig. 1 ) or squatting above the patient in bed (group 4, figure 2 ). indicators of cc quality were measured as defined in the erc guidelines 2015 (pressure point and depth, compression frequency, complete relief, sufficient pressure depth) [1] . all 20 paramedics performed cc during each scenario (group 1-4). results: there were no statistical differences in quality of cc between groups 1, 3 and 4. notably, group 2 performed significantly worse in respect to the proportion of cc with correct pressure point (p = 0.044 vs group 1), correct cc depth (p=0.004 vs. group 1, p=0.035 vs. group 3, p=0.006 vs. group 4). the results are shown in table 1 . conclusions: carrying out guideline-compliant cc [1] during iht is feasible with multiple provider positions. based on the present results, kneeling or squatting position next to the patient ( figure 1 and 2) is recommended, whereas "walking next to the bed" while performing cc should be avoided. methods: a retrospective review of clinical notes was undertaken for patients admitted to icu following return of spontaneous circulation but whom remained comatose. this audit encompassed three-month periods before and after introduction of the care bundle in october 2017. audit standards were assigned from target parameters documented in the bundle and reflected guidance from the cheshire and merseyside critical care network. results: 39 patients were included in our audit; 15 admitted prior to and 24 admitted following implementation of the care bundle. in patients whom targeted temperature management was indicated, improved adherence to thermoregulation between 34-36°c was observed (50 vs 71%). significant improvements were since in the observance to target values for oxygen saturation (0 vs 70.8%, p=0.0023) and mean arterial pressure (20 vs 95.8%, p<0.0001) following the introduction of the care bundle. improved observance of ventilation targets was also seen; maintenance of p a co 2 >4.5 kpa (40 vs 75%, p=0.0441) and tidal volumes <8 ml/kg ideal body weight (0 to 37.5%, p=0.0069). conclusions: the introduction of a post-cardiac arrest care bundle in our icu has improved care by providing discrete physiological targets to guide nursing staff and standardising management between clinicians. variations in care are associated with poorer patient outcomes [2] and introduction of this bundle has reduced disparities in practice. array of cardiac diseases and reported survival rate is low in spite of advances in resuscitation and ems services. methods: single-centre retrospective study analyzed outcomes of 42 ohca patients admitted to cardiac icu between 2010.-2015. we studied demographic data, initial rhythm, type of cpr, comorbidities and various post admission diagnostic findings in order to identify their impact on survival. results: ohca comprised 0,5% of all admissions. mean los was 8.24 days (0-64). mean age was 65,4y (29-90), m: f ratio 29:13 and bystander cpr was performed in only 19% ohca patients. the most common initial rhythm was vf (45.2%), followed by vt (16.6%), pea was found in 2,9% and asystole in 1.9% of pt more than half of pt received adrenalin (55%) and defibrillation (57%) and only 17% required a temporary pacemaker. 38% of pt had an ecg consistent with mi after rosc, 19% underwent coronary angiography resulting in pci in 75% of cases. in 5 pt (12%) therapeutic hypothermia protocol was performed. most ohca pt had hypertension (60%) and hyperlipidaemia (69%) as the most common risk factors followed by cardiomyopathy (33%), diabetes (29%) and cad (21%). only 9% had a preexisting significant valvular disease and the rest were extracardial comorbidities: chronic renal disease (17%), copd (9%) and cerebrovascular disease (9%). 14 patients survived (33%) and gcs on admission was the only significant impact factor on survival along with comorbidities (mean gsc was 6 in survivors vs. 3 in deceased). interestingly, age, initial rhythm, troponin i level, ph and therapeutic hypothermia had no impact on survival. conclusions: our data demonstrate the importance of early onsite resuscitation as the most important factor of neuroprotection and outcome and puts an emphasis on the importance of cpr education for layman population. prediction of acute coronary ischaemia and angiographic findings in patients with out-of-hospital cardiac arrest j higny 1 , a guédès 2 , c hanet 2 , v dangoisse 2 , l gabriel 2 , j jamart 3 introduction: coronary artery disease (cad) is the leading cause of out-of-hospital cardiac arrest (ohca). however, diagnosis of acute coronary ischaemia (aci) remains challenging, particularly in patients without st-segment elevation on the post-resuscitation ecg. in this regard, a consensus statement recommends the implementation of a work-up strategy in the emergency room (er) to exclude noncoronary causes of collapse within 2 hours. methods: retrospective single-centre study performed on 64 consecutive patients with resuscitated ohca who underwent a diagnostic coronary angiography (ca). we present data on coronary angiograms for patients who underwent cardiac catheterization after resuscitation. afterwards, we sought to identify parameters associated with aci. results: st-segment elevation was noted in 29 patients (45%). stsegment depression or t-wave abnormalities were noted in 35 patients (55%). invasive coronary strategy allowed to identify an acute culprit lesion in 46 cases (72%). 29 patients with st-segment elevation underwent an immediate angioplasty for an acute coronary occlusion. 17 patients without st-segment elevation underwent an ad hoc percutaneous coronary intervention for a critical lesion. stable cad was found in 9 cases (14%) and a normal angiogram was found in only 9 cases (14%) (figure 1 ). conclusions: aci was the leading precipitant of collapse. stsegment elevation was highly predictive of coronary occlusion. in addition, a culprit coronary lesion was identified in nearly 50% of patients undergoing ca despite the lack of stsegment elevation. finally, our findings suggest that the identification of risk criteria may help to improve the recognition of aci after ohca. the prediction of outcome for in-hospital cardiac arrest (pihca) score e piscator 1 , k göransson 1 , s forsberg 1 , m bottai 2 , m ebell 3 , j herlitz 4 , t djärv 1 figure. predictive value for classification into <3% likelihood of favorable neurologic survival was 97.4%. false classification into < 3% likelihood of favorable neurologic survival was 0.57%. the phica score has potential to be used as an aid for objective prearrest assessment of the chance of favorable neurologic survival after ihca, as part of decision making for a dnar order. introduction: prognosis of survival in patients with cardiac arrest remains poor. during and after cardiopulmonary resuscitation, pathophysiological disturbances in relation with a cytokine storm, are described as "post-resuscitation" disease like a combination of cardiogenic and vasodilatory shocks. veno-arterial extracorporeal membrane oxygenation (va ecmo) allows to restore adequate perfusion but little is known about its effect on left ventricular (lv) function and about the role of cytokines. methods: this study was performed in an experimental model of cardiac arrest performed in 3 groups of 3 anesthetized and mechanically ventilated pigs. cardiac arrest was obtained by application of electrical current to epicardium inducing ventricular fibrillation. after a no-flow period of 5 minutes, medical resuscitation with catecholamines and vasopressors was performed in "control" group while va ecmo was started in "ecmo" group and va ecmo in combination with cytosorb (extracorporeal blood purification therapy designed to reduce excessive levels of inflammatory mediators such as cytokines) was started in "ecmo-cyto" group. lv function was assessed with transthoracic echocardiography and arterial pressure with aortic pressure catheter. results: hemodynamic stability was obtained after 22 ± 6 and 24 ± 7 minutes in ecmo and ecmo-cyto groups, respectively. no return of spontaneous circulation was observed in control group. at 15 minutes following cardiac arrest, lv area fractional change on short axis was normalized in ecmo and ecmo-cyto groups (31± 3 and 34 ± 4 %, respectively). vasopressor requirements were significantly lower in ecmo-cyto group than in ecmo group. conclusions: after cardiac arrest (no-flow) of 5 minutes duration, va ecmo allowed complete lv recovery and hemodynamic stability within 30 minutes of "post-resuscitation" disease. cytosorb added to va ecmo could contribute to reduce post-resuscitation vasodilatation. impact of rapid response car system on ecmo in out-of-hospital cardiac arrest: a retrospective cohort study m nasu 1 , r sato 2 , k takahashi introduction: extracorporeal life support (ecls) has been reported to be more effective than conventional cardio-pulmonary resuscitation (cpr). in ecls, a shorter time from arrival to implantation of extracorporeal membrane oxygenation (ecmo; door-to-ecmo) time has been reported to be associated with better survival rates. this study aimed to examine the impact of the physician-based emergency medical services (p-ems) using a rapid response car (rrc) on door-to-ecmo time in patients with out-of-hospital cardiac arrest (ohca to study the interest and the educational contribution in the short and medium term of medical simulation compared to a classical training. methods: cohort, prospective, observational, single-center, randomized study with control group including 30 residents (20 in anesthesia resuscitation and 10 in emergency medicine). all benefited from a theoretical training with a reminder of the latest recommendations on the management of cardiac arrest and anaphylactic shock. they were randomized into 2 groups and received practical training on a high-fidelity simulator for the management of either cardiac arrest (acc group) or anaphylactic shock (ca group). each group was evaluated at 6 weeks (t0) and at 6 months on two scenarios: refractory ventricular fibrillation (fv) scored on 20 points and grade 3 anaphylactic reaction (ra3) scored on 30 points. each group served as the control group for the pathology in which they did not receive specific simulator training. the results are expressed on average with their standard deviations with "p" <0.05. introduction: simulation is a tool for improving the quality and safety of care, and its recognized as an essential method of evidence-based education. emergency medicine is a discipline in which there is a constant concern for the safety of patients. the emergency physician is often called upon to take charge of critical situations that use knowledge, know-how and knowledge as skills that must be mastered and whose theoretical learning alone is insufficient. methods: it´s a prospective study including residents in emergency medicine performing their specialty courses in emergency services and emergency medical assistance in the region of sousse from january to june 2018. they were randomized into two groups: the one benefiting from a traditional education and the other from an education based on simulation sessions. the chosen scenario was the management of a cardiac arrest. a pre-test and a post-test were performed in both groups. results: we included 30 emergency residents who did not receive specialized training in the management of cardiac arrest, there was a female predominance with an average age of 27, there was no significant difference regarding the pretest between the two groups with 10.08 there was no significant difference with respect to the pre-test score between the two groups 10.08 ± 2.7 / 20 for the control group versus 10.34 ± 3.3 / 20 for the simulation group. there was a significant progression after the course with an average posttest score of 13.87 ± 1.8 in the simulation group while this score was 11.94 ± 2.3 in the control group with a statistically significant difference (p <0.001). conclusions: simulation learning has led to a better acquisition of cognitive knowledge by learners. the simulation is not intended to replace bed-based teaching, nor theoretical or faculty teaching, but it is an essential complement . in tunisia, the simulation must continue its current integration in the initial and continuous training of doctors. introduction: recent studies have shown that obesity and its related metabolic dysfunction exacerbates outcomes of ischemic brain injuries in some brain areas, such as the hippocampus and cerebral cortex when subjected to transient global cerebral ischemia (tgci). however, the impact of obesity in the striatum after tgci has not yet been addressed. the objective of this study was to investigate the effects of obesity on tgci-induced neuronal damage and inflammation in the striatum and to examine the role of mtor which is involved in the pathogenesis of metabolic and neurological diseases. methods: gerbils were fed with a normal diet (nd) or high-fat diet (hfd) for 12 weeks and then subjected to 5 min of tgci. hfd-fed gerbils showed the significant increase in body weight, blood glucose level, serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol without affecting food intake. results: in hfd-fed gerbils, neuronal loss occurred in the dorsolateral striatum 2 days after tgci and increased neuronal loss were observed cholesterol days after tgci; however, no neuronal loss was the in ndfed gerbils after tgci, as assessed by neuronal nuclear antigen immunohistochemistry and fluoro-jade b histofluorescence staining. the hfd-fed gerbils also showed severe activated microglia and further increased immunoreactivities and protein levels of tumor necrosis factor-alpha, interukin-1beta, mammalian target of rapamycin (mtor) and phosphorylated-mtor in the striatum during pre-and postischemic conditions compared with the nd-fed gerbils. in addition, we found that treatment with rapamycin, a mtor inhibitor, in the hfd-fed gerbils significantly attenuated hfd-induced striatal neuronal death without changing physiological parameters. conclusions: these findings reveal that chronic hfd-induced obesity results in severe neuroinflammation and significant increase of mtor activation, which could contribute to neuronal death in the stratum following tgci. abnormal mtor activation might play a key role. associations between partial pressure of oxygen and neurological outcome in out-of-hospital cardiac arrest patients introduction: exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (ohca) patients following return of spontaneous circulation (rosc) but its effects on neurological outcome are uncertain and study results are inconsistent. methods: exploratory post-hoc substudy of the target temperature management (ttm) trial [1] , including 939 patients after ohca with rosc. the association between serial arterial partial pressures of oxygen (pao 2 ) during 37 hours following rosc and neurological outcome at 6 months, evaluated by cerebral performance category (cpc), dichotomized to good (cpc 1-2) and poor (cpc 3-5), was investigated. in our analyses, we tested the association of hyperoxemia pao 2 > 40 kpa and hypoxemia pao 2 < 8 kpa, time weighted mean pao 2 , (twm-pao 2 ) (fig 1) , maximum pao 2 difference (δ pao 2 ) and gradually increasing pao 2 levels (13.3 -53.3 kpa) with poor neurological outcome. a subsequent analysis investigated the association between pao 2 and a biomarker of brain injury, peak serum tau levels. results: 869 patients were eligible for analysis. 300 patients (35%) were exposed to hyperoxemia or hypoxemia after rosc (table 1) . our analyses did not reveal a significant association between hyperoxemia, hypoxemia, twm-pao 2 exposure or δ pao 2 and poor neurological outcome at 6-month follow-up after correction for co-variates (all analyses p= 0.146 -0.847) (fig 2) . we were not able to define a pao 2 level associated with the onset of poor neurological outcome. peak serum tau levels at either 48 or 72 hours after rosc were not associated with pao 2 . conclusions: hyperoxemia or hypoxemia exposure occurred in one third of the patients during the first 37 hours of hospitalization and was not significantly associated with poor neurological outcome after 6 months or with the peak s-tau levels at either 48 or 72 hours after rosc. introduction: cerebral hypoperfusion may aggravate the developing neurological damage after cardiac arrest. near-infrared spectroscopy (nirs) provides information on cerebral oxygenation but its clinical relevance during post-resuscitation care is undefined. we wanted to assess the possible association between cerebral oxygenation and clinical outcome after out-of-hospital cardiac arrest (ohca). methods: we performed a post hoc analysis of a randomised clinical trial (comacare) where both moderate hyperoxia and high-normal arterial carbon dioxide tension (paco 2 ) increased regional cerebral oxygen saturation (rso 2 ) as compared with normoxia and low-normal paco 2 , respectively. rso 2 was measured from 118 ohca patients with nirs during the first 36 h of intensive care and neurological outcome was assessed using the cerebral performance category (cpc) scale at 6 months after cardiac arrest. we calculated the median rso 2 for patients with good (cpc 1-2) and poor (cpc 3-5) outcome and compared the results using the mann-whitney u test. we compared the rso 2 over time with outcome using a generalised mixed model. finally, we added median rso 2 to a binary logistic regression model to control for the effects of possible confounding factors. results: the median (interquartile range [iqr]) rso 2 during the first 36 h of intensive care was 70.0% (63.5-77.0%) in patients with good outcome compared to 71.8% (63.3-74.0%) in patients with poor outcome, p = 0.943. we did not find significant association between rso 2 over time and neurological outcome ( figure 1 ). in the binary logistic regression model rso 2 was not a statistically significant predictor of good outcome (or 0.99, 95% ci 0.94-1.04, p = 0.635). conclusions: we did not find any association between cerebral oxygenation during the first 36 h of post-resuscitation intensive care and neurological outcome at 6 months after cardiac arrest. fig. 2 introduction: near-infrared spectroscopy (nirs) provides a noninvasive means to assess cerebral oxygenation during postresuscitation care but its clinical value is unclear. we determined the possible association between cerebral oxygenation and the magnitude of brain injury assessed with neuron-specific enolase (nse) serum concentration at 48 h after out-of-hospital cardiac arrest (ohca). methods: we performed a post hoc analysis of a randomised clinical trial (comacare) comparing two different levels of carbon dioxide, oxygen and arterial pressure after ohca and successful resuscitation. we measured rso 2 continuously with nirs from 118 patients during the first 36 h of intensive care. we determined the nse concentrations at 48 h after cardiac arrest from serum samples using an electrochemiluminescent immunoassay kit. the samples were tested for haemolysis and all samples with a haemolysis index > 500 mg of free haemoglobin per litre (n = 2) were excluded from the analyses. we calculated the median rso 2 for all patients and used a scatterplot and spearman's rank-order correlation to assess the possible relationship between median rso 2 and nse at 48 h. in addition, we compared the nse concentrations at 48 h after cardiac arrest in patients with good (cerebral performance category scale [cpc] 1-2) and poor (cpc 3-5) neurological outcome at 6 months using the mann-whitney u test. results: we did not find significant correlation between median rso 2 and serum nse concentration at 48 h after cardiac arrest, rs = -0.08, p = 0.392 (figure 1 ). the median (iqr) nse concentration at 48 h was 17.5 (13.4-25.0) μg/l and 35.2 (22.6-95.8) μg/l in patients with good and poor outcome, respectively, p < 0.001. conclusions: we did not find any association between cerebral oxygenation during the first 36 h of post-resuscitation intensive care and nse serum concentrations at 48 h after cardiac arrest. the association between lactate, cerebral oxygenation and brain damage in post-cardiac arrest patients introduction: patients admitted to the intensive care unit (icu) after being successfully resuscitated from a cardiac arrest (ca) have a large cerebral penumbra at risk for secondary ischemic damage in case of suboptimal brain oxygenation. therefore, resuscitation during icu stay should be guided by parameters that adequately predict cerebral hypoxia. the value of lactate as resuscitation parameter may be questioned in post-ca patients since the brain critically depends on aerobic metabolism. we aimed to investigate the relationship between arterial lactate, cerebral cortex tissue oxygenation (scto2) by near infrared spectroscopy (foresight) and unfavorable neurological outcome at 180days (cpc score 3-5) methods: subanalysis from the neuroprotect post-ca trial. lactate values and scto2 were recorded hourly in 102 post-ca patients during 24hours ttm33 and subsequent rewarming. results: in total 3290 paired lactate/ scto2 measurements were analysed. we found no correlation between paired lactate and scto² (fig.1) . moreover, temporary trends in lactate did not correlate with corresponding trends in scto2 during the same one-hour time interval (r²=0.003) (fig 2) . if lactate values above 2.0 mmol/l are considered to be abnormal, lactate could not adequately detect clinical important brain ischemia (scto2 < 60%): sensitivity 62% and specificity 53% (table 1 , 2). nevertheless, time weighted lactate at 6h (or 1.38; p 0.01), 12h (or 1.38, p 0.01), 24h (or 1.53; p 0.003) and 36h (or 1.60; p 0.005) were inversely correlated with unfavorable neurological outcome at 180days (fig 1, 2) . conclusions: although lactate was a marker of prognosis in post-ca patients, it should not be used to guide resuscitation since lactate values were not correlated with scto2 and changes in lactate do not correspond with changes in scto2 during the same time interval. simplified introduction: the aim of the study was to investigate whether simplified continuous eeg monitoring (ceeg) [1] post-cardiac arrest can be reliably interpreted by icu physicians after a short structured training, and whether acceptable interrater agreement compared to an eeg-expert can be achieved. methods: five icu physicians received training in interpretation of simplified ceeg (fig 1) consisting of lectures, hands-on ceeginterpretation, and a video tutorial -total training duration 1 day. the icu physicians then interpreted 71 simplified ceeg recordings. basic eeg background patterns and presence of epileptiform discharges or seizure activity were assessed on 5-grade rank-ordered scales based on a standardized eeg terminology [2] . an experienced eeg-expert was used as reference. results: there was substantial agreement (κ 0.69) for eeg background patterns and moderate agreement (κ 0.43) for epileptiform discharges between icu physicians and the eeg-expert. sensitivity for detecting seizure activity by the icu physicians was limited (50%), but with high specificity (87%). among icu physicians interrater agreement was substantial (κ 0.63) for eeg background pattern and moderate (κ 0.54) for epileptiform discharges. conclusions: after a one-day educational effort clinically relevant agreement was achieved for basic eeg background patterns after cardiac arrest. assessment of epileptiform patterns was less reliable, but bedside screening by the icu physician may still be clinically useful for early detection of seizures. interpretation of simplified ceeg requires awareness of its limitations and support from an eeg-expert when clinically indicated. introduction: hypoxic-ischemic injury on head computed tomography (ct), which manifests with varying degrees of cerebral edema and loss of gray-white matter differentiation, is a poor prognostic sign after resuscitated out-of-hospital cardiac arrest that may influence early clinical decision-making. agreement among physicians on the presence of hypoxic-ischemic injury on early head ct is unknown. methods: we recruited 10 faculty physician participants (2 emergency medicine, 3 critical care, 3 neurocritical care, and 2 general radiology; average 8.2 years of practice) across 3 academic medical centers each with >100 admissions for resuscitated out-of-hospital cardiac arrest each year. participants, blinded to clinical context, reviewed 20 unique head cts obtained within 2 hours of cardiac arrest that were randomly selected from a local registry. a blinded neuroradiologist also reviewed all scans (gold standard). participants determined if hypoxic-ischemic injury was present on each ct, and agreement was determined using multi-and dual-rater kappa statistics with 95% confidence intervals. results: overall agreement among physicians regarding the presence of hypoxic-ischemic injury on head ct was fair (kappa 0.34; 95% ci, 0.19-0.49) with agreement consistent across most specialties (table 1) . when compared to the neuroradiologist, individual physician agreement ranged widely, from poor (kappa 0.12) to substantial (kappa 0.68), with 6 of 10 physicians having fair or worse agreement compared to the gold standard interpretation. conclusions: the finding of hypoxic-ischemic injury on early head ct after cardiac arrest had high interobserver variability as interpreted by acute care physicians and general radiologists. pending the development of objective diagnostic criteria, clinicians should bear in mind the subjectivity and subtlety of cerebral edema or loss of graywhite matter differentiation soon after return of spontaneous circulation in these patients. figure 1 ). baseline characteristics and differences between the wlst and no-wlst groups are shown in table 1 . utilization of neuro-prognostication tests is shown in table 2 . while ct and eeg were commonly employed, ssep and mri were used less frequently. basic multimodal neuroprognostication (arbitrarily defined as at least one ct or mri, plus eeg, plus ssep) was performed only in 34.1% of all patients undergoing wlst but the rate increased significantly over six years (p<0.001) and was higher in the time period after 2015, compared to the one prior to 2015 ( figure 2 ). this association remained significant after adjustment for confounders such as age, arrest rhythm, downtime, targeted temperature management, apache ii score and organ failure in a logistic regression model (p=0.004). in an institution with access to a wide range of imaging and neurophysiology tests, mri and ssep remained underutilized but the rate of basic multimodal neuro-prognostication increased significantly over the study period, especially in the period after 2015. introduction: although multiple reports using animal models have confirmed that melatonin appears to promote neuroprotective effects following ischemia/reperfusion-induced brain injury, the relationship between its protective effects and the activation of autophagy in cerebellar purkinje cells following the asphyxial cardiac arrest and cardiopulmonary resuscitation (ca/cpr) remains unclear. methods: rats used in this study were randomly assigned to 6 groups as follows; vehicle-treated sham-operated group, vehicletreated asphyxial ca/cpr-operated group, melatonin-treated shamoperated group, melatonin-treated asphyxial ca/cpr-operated group, melatonin plus (+) 4p-pdot (the mt2 melatonin receptor antagonist)-treated sham-operated group and melatonin+4p-pdot-treated asphyxial ca/cpr-operated group. results: our results demonstrate that melatonin (20 mg/kg, ip, 1 time before ca and 4 times after ca) significantly improved the survival rates and neurological deficits compared with the vehicle-treated asphyxial ca/cpr rats (survival rates ≥ 40% vs 10%). we also demonstrate that melatonin exhibited the protective effect against asphyxial ca/cpr-induced purkinje cell death. the protective effect of melatonin in the purkinje cell death following asphyxial ca/cpr paralleled a dramatic reduction in superoxide anion radical (o2·-), intense enhancements of cuzn superoxide dismutase (sod1) and mnsod (sod2) expressions, as well as a remarkable attenuation of autophagic activation (lc3 and beclin-1), which is mt2 melatonin receptor-associated. furthermore, the protective effect of melatonin was notably reversed by treatment with 4p-pdot. conclusions: this study shows that melatonin conferred neuroprotection against asphyxial ca/cpr-induced cerebellar purkinje cell death by inhibiting autophagic activation by reducing expressions of ros, while increasing of antioxidative enzymes, and suggests that mt2 is involved in the neuroprotective effect of melatonin in cerebellar purkinje cell death induced by asphyxial ca/cpr. introduction: fucoidan is a sulfated polysaccharide derived from brown algae and possesses various beneficial activities, such as antiinflammatory and antioxidant properties. previous studies have shown that fucoidan displays protective effect against ischemiareperfusion injury in some organs. however, few studies have been reported regarding the protective effect of fucoidan against cerebral ischemic injury and its related mechanisms. methods: therefore, in this study, we examined the neuroprotective effect of fucoidan against cerebral ischemic injury, as well as underlying mechanisms using a gerbil model of transient global cerebral ischemia (tgci) which shows loss of pyramidal neurons in the hippocampal cornu ammonis 1 (ca1) area. fucoidan (25 and 50 mg/kg) was intraperitoneally administered once daily for 3 days before tgci. results: pretreatment with 50 mg/kg of fucoidan, not 25 mg/kg fucoidan, attenuated tgci-induced hyperactivity and protected ca1 pyramidal neurons from ischemic injury following tgci. in addition, pretreatment with 50 mg/kg of fucoidan inhibited activations of resident astrocytes and microglia in the ischemic ca1 area. furthermore, pretreatment with 50 mg/kg of fucoidan significantly reduced the increased 4-hydroxy-2-noneal and superoxide anion radical production in the ischemic ca1 area after tgci and significantly increased expressions of superoxide dismutase 1 (sod1) and sod2 in the ca1 pyramidal neurons compared with the vehicle-treated-group. we found that treatment with diethyldithiocarbamate (an inhibitor of sods) to the fucoidan-treated-group notably abolished the fucoidanmediated neuroprotection in the ischemic ca1 area following tgci. conclusions: these results indicate that fucoidan can effectively protect neurons from tgci-induced ischemic injury through attenuation of activated resident glial cells and reduction of oxidative stress following increasing sods. thus, we strongly suggest that fucoidan can be used as a useful preventive agent in cerebral ischemia. the effects of cold fluids for induction of therapeutic hypothermia on reaching target temperature and complications-a sub-study of the tth48 study a holm 1 , m skrifvars 2 , fs taccone ). there was no difference in early bleeding incidences (fig 1) . during late observation, ttm patients had fewer minor bleeding (55.2% vs. 100%) and more intracranial bleeding (23.1% vs. 0%; fig 2) . adjusted calculated risk ratio for major bleeding (including intracranial) for ttm was 0.24 (95%ci 0.10-0.54) at baseline and 1.45 (95%ci 1.18-1.77) over time. conclusions: bleeding complications were common. although the risk ratio for major bleeding increased over time in ttm patients, residual and unmeasured confounding in addition to selection and detection bias may limit the clinical relevance of this finding. methods: patients with neurological deficit > 10 by nhiss were included. the t°of the brain was recorded non-invasively using radiothermometer rtm-01-res (russia). we measured t°in 18 symmetric regions of left & right hemispheres, calculated the average t°of brain, fig. 1 (abstract p213) . temperature of patients given and not given pre-icu fluids (table 1) . conclusions: observed moderate brain t°heterogenecity in hp, marked increase brain t°heterogenecity in is & sharp decline of t°h eterogenecity in cci. supposedly, correcting the impairment of cerebral tb (increase or decrease t°) through physical (selective cerebral hypothermia, magnetic stimulation etc.) or pharmacological (sedation) can contribute to positive therapeutic results in is & cci. nonivasive radiothermometry of the brain can be an objective method of patients' condition evaluation & their rehabilitation potential. introduction: basilar artery stroke has a multitude of different presentations and may not be captured on plain computed tomography (ct). it can progress to severe disability, locked in syndrome and death [1] . with the advent of thrombolytic and endovascular therapies, prompt diagnosis can change the outcome. we present a case of basilar artery stroke, which was heralded by tongue spasticity and dysarthria, indicative of pseudobulbar palsy. methods: case reviewed with consent. a literature search was conducted using pubmed and medline. results: a 53-year-old presented with pulmonary oedema and hypertension. he was transferred to our intensive care unit for treatment of a suspected anaphylaxis. his marked lingual swelling was associated with dysarthria. glyceryl-trinitrate and labetalol infusions were started for hypertension. he developed left sided weakness and deteriorated over several days to the point that he could only move his right foot (table 1) . magnetic resonance imaging (mri) showed midbrain ischaemia and angiogram showed no flow in the basilar artery (fig 1,2) . conclusions: common presenting features of basilar artery occlusion include dysarthria, vertigo, vomiting, headache and motor defects; these may evolve gradually or be intermittent [1, 2] . presentation with pseudobulbar palsy is described in early literature [2] . delayed recognition of the stroke led to aggressive treatment of hypertension, potentially compromising perfusion to the penumbral area [2, 3] . this case highlights the need for a wide index of suspicion with posterior strokes. consent: informed consent to publish has been obtained from the patient prognosis is related to gcs < or = 8 on admission (p = 0.003) and to malignant cerebral edema (p = 0.004). conclusions: our study has shown some predictive factors closely related to mortality and morbidity in patients with acute ischemic stroke. gcs at admittance < or = 8 and onset of malignant cerebral edema lead to a worst prognosis at discharge from nicu. coherence analysis of cerebral oxygenation using multichannel functional near-infrared spectroscopy evaluates cerebral perfusion in hemodynamic stroke tj kim 1 table 1 ). in addition, severe stroke patients were more likely to have higher phase coherence in interval iii (p =0.078). conclusions: our results demonstrated that the higher phase coherence of oxyhb in myogenic signal, which was originated locally from smooth muscle cells in brain was related to impaired cerebral perfusion. this suggests that monitoring cerebral oxygenation using fnirs could be a useful noninvasive measuring tool for evaluating impaired cerebral autoregulation in stroke patients. is esmolol associated with worse outcome at the acute phase of ischemic stroke that receives thrombolysis? introduction: ischemic stroke patients experienced frequent early neurological deterioration (end) events. since ischemic stroke has also been shown as inflammatory disease, the neutrophil-tolymphocyte ratio (nlr) may associated with end events. however, the direct study regarding this association has not been addressed. poor grade sah, use of vasopressors, mechanical ventilation, intracranial pressure monitoring, external ventricular drainage, blood transfusions and renal replacement therapy were all more frequent among nonsurvivors (all p<0.001). mortality was also higher with initial lactate above 2 mmol/l, in those admitted to public hospitals and when admission to icu was delayed more than 24 hours after ictus. after adjusting for common predictors (age, gender and wfns) saps 3 non-neuro, sofa non-neuro, early vasopressor use and admission to a public hospital were independently associated with hospital mortality. moreover, the area under the curve for prediction of mortality with saps3, sofa and wfns was 0.86 ( figure 1 ). hospital, austria. the association of intensity and duration of intracranial hypertension episodes with 12-month glasgow outcome score (gos) was visualized using the methodology introduced by güiza et al. [1] . results: in both cohorts, it could be demonstrated that the combination of duration and intensity defined the tolerance to intracranial hypertension, and that a semi-exponential curve separated episodes associated with better outcomes from those associated with worse outcomes. the association with worse outcomes occurred at a lower pressure-time burden than what has been previously observed in patients with tbi. nevertheless, the percentage of monitoring time spent by every patient in the zone associated with poor gos was independently associated with worse 12-month neurological outcome, even after correcting for age and fisher score ( introduction: apnea test is an essential component in the clinical determination of brain death, but it may incur a significant risk of complications such as hypotension, hypoxia and even cardiac arrest [1] . we analyzed the risk factors associated with failed apnea test during brain death assessment in order to predict and avoid these adverse events. methods: medical records of apnea tests performed for brain-dead donor between january 2009 and january 2016 in our institution, were reviewed retrospectively. age, gender, etiology of brain death, use of catecholamine and results of arterial bleed gas analysis (abga), systolic/diastolic blood pressure (sbp/dbp), mean arterial pressure (map) and central venous pressure (cvp) prior to apnea test initiation were collected as variables. a-a gradient and pao2/fio2 were calculated for more precise assessment of the respiratory system. in total, 267 cases were divided into a group which was completed apnea test and the other which was failed the test. introduction: tunisia has already suffered recurrent outbreaks since 1997. 2018 outbreak started relatively earlier this year. we were interpellated by the frequency of neuroinvasive presentation of the disease. methods: we report a case series of 11 patients presented to icu with niwnd. results: we report 11 cases of niwnd with different severe presentations overlapping neurological manifestation including encephalitis (n=8/11), meningitis (n=10/11) and flaccid paralysis (n=8/11). almost all patients live in the locality of sousse. six patients presented a long course of isolated fever before developing neurological signs. cerebrospinal fluid was consistent with encephalitis within the 11 patients. cerebromedullar mri identified brain lesions (n=8/10), myelitis (n=1/10) and polyradiculoneuritis (n=1/10).three patients had electromyography for flaccid paralysis showed diffuse axonal polyneuropathy with motoneuron involvement. ten cases had a positive wnv igm antibody and nine had a positive wnv igg antibody in serum. urine polymerase chain reaction was positive for wnv in 8/10 patients. ten patients were mechanically ventilated. all patients were managed symptomatically. two received high doses of methylprednisolone for 3 days, one patient received polyclonal immunoglobulin intravenous and one patient had plasmapheresis. two patients died consecutive to brainstem lesions. two patients recovered significantly and discharged with no complications. five other patients evolved to persistent flaccid paralysis with a minimal consciousness state and weaning difficulties requiring tracheostomy. the last remaining patient is still evolving. conclusions: modification of the regional climatic conditions accounted probably for the early 2018 outbreak of niwnd. this initial case series displays the severity and the poor outcomes of niwnd with higher incidence compared to past epidemics. noninvasive estimation of intracranial pressure with transcranial doppler: a prospective multicenter validation study c robba 1 , c fig. 1 ], mean bias was -3.24 mmhg (limits of agreement are ± 2 sd 24.6 mmhg). 7.5% measures were outside the limit of agreement in the overall population. however, when icp was high, 43% of measures were out of the limit of agreement. the auc [ fig. 2 introduction: surgical treatment of aortic aneurysm needs extracorporeal circulation (ecc), aorta clamp and hypothermia, and it is often related to poor systemic perfusion and blood flow velocity. one of the main concerns of intensive care team is to prevent secondary neurological injury after long time without blood flow pulsatility, such as brain edema and seizure. the most common parameters for neuromonitoring would be intracranial pressure and eeg, however, for non-neurological patients this information is unusual and prevents optimal management. methods: we aimed to assess brain compliance and neurological condition of icu patients on immediate post-operative recovery of bentall-de bono procedure and/or other aortic aneurysm surgical treatment using a novel non-invasive intracranial pressure (icp) device. this device uses mechanical displacement sensor capturing extracranial continuous volumetric variation of the skull and this information proportionally reflects intracranial dynamic [1] . results: twenty patients were included in this study. ecc mean time was 111 minutes for 19 patients and only one did not need it. eleven presented altered icp curves with poor brain compliance (p2/p1 ratio > 1.0) assessed by icp curve morphology analysis. volemic optimization and neuroprotective measures were taken based on this icp information for acute case management. among these patients with altered icp curves, eight were discharged from icu with good clinical condition and glasgow coma scale of 15. overall mortality rate was six out of twenty (30%) and three of these had altered icp curves. conclusions: brain monitoring of cardiovascular post-operative patients is important to prevent secondary neurological complications and can be a helpful tool for neuroprotective acute management on icu. the technique supplies electrical current to muscle, combined with passive cycling. prior to a clinical trial, we first investigated the effects of one session of fes in healthy volunteers. methods: healthy male volunteers (n=15) were recruited. the participants had their postural sway assessed on a pressure sensitive board, and measurement of maximal inspiratory pressure (mip). ultrasounds were taken assessing thickness of the quadriceps and rectus abdominis. they performed 20 minutes of supine passive cycling, with fes supplying the lower limbs and abdomen. after a 1 minute rest, the tests were repeated. a further 14 participants performed just the initial baseline tests, to help assess muscular factors affecting balance and sway. results: the current needed for palpable contraction was significantly correlated to weight in the abdomen (r=0.79, p<0.001) and quadriceps (r=0.82, p<0.001). current required to stimulate the abdominal muscles was also correlated to depth of the subcutaneous fat layer (r=0.85, p<0.001) and echogenicity of the muscle (r=0.65, p=0.012). pre-cycling, left and right vastus lateralis thickness inversely correlated to postural sway in the antero-posterior (r=-0.638, p<0.001) plane. compared to pre-cycling, postural sway in the antero-posterior and lateral planes increased significantly after cycling. there was a significant decrease in mip after cycling and greater reductions in mip were found in participants who had thinner rectus abdomni. conclusions: sway at baseline is related to quadriceps thickness, which atrophies during critical illness, and could worsen balance. mip is reduced during fes and the severity of reduction is related to the thickness of the abdominal wall muscles at baseline, suggesting that fes can fatigue the diaphragm and abdominal muscles. in awake healthy volunteers, fes is a safe, comfortable technique. introduction: in most cases postoperative cognitive dysfunction (pocd) is transient, but still some patients suffer from persistent cognitive impairment which is associated with increased length of hospital stay, early withdrawal from labor market and higher mortality. available data on the prevalence of pocd after cardiac surgery is very diverse from 20% to 90% upon discharge and up 20% 3 months after surgery. we aimed to investigate the prevalence of short-term and long-term pocd after off-pump coronary artery bypass grafting (cabg) surgery. methods: psychometric testing was performed in 230 (mean age 63.5±8.2) patients before, 10 days and 6 months after the surgery. we used following tests to assess cognitive capacity: auditory verbal learning test (avlt), digit span test (dst), digit-letter substitution test (dlst), stroop's test and trail making test (tmt). a decline in comparison to preoperative test results for 20% or more in two or more tests was declared as pocd. results: the prevalence of pocd after 10 days was 31.7% (73 patients) and 9.1% (21 patients) after 6 months. when comparing patients who developed pocd with those who did not we found the former were older (69.2±8.7 vs 61.1±10.3 years; p<0.001), had lower education level (13.7±2.1 vs 10.6± 2.4 years; p<0.05) and had longer surgery duration (250.4±12.2 vs 232.1±15.9 minutes; p<0.05). the most affected cognitive domains were long term memory (avlt) and executive function (tmt) and least affectedworking memory (dst) and selective attention (stroop's test). conclusions: in our prospective study the prevalence of long-term pocd after cardiac surgery was slightly less (9.1%) in comparison to available data (from 9% to 20%). it might be due differences in psychometric testing and interpretation of its results among authors. advanced age, low cognitive reserve and long duration surgeries are linked with higher incidences of pocd. introduction: postoperative cognitive dysfunction (pocd) is a common and widely described phenomenon in surgical patients. advanced age, major surgery, certain general anesthetics, genetic factors, sleep deprivation and other factors were described as contributing factors to pocd. the hospital stay itself is a major 'social' trauma for patients; social isolation, sleep deprivation and changes in daily regimen may effect neurocognitive behavior of patients. in this trial we tried to assess the link between pocd and the length of hospital stay in cardiac surgery patients. methods: 94 patients who underwent 'off-pump' coronary artery bypass grafting (cabg) surgery selected for this trial. neuropsychological testing was performed prior to the operation and upon discharge. we used auditory verbal learning test (avlt), digit span test (dst), digit-letter substitution test (dlst), stroop test and trail making test (tmt). a 20% or more decline in two or more tests in comparison to preoperative test results was declared as pocd. patients were allocated into two groups according to the length of hospital stay: the short-stay group (group 1) included patients (n=36) who were discharged on the 8th day after surgery or earlier and the long-stay (group 2) group consisted of patients (n=58) who were discharged on the 9th day after surgery or later. patients received similar anesthesia, postoperative care and were operated by the same surgical team. reasons for prolonged duration of hospital stay were mainly surgical. results: 11 patients (30.6%) in group 1 and 21 patients (36.2%) in group 2 had pocd upon discharge (p<0.05). mean length of hospital stay were 7±1.2 and 10±1.4 days in group 1 and group 2 patients respectively (p<0.05). conclusions: prolonged length of hospital stay increased the prevalence of pocd in our trial. studies with various types of surgical procedures and larger patient populations needed to further understand the effect of length of hospital stay to pocd. the influence of multiple trauma with head trauma on posttraumatic meningitis: a nation-wide study with hospital-based trauma registry in japan introduction: posttraumatic meningitis is one of severe complications and results in increased mortality and longer hospital stay among head trauma patients. however, it remains unclear whether there is a difference in the incidence of post-traumatic meningitis due to single traumatic brain injury (tbi) and multiple trauma including head injury. methods: this study was a retrospective observational study during 12 years we included trauma patients registered in japanese trauma data bank whose head ais score was >3 in this study. multivariable logistic regression analysis was used to assess potential factors associated with posttraumatic meningitis such as csf fistula, skull base fracture, type of injury that divided into single tbi and multiple trauma. introduction: the aim of this study was to determine if regional cerebral oxygenation (rsco2) can be used as an indicator of tissue perfusion in icu patients with tbi [1, 2] , and to determine the prognostic value of cerebral oxygenation rsco2 in survival prediction. methods: patients were enrolled retrospectively from january 2012 through july 2018 in the icu of derince kocaeli training hospital. 250 patients with trauma patients and traumatic braine injury patients who were admitted to the icu from the emergency room were included in the study. the sedation levels of the patients were followed up with bis. the rsco2, bis was taken as well as blood lactate level, mean arterial blood pressure and cardiac output at baseline time, 6, 12, 24, 48 and 72 hours. results: no significant difference was also detected between the value of rsco2 in all patients . it was average sco2 (right) 60.54 ±4.8 and average rsco2 (left) 55.63± 5.4. conclusions: cerebral regional oxygen saturation might be helpful as one of the perfusion parameters in patients with tbi but it could have no prognostic value in mortality prediction. however, further studies with larger sample size are still needed to validate these results. introduction: tbi in elderly is an increasingly cause of admission in icu. data regarding management and prognosis of these patients are lacking. validated prognostic models refer to younger patients and do not adequately consider the influence of pre-injury functional status, which often compromises with aging. frailty has been defined as a state age-related of increased vulnerability and decline in autonomy of daily life activity. aim of the study is to evaluate the impact of frailty on outcome in tbi elderly patients. methods: moderate and severe tbi patients >65years, admitted in neuroicu from january 2017 to may 2018, were prospectively enrolled. data of age, comorbidity, glasgow coma scale (gcs), pupils' reactivity, ct scan characteristics, neurosurgical intervention and gose (extended glasgow outcome scale) at 6-months were collected. frailty status was measured by clinical frailty scale (cfs) [1] and patients were divided as frail (cfs>4) and not frail (cfs<4). bad outcome was defined as gose<4. results: 22(37%) of the 60 studied patients were frail. frailty was not related to age. frail patients had more comorbidities and worse pupils' reactivity at admission (table 1) . other variables did not differ between groups. in univariate analysis neurological diseases, gcs, tsah (traumatic subarachnoid haemorrhage), compressed/absent basal cisterns, non-reactive pupils and cfs were significantly associated to bad outcome. in multivariate analysis only gcs and cfs remained associated to bad outcome ( table 2) . conclusions: pre-injury frailty is strongly associated to outcome in tbi elderly patients. the age of the patients was 48.4±15.6 years. patients were operated on for intracranial traumatic (39 cases) and non-traumatic hematomas (5), brain tumors (4) and the need for plastic of postoperative skull defects (6). general endotracheal total intravenous anesthesia with fentanyl, propofol, rocuronium, or tracrium was used. after tracheal intubation, 4-12 nerves were blocked (e.g., supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, great auricular, greater and lesser occipital nerves), depending on the surgical site. 0.75-1.0% ropivacaine was used. for blockade of one nerve used 0.5-2.0 ml of local anesthetic. fentanyl was applied on section of a periosteum, dura matter and at inefficiency of blockade of nerves. anesthesiology monitoring included hr, ecg, spo2, nib, respiratory parameters, eeg (csi), body temperature, blood glucose and lactate levels. in 2 and 10-12 hours post-surgery, the intensity of pain was ranked by alert patients using vas. results: the volume of local anesthetic for blockade in one patient was 7.7± 1.7 ml. in 5 (9.3%) from 54 patients, an additional fentanyl injection was required to skin incision due to an increase in blood pressure and heart rate by 25% of the baseline values, and an increase in csi until 80 un. patients available to productive contact in 2 hours post-surgery ranked the pain by vas at 1 (0;2) point, and in 10-12 hours post-surgery ranked it at 2 (1;3) p. conclusions: at patients with craniotomies scalpe-block with lowvolumes of a ropivacaine showed high efficiency (90.7%). were transferred to hospital ward or 53 (13.1%) to the center of intensive nursing care; 2 (0.5%) went to the surgical recovery room. acute renal failure, hypernatremia and hyperphosphatemia were independent predictors of mortality as described in table 2 . conclusions: hypernatremia and hyperphosphatemia were independent predictors of mortality in critically ill patients. introduction: the strong ion difference (sid) is essential for the assessment of acid-base equilibrium, thus requiring an accurate measurement of plasma electrolytes. currently there is no gold standard for electrolyte measurements and sid computation. differences in electrolyte values obtained with point-of-care (poc) and central laboratory (lab) analyzers have been reported [1, 2] . in previous studies [3, 4] we have shown that changes in pco2 induce electrolyte shifts from red blood cells to plasma (and vice versa), yielding variations in sid. aim of the present in-vitro study was to induce sid changes through acute changes in pco2 and compare values of electrolytes and sid obtained with poc and lab techniques. methods: blood samples from 10 healthy volunteers were tonometered (equilibrator, rna medical) with 3 gas mixtures at fractions of co2 (fco2) of 2, 12, and 20%. electrolytes were measured quasisimultaneously with a poc analyzer (abl800 flex, radiometer) and a routine lab method (cobas 8000 ise, roche). for both techniques a simplified sid was computed as sodium + potassiumchloride. results: bland-altman analysis of sid calculated with poc and lab showed a proportional bias (slope = 0.64, r2 = 0.55, p <0.0001), indicating a variable agreement between methods according to the average sid value (fig.1) . sid values measured with poc and lab at different fco 2 differed significantly (p<0.001, fig.2) . a similar discrepancy was observed for chloride (p <0.001, fig.2 ), while sodium (p=0.439) and potassium (p=0.086) were similar. conclusions: sid measured with poc and lab differed significantly, mainly due to a variable discrepancy in chloride. our findings suggest that our poc analyzer is superior to the lab in measuring electrolytes and thus compute sid. introduction: this study evaluated the safety of half dose insulin (hdi) versus standard dose insulin (sdi) for the treatment of hyperkalemia in a medical intensive care unit (micu) population with renal insufficiency. recent emergency medicine data demonstrated a lower incidence of hypoglycemia in patients with renal insufficiency when hdi was used for the treatment of hyperkalemia [1] . there is limited data describing the safety of hdi in a micu population with renal insufficiency. methods: this was a retrospective, chart review of patients admitted to the micu with a diagnosis of aki and/or ckd stage 3-5 with a serum potassium ≥ 5.8 meq/l from january 2013 to september 2018. sdi is defined as 10 units of regular iv insulin and hdi as 5 units. the primary outcome was the incidence of hypoglycemia within 12 hours of insulin administration. secondary outcomes included severe hypoglycemia and change of serum potassium after insulin administration. results: a total of 265 patients were screened and 98 were included for analysis. the incidence of hypoglycemia occurred in 6/ 45 patients (13.3%) and 6/53 patients (11.3%) who received sdi and hdi, respectively. one patient in the sdi group and two patients in the hdi group developed severe hypoglycemia. the mean decrease in serum potassium after insulin administration was 1.0 meq/l in both groups. patients in the hdi group who were re-dosed with 5 units of regular insulin did not have any hypoglycemic events. conclusions: in a micu population with renal insufficiency, sdi and hdi regimens appear safe and effective for the treatment of hyperkalemia. introduction: sepsis and septic shock are common causes of admission in the intensive care unit with a high mortality rate [1, 2] . hence, electrolyte disturbances are common in this group of patients. acute hypernatremia is one of the multiple features of homeostasis disturbances and available data in the literature suggest that its incidence can reach 47% [3, 4] . (fig 1, 2) . the main source of sepsis was pneumonia with 37 affected patients (41.57%). conclusions: hypernatremia is significantly associated with higher mortality in septic patients. 2 (abstract p246) . the outcome versus the sodium levels higher in the group 2 -80% vs 39.1% (p=0.031). there were no significant differences between the groups in length of stay in the icu. in group 1, there was an increase of serum phosphorus level and in the group 2the tendency to decrease. however, statistically significant differences were obtained only on the 2nd day after surgery 1.74±0.84 mmol/l (group 1) vs 0.88±0.26 mmol/l (group 2) (p=0.01). the roc curve was constructed to assess the predictive significance of serum phosphorus levels (fig. 1) . auc was 0.687; 95% ci 0.574-0.799; p=0.002; sensitivity 55.2%, specificity 83.9%. the kaplan-meier survival analysis (fig. 2) introduction: the rate of extubation failure might be higher in obese patients than in non-obese patients. effect of obesity on mortality is controversial [1, 2] (obesity paradox). several pathophysiological changes contribute to an increase of respiratory complications [1] . we sought to identify incidence of extubation failure in obese and non-obese patients. methods: the primary endpoint of this post-hoc analysis of a prospective, observational, multicenter study [3] performed in 26 intensive care units was extubation failure, defined as the need for reintubation within 48 hours following extubation. only patients with body mass index (bmi) recorded were included. results: between december 1, 2013 and may 1, 2015, among the 1427 patients with bmi available undergoing extubation, 301 obese patients (21%) and 1126 non-obese patients (79%) were enrolled. extubation-failure rate was 7.6% (23/301) in obese patients, and 11.0% (124/1126) in non-obese patients (p=0.09). delay of reintubation did not differ between obese and nonobese patients (figure 1 ). length of intubation > 8 days was significantly more frequent in obese patients (84/301, 29%) than in non-obese patients (195/1126, 18%, p<0.0001). precautions to anticipate extubation failure were more often taken in obese patients (153/301, 51%) than in non-obese patients (426/700, 38%, p<0.0001). spontaneous breathing trial (sbt) characteristics differed between obese and non-obese patients (table 1) . physiotherapy was more often used in obese patients (173/301, 57%) than in non-obese patients (556/1126, 49%, p=0.01). conclusions: incidence of extubation failure did not differ between obese and non-obese patients. in obese patients, clinicians anticipate more a possible extubation failure, delaying the moment of extubation, performing more physiotherapy and providing an optimal sbt. introduction: in the acute phase of critical illness, growth hormone (gh) resistance develops, reflected by increased gh and decreased insulin-like growth factor-i (igf-i), mimicking fasting in health. the epanic rct observed fewer complications such as muscle weakness and faster recovery with accepting a macronutrient deficit in the first icu week, as compared with early full feeding [1, 2] . we characterized its impact on the gh axis in relation to the risk of acquiring muscle weakness. methods: in this epanic rct sub-analysis, for 564 matched patients per group, and all patients assessed for muscle weakness (n=600), serum gh, igf-i, igf binding protein 3 (igfbp3) and igfbp1 were measured upon icu admission and at day 4 or the last icu day for patients with shorter icu stay (d4/ld). for 10 matched patients per group, gh was quantified every 10 min between 9 pm and 6 am, and deconvolved to estimate gh secretion. groups were compared with wilcoxon test or repeated-measures anova. associations between changes from baseline to d4/ld and muscle weakness were assessed with logistic regression analysis, adjusted for baseline risk factors, baseline hormone concentrations and randomization. results: in the fully fed group gh, igf-i and igfbp3 increased, whereas igfbp1 decreased from admission to d4/ld (all p<0.001). accepting an early macronutrient deficit prevented the rise in gh and igf-i and the decrease in igfbp1 (all p<0.005) but did not affect igfbp3, whereas basal, but not pulsatile, gh secretion was lowered (p=0.005). a stronger rise in gh and igf-i was independently associated with a lower risk of acquiring muscle weakness (or (95%ci) per ng/ml change 0.88 (0.81-0.96) for gh; 0.98 (0.97-0.99) for igf-i). conclusions: accepting an early macronutrient deficit suppressed basal gh secretion and reduced igf-i bioavailability during critical illness, which may counteract its protection against muscle weakness. introduction: aim of the study was to relate hypokalemia (hypok) and hypoglycemia as diabetic ketoacidosis (dka) treatment complications and precocious insulin interruption also use of sodium bicarbonate with length of stay (los) in intensive care unit (icu). methods: analysis of retrospective cohort study data of 100 patient (pt) treated for dka at icu of hospital kaunas clinics of lithuanian university of health sciences during 2012-2018 has been carried out. serum kalemia, glycaemia; rate of episodes of hypok, hypoglycaemia and precocious insulin interruption; use of sodium bicarbonate, in relation with los in icu were analysed. spss 23.0 was used for statistic calculations. traits evaluated as significant at p<0.05. results: at the beginning of dka treatment hypok (3.1±0.3 mmol/l) was recorded in 53/100 (53%) pt. due to disregarding of blood ph (6.8 -7.3 (7.1 ± 0.1) kalemia was falsely misinterpreted as "normo-" or "hyperkalemia" 3.5 -6.1 (4.8 ± 0.8mmol/l) in 49 of 63 (78%) pt, as normo-and hyperkalemia thus not treated and complicated by hypok additionally in 20/49 (41%) pt. in hypok los in icu was 52.2 ± 31.3 vs 31.7 ± 18.2 h, p<0.05. insulin use has caused hypoglycaemia (1.2 -3.3 (2.5 ± 0.7 mmol/l)) in 20/100 (20%) pt, los in icu 62.1 ± 40.3 vs 37.7 ± 21.4 h, p<0.05. insulin use was interrupted in case of normo -and hypoglycaemia with still persisting ketoacidosis in 34/ 100 (34%) pt, los in icu was found to be 56.2 ± 32.1 vs 35.5 ± 22.5 h, p<0.05. sodium bicarbonate was given for symptomatic treatment of acidosis during the first 10 h of dka in 21/100 (21%) pt with stable hemodynamic: hco3buffer has increased (4.2 ± 3.1-7.5 ± 3.0 mmol/l), p<0.05, but ketoacidosis has still persisted, los in icu was 54.8 ± 30.0 vs 39.3 ± 26.5 h, p<0.05. conclusions: hypok (53%), hypoglycemia (21%), precocious interruption of insulin use (34%) have prolonged los in icu almost twice. symptomatic treatment of ketoacidosis with sodium bicarbonate (1/5 pt) didn't control it and has prolonged los in icu. introduction: cystathionine-γ -lyase (cse), a regulator of glucocorticoid (gc)-induced gluconeogenesis [1] , correlates with endogenous glucose production in septic shock [2] . the hyperglycemic stress response to noradrenaline (noa) is mediated by the kidney [3] and less pronounced with low cse [4] . gc receptor (gr)-mediated gene expression is differentially regulated: the gr monomer is considered to repress inflammation, and gc side effects are attributed to the gr dimer; recent reports challenge this view [5] . gc-induced gluconeogenic gene expression is reduced in gr dimerization deficient (grdim) mice [6] . the aim of this study is to investigate renal cse expression and systemic metabolism in grdim and grwt mice in a resuscitated model of lps-induced endotoxic shock. methods: anesthetized grdim (n=10) and grwt (n=9) mice were surgically instrumented, monitored, resuscitated and challenged with lps. noa was administered to maintain map and 13 c 6 glucose was continuously infused. 6h after lps, cse expression was determined via immunohistochemistry of formalin-fixed paraffin sections (n=8 p.gr.). results: grdim required 2.5-fold more noa than grwt and had 1.5fold higher glucose and 1.9-fold higher lactate 6h after lps. this was concomitant with elevated endogenous glucose production (2-fold), 10% lower glucose oxidation and 1.8-fold higher renal cse expression in grdim. conclusions: increased cse expression together with higher glucose production (confirming [2, 4] ) and glucose levels in grdim mice suggest an association that may link cse to gc signaling. the higher noa administration in grdim mice could contribute to these effects. introduction: to achieve safe glycemic control in critically ill patients frequent blood glucose (bg) measurements and according titration of insulin infusion rates are required. automated systems can help to reduce increased workload associated with diabetes management. this bi-centric pilot study combined for the first time an intraarterial glucose sensor with a decision support system for insulin dosing (sgcplus system) in critically ill patients with hyperglycemia. methods: twenty-two patients (3 females, 19 males, 12 with preexisting diabetes mellitus, age 65.7 ± 12.7 years, bmi 27.3 ± 3.5 kg/ m2, creatinine level 1.4 ± 1.2 mg/dl, saps (simplified acute physiology score) 64.6 ± 18.3, tiss-28 (therapeutic intervention scoring system) 39.2 ± 5.5 who were equipped with an arterial line and required iv insulin therapy were managed by the sgcplus system during their medical treatment at the intensive care unit. results: 1845 sgcplus-based bg determinations were performed and 0.8 ± 0.8 sensor calibrations per day were required. sensor glucose readings correlated well with reference bg (figure 1 ). mean treatment duration was 6.0 ± 3.8 days. time to target was 100 ± 178 min (80-150 mg/dl) and 135 ± 267 min (100-160 mg/dl). mean blood glucose was 142 ± 32 mg/dl with seven blood glucose values <70mg/dl. mean daily insulin dose was 62 ± 38 u and mean daily carbohydrate intake 148 ± 50 g /day (enteral nutrition) and 114 ± 50 g/day (parenteral nutrition). acceptance of sgcplus suggestions was high (>90%). the novel intraarterial glucose sensor demonstrated to be highly accurate. the sgcplus system can be safely applied in critically ill patients with hyperglycemia and enables good glycemic control. introduction: we aimed to assess the effect of frailty as assessed by clinical frailty scale (cfs) and karnofsky performance score (kps) on critical care (cc) and hospital mortality in this group at a nonspecialist tertiary critical care unit. methods: patients admitted to critical care were identified from our electronic database by screening for liver disease or cirrhosis in the admission diagnoses. those with an aetiology of liver disease other than alcoholic liver disease (ald) were excluded. data was collected on patient demographics, length of stay, status at discharge from critical care and hospital and cfs. kps was also calculated where sufficient in-formation was available in the medical record. data was analysed using logistic regression multivariate analysis with stata 14 software. [1] . results: tg13 diagnosis criteria and severity grading criteria for acute cholangitis and acute cholecystitis were judged from numerous validation studies as useful indicators in clinical practice and adopted as tg18 diagnostic criteria and severity grading without any modification. provide initial treatment, such as sufficient fluid replacement, electrolyte compensation, and intravenous administration of analgesics and full-dose antimicrobial agents, as soon as a diagnosis has been made. in new flowchart for the treatment of acute cholecystitis (ac) in the tg18, grade iii ac was indicated for gallbladder drainage, but some grade iii ac can be treated by laparoscopic cholecystectomy (lap-c) at advanced centers with specialized surgeons experienced in this procedure and for patients that satisfy certain strict criteria. we also redefine the management bundles for acute cholangitis and cholecystitis. introduction: 13 c-acetate breath tests provide a non-invasive assessment of gastric emptying [1] and could, hence, be used to judge tolerance to enteral nutrition. result values like t50 (time for 50% absorption) correlate with scintigraphic measurements. the data evaluation is based on model equations like the β -exponential function (bex) [1] . it considers a mono-phasic breath gas response. this may not be the case during critical illness, which could reduce precision too low for a reliable personalized assessment [2] . methods: we recently developed an evaluation of irregular gastric emptying patterns, which separates absorption from post-absorptive distribution and retention of tracer and from the terminal respiratory release of the oxidized tracer [3] . using breath test data of 31 icu patients (mean saps2 36 +/-14) the precision of this approach was compared with a bex analysis to explore how often an extended analysis is warranted and whether it improves the reliability of estimates. results: 15 patients had a release profile consisting of series of peaks with a periodicity of 60-90 min. a first dominant peak carries about 95% of the released moiety, as reported [4] for controls. for these patients the precision in t50 for the bex approach was 70 +/-30% of that observed for the new approach. for the other patients, the secondary peaks had a similar periodicity but were more pronounced, indicating persisting peristaltis, which has been linked to tolerance to enteral nutrition [4] . the bex approach achieved a precision of 40 +/-27 % relative to the new one, challenging its applicability for these patients. introduction: clinical scoring systems used to prognosticate the severity of acute pancreatitis (ap), such as apache ii, are cumbersome and usually require 24 hours or more after presentation to become accurate, at which time the window for early therapeutic intervention has likely passed. sirs at presentation is sensitive but poorly specific for severe ap. we postulated that sirs and accompanying hypoxemia would specify at presentation patients with ap who have severe inflammation and are at risk for clinically severe disease. methods: patients with ap who had sirs and hypoxemia at presentation were enrolled in an open-label study evaluating the safety and efficacy of cm4620-ie, a calcium release-activated calcium (crac) channel inhibitor (nct03401190). hypoxemia was defined as an estimated pao2 <75 mm hg calculated using a log-linear equation and the spo2 on room air at the time of presentation. a contrastenhanced computed tomography (cect) was performed at presentation and a cbc with differential, d-dimer and crp were analyzed daily. the cect was read by a blinded central reader who assessed the degree of inflammation using the balthazar scoring system (table 1) . results: 13 patients, seven men and six women, have been randomized in the study. the mean estimated pao2 at presentation was 74 mm hg. 10 patients had 2 sirs criteria present and the other 3 patients had 3 sirs criteria present. the median value for age was 53.5 (iqr 48-56), initial neutrophil-lymphocyte ratio (nlr) 10.6 (6. 3 introduction: to investigate whether circulating immune profiles were able to serve as early biomarkers in predicting persistent organ failure (pof methods: thirty-nine patients with predicted severe acute pancreatitis (psap) and 9 healthy control subjects were prospectively enrolled in our study. we measured the expression of monocytic human leukocyte antigen-dr (mhla-dr), the proportions of dendritic cells (dc) and its subtypes (including myeloid dendritic cell (mdc) and plasmacytoid dendritic cell (pdc)), the different cytokineproducing cd4+ t helper (th) cells and regular t (treg) cells. plasma crp and several inflammatory mediators levels were measured by elisa. results: compared with healthy controls, there is a significant decrease in the expression of mhla-dr, the frequencies of total circulating dcs and its subsets, and percentage of th1 cells in patients with psap. however, we found significantly higher frequencies of th17 cells, higher proportion of treg cells than healthy subjects. of interest, we observed that there was a significant decrease in the positive percentage and mean fluorescence intensity (mfi) of mhla-dr, the proportions of total dcs and pdc, and th1 cells in patients with pof compared with transient organ failure (tof). besides, there is a significantly higher frequency of th17 cells in pof than those in tof. area under the receiver-operating characteristic curve analysis showed that disease severity scores had a moderate discriminative power for predicting pof in patients with psap. more importantly, the expression of mhla-dr and the percentage of dcs and pdc had a significantly higher auroc and thus, better predictive ability than disease severity in patients with psap. conclusions: circulating immune profile show multiple aberrations in patients with psap who have developed pof. both the expression of mhla-dr and the percentage of total dc and pdc may be early good biomarkers for predicting risk of pof in patients with psap. introduction: pancreatic fistula (popf) due to anastomosis insufficiency is a common (12-30%) complication after pancreaticoduodenectomy and often discovered with delay, causing severe morbidity, icu stay and deaths. microdialysis (md) catheters have been shown to detect inflammation and ischemia in several postoperative conditions and organs. the aim was to investigate if md catheter monitoring could facilitate earlier detection of popf than current standard of care. methods: in a prospective, observational study 35 patients (44 to 88 years) were investigated. a md catheter was fixed to the pancreaticojejunal anastomosis. samples for analysis of glucose, lactate, pyruvate and glycerol were acquired hourly during the first 24 hours, then every 2-4 hours to discharge. popf was defined according to the international study group of pancreatic fistula 2016 update definition. results: patients who developed popf (n=7) had significantly higher glycerol levels (p<0.01) in microdialysate than did patients without popf (n=28) during the first 24 h. thereafter, the difference diminished. a glycerol concentration >400 μmol/l during the first 12 h detected patients who later developed popf with a sensitivity of 100 % and a specificity of 92%. lactate and lactate to pyruvate ratio were significantly higher (p<0.05) and glucose was significantly lower (p<0.05) in patients with popf from about 24 h. fig. 1 shows microdialysis measurements in patients with (red lines) and without (blue lines) popf. conclusions: a high level of glycerol in microdialysate is an early (first 12 hours) indicator of popf. glucose, lactate and lactate to pyruvate ratio are indicators of peritonitis caused by the leakage. thus, md monitoring detects popf several days earlier than current methods and may play an important clinical tool in the future. we are currently conducting a rct to explore if md monitoring will improve prognosis in these patients the phenomenon of total impaired of metabolic activity of gut microbiota in critically ill septic patients introduction: during a critical condition, dramatic disturbances occur not only in the change of species diversity, but in gut microbiota metabolism as well, that might lead to nonreversible breakdowns of host homeostasis and death [1] . metabolic activity of microbes can be assessed by the measurement of the levels of aromatic microbial metabolite (amm) in blood serum, which are associated with the severity and mortality of icu patients. critically ill patients are characterized by the totally different sfs profile than in healthy people, particularly by the absence of phpa; but dominated by p-hphaa and p-hphla [2] . the purpose of our study is to assess the gut metabolic activity via amm in sepsis. methods: in this study 40 simultaneously serum and fecal samples (sfs) were taken from icu patients: 14 -with sepsis, 21-chronic critical ill (cci) patients and control -5 sfs from healthy people. after liquid-liquid extraction from serum and fecal samples, 9 phenylcarboxylic acids (amm) were measured using gc/ms (thermo scientific). results: the sum of the level of 9 most relevant amm in serum samples were higher in patients with sepsis (median -4.7 μm) than in cci patients (1.1 μm) and healthy people (1.3 μm). at the same time the opposite pattern was observed in the fecal samples -2.4, 31.9 and 68.7 μm, respectively. the ratios of sums amm gut/serum were higher in healthy people than icu patients (fig. 1) introduction: the aim of this study is to describe the characteristic of bioelectric impedance vector analysis (biva) and muscular ultrasound during the first week after admission in the icu, and their correlation with indices of metabolic support. biva is a commonly used approach for body composition measurements [1] . muscular ultrasound represents a valid tool to provide qualitative and quantitative details about muscle disease [2] . methods: consecutive patients admitted to icu and expected to require mechanical ventilation for at least 72 hours were enrolled in the study. within the first 24 hours of icu admission (t1), patients were evaluated with muscular ultrasonography comprehensive of diaphragm thickness (dth) and rectus femoris cross-sectional area (csa). at the same time, biva and biochemical analysis. all the same measures were repeated at day 3 (t3) and 7 (t7) (figure 1 (table 1) . dividing the patients in two groups based on prealbumine changes (t3 vs t1: increase, anabolic vs decrease, catabolic), those in which prealbumine increased had a higher reduction in muscle mass ( figure 2 ). conclusions: this study showed how the pa tends to be reduced in the first week of icu stay. it is correlated with a concomitant introduction: the modified nutrition risk in critically ill (mnutric) has been developed in order to identify critically ill patients who may receive benefit from nutrition support [1] . several evidences showed the association between the mnutric score and clinical outcomes [2, 3] , however there are no data in thai critically ill patients. the purpose of this study was to find the association between mnu-tric score and 28-day mortality in medical intensive care unit (icu) patients, ramathibodi hospital. methods: we retrospectively reviewed the medical patient records from june 2016 to january 2017. a mnutric score of each patient was calculated to evaluate the risk of malnutrition. statistical analysis of the association between mnutric score and 28-day mortality, length of stay in icu and hospital were performed. results: a total of 78 critically ill patients were included in the study. the 28-day mortality was 53.06% in patients with high mnutric score (5-9) and 13.79% in patients with low mnutric score (0-4). modified nutric score was significantly correlated with 28 day mortality (r = 0.390, p<0.001), length of stay in icu (r = 0.394, p<0.001) and length of stay in hospital(r = 0.414, p<0.001). in the receiver operating characteristic (roc) curve analysis, the auc of mnutric score and 28-day mortality was 0.788 (95% confidence interval (ci), 0.686-0.889) (fig 1) . optimal cut-off value of 6 showed sensitivity of 66.7% and specificity of 77.1% in mortality prediction (youden's index, 0.438). additionally, patients who received adequate nutrition supplement within 7 days was 87.20% for calorie and 64.10% for protein. there was no association between nutrition support and 28-day mortality. conclusions: in thai medical intensive care population, the mnutric score was associated with 28-day mortality in critically ill patients. fig. 1 (abstract p264) . within the first 24 hours of icu admission (t1), patients will be evaluated with muscular ultrasonography comprehensive of diaphragm thickness and rectus femoris (medial vastus) cross-sectional area. at the same time, anthropometric measure will be collected (such as body height, ideal body weight, real body weight declared, right arm circumference) as well as biva measure (xc, r, pa, lean body weight and % of extracellular body weight) and biochemical analysis (inclusive albumin, pre-albumin, blood count, lymphocyte count, magnesium, phosphorus, reticulocytes, renal and hepatic function test). the day after, the fluid balance will be calculated as well as the nitrogen balance. all the same measures will be repeated at day 3 (t3) and 7 days (t7) introduction: ultrasonography is an essential imaging modality in critical care to diagnose and guide for therapeutic management of shock, multiple organ failure, etc. enteral tube feed intolerance occurs frequently in hospitalized patients and more so in critically ill patients. in present study, we consider that nursing staff may be able to use bedside ultrasound as an alternative to standard aspiration protocol or radiographic studies to assess gastric volume and nasogastric (ng) tube in patients with enteral feed intolerance. methods: in present prospective, single-center study, we performed ultrasound residual stomach volume and ng tube placement assessments of adult critically ill patients (figure 1 ) compared to standard protocol of stomach volume assessment (routine daily shift 60-ml syringe aspirations) and ng (nasogastric) tube placement verified by abdominal x ray. we used an abdominal (linear ultrasound transducer) probe (4-10 mhz). the residual volume was calculated according to formula: gv (ml) = 27 +14.6 x right-lateral csa-1.28 x age). results: hundred simultaneous double (ten critically ill patients) ultrasound measurements sessions were performed by nursing staff of our intensive care (icu) (fig 1) . double simultaneous measurements of the ultrasound assessments were compared to standard nurse icu protocol for assessment of residual volume of stomach. the new ultrasound assessment method demonstrated excellent intra-class reliability (icc-0.96 (0.95-0.98, p<0.001) and strong correlation with standard residual volume assessment method (icc-0.82 (0.7-0.89, p<0.001). ng tube placement was successfully verified by ultrasound measurements in all ten critically ill patients and, thereafter, confirmed by abdominal x-rays. conclusions: preliminary results of our study demonstrated good correlations between both methods of ng tube placement and residual stomach volume: standard icu nurse protocol and ultrasound assessment. evaluating the documentation of nasogastric tube insertion and adherence to safety checking l roberts 1 introduction: enteral feeding into a misplaced nasogastric (ng) tube is recognised by the national patient safety agency as a never event. ng tubes are commonly indicated in level 2/3 patients, thus we set out to evaluate current practice in critical care. the aim was to evaluate: documentation of insertion, adherence to safety guidance pertaining to checking safe use, chest x-ray interpretation. methods: this prospective cohort study was based on inpatients in critical care who had insertion of ng tubes over four weeks; there were 57 insertions. data was analysed from patients' medical notes and the hospital's imaging system. results: 65% of insertions were documented using proformas. 97.1% of proforma documentations included 4 or more details: type of tube, tube length at the nostril, nex measurement, aspirate adequacy, chest x-ray adequacy, whether it was safe to feed. only 13.6% of hand-written documentations included 4 or more details. 51% of initial aspirates were obtained on insertion, of these, 57% had an appropriate ph between 1 and 5.5. this led to 74% of patients having chest x-rays to confirm initial placement of the ng tube. only 54% of chest x-rays adequately satisfied the four criteria. written documentation in medical notes stating if it was safe to feed was completed in 67% of cases. conclusions: we found that proformas ensure a higher level of detail and uniformity in the documentation of ng tube insertions. there was a high incidence of chest x-rays performed to confirm correct placement of tubes due to difficulties in obtaining aspirates and failure to follow guidelines. a need for a uniform, ward-specific proforma on ng tube insertion has been identified, as well as a teaching session on chest x-ray interpretation and on techniques to aid obtaining aspirates. we have established critical care's shortcomings in ng tube insertion documentation and tube safety checking. introduction: pressure ulcers(pu) are considered as important types of public health problems, due to high mortality and cost. we aimed to investigate the efficiency of curcumin and fish oil on prevention and treatment of pu using a feasible mice model. methods: 28 mice were randomly divided into control(group 1), curcumin(group 2), fish oil(group 3), curcumin and fish oil(group 4) groups. 5mm skin bridge between two 1000 gauss magnets was formed on the back of mice, followed by 3 ischemia reperfusion cycles as 12 hours of rest after 12 hours of magnet placement [1] . a single dose of curcumin and fish oil was injected intraperitoneally. tissue samples had taken 10th day of first compression, rates of pu, inflammation, reepithelisation, neovascularisation and granulation were examined histopathologically. the data analyzed by pearson chi-square test. results: third degree pu were observed in all groups.there was no significant difference between groups in terms of inflammation.the formation of reepithelisation showed a significant difference between groups.partial reepithelisation ratios in group 3 and group 4 was elevated.there was significant difference between groups in terms of neovascularisation, the highest rate as 75% was observed in group 4.formation of granulation was observed at maximum rate as 46.2% at group 3. conclusions: depending on positive results of curcumin, fish oil, cur-cumin+fish oil on wound healing it may be advised to use them in treatment of acute pu.after similar rate of pu with control group we consider that it should be beneficial to evaluate the effect of these therapies with more studies by changing the mode of administration, time of initiation and duration of therapy. introduction: inflammation is a key driver of malnutrition during acute illness and has different metabolic effects including insulin resistance and reduction of appetite. whether inflammation influences the response to nutritional therapy in patients with disease-related malnutrition remains undefined. we examined whether the effect of nutritional support on the risk of mortality differs based on the inflammatory status of patients. methods: this is a secondary analysis of a multicentre trial in eight swiss hospitals, where patients with a nutritional risk score (nrs) of ≥3 upon hospital admission were randomly assigned to receive protocol-guided individualized nutritional support according to nutrition guidelines (intervention group) or a control group. the inflammatory status was defined based on admission crp levels as low inflammation (cpr <10 mg/dl), moderate inflammation (crp 10-100 mg/dl) and high inflammation (crp >100 mg/dl). results: we included a total of 1,950 patients of which 27.33%, 45.85% and 26.82% had low, moderate and high inflammation levels on admission. while overall there was a significant reduction in 30day mortality associated with nutritional support (adjusted or in the overall cohort 0.65, 95%ci 0.46 -0.91), the subgroup of patients with high inflammation did not show reduced mortality (adjusted or 1.36, 95%ci 0.76 -2.41, p for interaction = 0.005). there was no difference in other secondary endpoints when stratified based on inflammation. nutritional support did not affect crp levels over time (kinetics). conclusions: this secondary analysis of a multicentre randomized trial provides evidence, that the inflammatory status of patients influences their response to nutritional support. these findings may help to better individualize nutritional therapy based on patients initial presentation. introduction: low plasma glutamine levels have been associated with unfavourable outcomes in critically ill patients. this study aimed to measure plasma glutamine levels in critically ill patients and to correlate glutamine levels with biomarkers and severity of illness. methods: we enrolled critically ill patients admitted to three icus in south africa, excluding those receiving glutamine supplementation prior to admission. we collected clinical, biochemical and dietary data. plasma glutamine levels were determined within 24 hours of admission, using liquid chromatography mass spectrometry and categorized as low (<420 μmol/l), normal (420-700 μmol/l) and high (>700 μmol/l). results: of the 330 patients (average age 47.42±16.56 years, 56% male), 68% were mechanically ventilated, with a mean apache ii score of 18.57±8.55 and a mean sofa score of 7.05±3.78. plasma glutamine levels were low in 58.5% (median plasma glutamine of 382.15 μmol/l). baseline plasma glutamine correlated inversely with crp (r=-0.287, p<0.001) and serum urea (r=-0.124, p<0.026), and positively with serum bilirubin (r=0.262, p<0.001) and serum alt (r=0.119, p=0.032). significantly more patients with low admission glutamine levels required mechanical ventilation (chi2=12.65, p<0.001) and had higher apache scores (p=0.003), higher sofa scores (p=0.003), higher crp values (p<0.001), higher serum urea (p=0.008), higher serum creatinine (p=0.023), lower serum albumin (p<0.001) and lower bilirubin levels (p=0.054). using multiple logistic regression analysis, apache score (odds ratio, [or] 1.032, p=0.018), sofa score (or 1.077, p=0.016) and crp (or 1.006, p<0.001) were significant predictors of low plasma glutamine levels. roc curve analysis revealed a crp threshold value of 87.95mg/l to be indicative of low plasma glutamine levels (auc 0.7, p<0.001). conclusions: 58.5% of critically ill patients had low plasma glutamine levels on admission to icu. this was associated with increased disease severity and higher crp. introduction: the east of england deanery operational delivery network in the united kingdom came together as a group of intensive care units to comply an evidence-based care bundle. one of the branches of this care bundle is on parenteral nutrition and states: 'parenteral nutrition should not be given to adequately nourished, critically ill patients in the first seven days of an icu stay.' this is based on evidence [1] [2] [3] that showed that 'in patients who are adequately nourished prior to icu admission, parental nutrition initiated within the first seven days has been associated with harm, or at best no benefit, in terms of survival and length of stay in icu.´the objective of this second cycle was to assess whether or not we are adhering to the guidelines, last year we were failing to hit targets and after some action i reassessed how we performed in the year 2017 compared to 2016. methods: a retrospective audit of the whole year of 2017 for all patients admitted to icu who had parenteral nutrition started at any point during their stay. results: there is a significant improvement in the percentage of patients who are being started incorrectly on tpn before 7 days (36% compared to 69%) (fig 1, 2) . i also found a total reduction in the number of patients prescribed tpn, a reduction in the number of bags being used and a reduction in length of hospital stays. conclusions: as we have recently switched over to an electronic icu programme for all documentation and prescriptions, as part of our plan and act in the pdsa cycle we are organising for several things to be put in place on the new system on prescription: pharmacy authorisation, links to guidelines and alert/justification boxes. i will do a further cycle in another year. jg and mpc contributed equally. introduction: recent rcts revealed clinical benefit of early macronutrient restriction in critical illness, which may be explained by enhanced autophagy, an evolutionary conserved process for intracellular damage elimination [1] . however, in the absence of specific and safe autophagy-activating drugs, enhancing autophagy through prolonged starvation may produce harmful side effects. a fasting-mimicking diet (fmd) may activate autophagy while avoiding harm of prolonged starvation, which also improved biomarkers of age-related diseases in an experimental study [2] . we evaluated if short-term interruption of continuous feeding can induce a metabolic fasting response in prolonged critically ill patients. methods: in a randomized cross-over design, 70 prolonged critically ill patients receiving artificial feeding were randomized to be fasted for 12 hours, followed by 12 hours full enteral and/or parenteral feeding, or vice versa. patients were included at day 8 in icu and blood glucose was maintained in the normal range. at the start and after 12 and 24 hours, we quantified total bilirubin, urea, insulin-like growth factor-i (igf-i) and beta-hydroxybutyrate (boh) in arterial blood. insulin requirements were extracted from patient files. changes over time were analyzed by repeated-measures anova after square root transformation. results: as compared to 12 hours of full feeding, 12 hours of fasting decreased bilirubin (-0.23±0.06mg/dl; p=0.001) and igf-i (-13.94 ±1.62ng/ml; p<0.0001), and increased boh (+0.47±0.07mmol/l; p<0.0001), without affecting urea concentrations (fig 1) . fasting reduced insulin requirements (-1.16±0.14iu/hour; p<0.0001). conclusions: short-term fasting induces a metabolic fasting response in prolonged critically ill patients, which provides perspectives for the design of a fmd, aimed at activating autophagy and ultimately at improving outcome of critically ill patients. introduction: recent evidence has led to changed feeding guidelines for critically ill patients, with a shift towards lower feeding targets during the acute phase [1] . when micronutrients are not provided separately, prolonged hypocaloric feeding could induce micronutrient deficiencies and increase risk of refeeding syndrome once full feeding is restarted, which are both potentially lethal complications [2] . since there is limited evidence how to optimize micronutrient provision in order to avoid deficiencies, we hypothesized that there is a great variation in current practice. methods: within the men section of the european society of intensive care medicine (esicm), we designed a questionnaire to gain insight in the current practice of micronutrient administration. in 3 email blasts, invitations were sent to all esicm members, with currently more than 300 respondents. the survey will be closed at december 10, 2018. results: first, we will describe demographic characteristics of the respondents, including geographical location, icu and hospital type, and function. second, we will describe some aspects of the current practice of micronutrient administration. we will identify the proportion of respondents having a protocol, on which evidence such protocol is based and whether it takes into account the stability and daylight sensitivity of micronutrients. next, bearing refeeding syndrome in mind, we will identify whether there are respondents who never measure and/or separately administer micronutrients and phosphate. finally, we will make a top 5 of the most measured and most supplemented micronutrients. conclusions: this survey will deliver more insight in the current practice of micronutrient provision across different types of icus and may identify areas for future research. furthermore, we will evaluate whether there is need to increase awareness for refeeding syndrome. introduction: large gastric residual volumes (grvs) have been used as surrogate markers of delayed gastric motility to define enteral feeding intolerance (efi). recent studies have challenged the definition of efi. study objectives: 1) investigate the potential relationship between grvs and clinically outcomes, 2) develop an algorithm for early identification of patients at increased risk of mortality due to efi. methods: a retrospective study of inpatient encounters from electronic health record charts within the dascena clinical database. 4,018 patients were included in the study; 295 patients had efi. eight vital signs (diastolic/systolic bp, heart rate, temperature, respiratory rate, grv, glasgow coma scale, and feeding rate) and their trends were input to the classifier. machine learning classifiers were created using the xgboost gradient boosted tree method with 3-fold cross validation. results: rate of change in grv (δ grv) was measured over a 5-day period, beginning at the time of efi onset (figure 1a) . figure 1b shows a high likelihood of mortality for patients with none or modest grv reduction. patients with an increase in grv over the five-day period after efi onset had the highest mortality likelihood. a stratification algorithm was developed to identify efi patients who died inhospital despite grv reduction at 1, 12, and 24 hours in advance of efi onset. area under the receiver operating characteristic (auroc) curves demonstrated high sensitivity and specificity of algorithm predictions of in-hospital death up to 24 hours in advance of efi onset (table 1) . conclusions: the analysis suggests an association between grv and mortality, especially in patients with persistent grv increase over the 5-day period after efi onset and the potential of algorithmic models to predict efi development. prospective validation of these fig. 1 (abstract p274) . changes in metabolic markers of fasting over time for both randomization groups algorithms may assist in clinical trial design to develop treatments for patients at highest risk of experiencing serious outcomes due to efi. a quality improvement project to improve the daily calorific target delivery via the enteral route in critically ill patients in a mixed surgical and medical intensive care unit (icu) b johnston, d long, r wenstone royal liverpool and broadgreen university hospital trust, critical care, liverpool, united kingdom critical care 2019, 23(suppl 2):p277 introduction: 'iatrogenic underfeeding' is widespread with the calo-ries study reporting only 10%-30% of prescribed daily kcal was actually delivered to patients [1] . in the present project, quality improvement methodology was utilised with the aim of delivering greater calories by implementing 24-hour volume-based feeding and allowing increased feeding rates for, 'catch up' of missed daily feed volume. methods: baseline data assessing the percentage of daily kcal delivered to ventilated patients was collected in september 2017. data was presented and new intervention guidelines agreed based upon the pepup protocol [2] . nurse champions were identified and were responsible for cascade training of the pepup protocol. educational tools to help determine daily calorific requirement and volume of feed required were provided. repeat data was collected at 6 months (cycle 2) after pepup implementation. results: ten patients were included in cycle 1. during cycle 1 the percentage of kcal achieved via enteral feeding was 45%. following intervention this increased to 82% (p<0.001) during cycle 2. this increased further to 95.3% of daily kcal when calories obtained from propofol were included. conclusions: a 24-hour volume-based feeding regimen is a simple and cost-effective method of improving enteral feeding targets. through the use of quality improvement methodology, we demonstrated that this approach is achievable. the success of this project has led to the adoption of the protocol in other icu units in a regional critical care network. effect of non-nutritional calories on the calory/protein ratio in icu patients s jakob, j takala university hospital bern, dept of intensive care medicine, bern, switzerland critical care 2019, 23(suppl 2):p278 introduction: nutritional diets are composed to match the needs of critically ill patients. while effective calory needs can be measured or calculated, the needs of proteins are more controversial. we aimed to calculate non-nutritional calories and assess how they influence the ratio of calories to protein delivered to the patients. methods: in this retrospective analysis, nutritional and nonnutritional calories and protein delivery were calculated in 220 consecutive icu patients receiving enteral nutrition in 2016. introduction: marked protein catabolism is common in neurocritical patients. optimal nutritional monitoring and protein nutritional adequacy could be associated with outcome in neurointensive care unit (ncu) patients. we aimed to evaluate the impact of monitoring and optimal support of protein using nitrogen balance on outcome in neurocritical patients. methods: a consecutive 69 patients who were admitted to ncu were included between july 2017 and february 2018. nitrogen balance was calculated using excreted urine urea nitrogen during icu admission. follow-up nitrogen balance monitoring was performed in 33 patients. we divided patients into two groups based on the results of nitrogen balance (positive balance and negative balance). moreover, we evaluated improvement of nitrogen balance in 33 patients. we assessed the outcome as length of stay in hospital, length of stay in ncu, and in-hospital mortality. we compared the clinical characteristics and outcome according to nitrogen balance. results: among the included patients (age, 58.1; and male. 59.4%), 53 (76.8%) patients had negative nitrogen balance. the negative balance group was more likely to have lower glasgow coma scale (gcs), longer length of stay in hospital, and longer length of stay in ncu. in 33 patients with follow-up nitrogen balance monitoring, improvement of nitrogen balance group had lower in-hospital mortality (10.5% vs. 50.0%, p = 0.019), and received adequate protein intake (1.8 g/kg/day vs. 1.1 g/kg/day, p = 0.001) compared to no change group (table 1) . there was no significant difference in baseline nitrogen balance, baseline body mass index, and gcs between two groups. conclusions: this study demonstrated that critical illness patients in ncu are underfeeding using nitrogen balance, however, adequate provision of protein was associated improvement of nitrogen balance and outcome. this suggests that adequate nutrition monitoring and support could be an important factor for prognosis in neurocritical patients. increased protein delivery within a hypocaloric protocol may be associated with lower 30-day mortality in critically ill patients introduction: to test the hypothesis, using real world evidence that increasing protein delivery and decreasing carbohydrates (cho) may improve clinical outcomes. methods: retrospective analysis of existing electronic medical records (emr) of patients admitted to the intensive care units (icu) at the geisinger health system. logistic regression analysis was used to determine correlation between protein delivered (which was proportional to the concentration of protein in the formula utilized) and clinical outcomes. results: 2000 medical encounters for a total number of 12,321 icu days were collected and analyzed. average age was 62.2 years (55.2% male) and 68.1% were obese and overweight. primary diagnoses included sepsis or septic shock, acute and/or chronic respiratory failure (or illness), cardiovascular diseases, stroke and cerebrovascular diseases among others. median hospital los was 13.6 days, 6.9 days in the icu, median days of invasive mechanical ventilation of 4. 30-day readmission rate among patients discharged alive was 19.3%. patients in the high protein group received lower amounts of chos (data not shown). unadjusted 30-day post-discharge mortality was inversely proportional to the amount of protein delivered (table 1) . conclusions: a significant improvement in mortality is observed with increased protein delivery while decreasing carbohydrate loads. prospective randomized trials are warranted to establish causality. introduction: acute kidney injury (aki) is associated with high mortality. the risk increases with severity of aki. our aim was to identify risk factors for development and subsequent progression of aki in critically ill patients. methods: we analysed 2525 patients without end-stage renal disease who were admitted to the icu in a tertiary care centre between january 2014 to december 2016 and did not have aki on admission. we identified risk factors for development and non-recovery of aki as defined by the kdigo criteria. results: the incidence of new aki in 7 days was 33% (aki i 42%, aki ii 35%, aki iii 23%). multivariate analysis revealed bmi, sofa score, chronic kidney disease (ckd) and cumulative fluid balance as independent risk factors for development of aki. among patients who developed aki in icu, 69% had full renal recovery, 8% partial recovery and 23% had no recovery of renal function by day 7. aki patients without renal recovery in 7 days had significantly higher hospital mortality (60%) compared to the other groups. independent risk factors for non-recovery of renal function were ckd, mechanical ventilation, diuretic use and extreme fluid balance before and after first day of aki. (table 1) the association between cumulative fluid balance before aki and 48 hours after aki with risk of aki non-recovery are shown in figure 1 and 2. conclusions: aki is common and mortality is highest in those who do not recover renal function. cumulative fluid accumulation impacts chances of aki development and progression. (table 2 ). all were in r2. 5/8 (63%) of those with an admission ck>10000 had aki 2 or 3. all 12 (15%) patients who required crrt for aki associated with rm were at risk for aki regardless of initial ck: vascular surgery (4/12), multi-organ dysfunction (7/12), and/or pre-existing renal disease (3/12). conclusions: raised ck is common in icu but its cause is multi factorial thus an isolated measure >5000 does not require immediate high output treatment for rm aki. aki is more common in patients who have more than 1 ck>5000 on 2 sequential days or those whose first ck was >10000 as rm may be contributing. a single ck>5000 in patients with a clear reason to develop rm should also start treatment. surgical outcomes of end-stage kidney disease patients who underwent major surgery p petchmak 1 , y wongmahisorn 1 , k trongtrakul 2 introduction: acute kidney injury (aki) occurs in more than 40% of successfully resuscitated out-of-hospital cardiac arrest patients treated with targeted temperature management (ttm) [1] . the effect of the duration of cooling on aki has not been well studied. in this post-hoc analysis of the tth48 randomized controlled trial that compared 24 vs 48-hours of ttm (33°c) after cardiac arrest [2] , we studied the impact of ttm length on the development of aki. fig. 1 . duration of ttm had a significant impact on the development of creatinine values during the first 7 days in the icu, p<0.05. this was primarily driven by an increase in creatinine during rewarming on day 2 for the 24hour and day 3 for the 48-hour group (fig 2) . conclusions: in a trial of 24 vs 48 hours of ttm after out-of-hospital cardiac arrest, the length of ttm did not affect the incidence of aki. fig. 2 (abstract p287) . creatinine over time patients [1] , but there are no published data on longer-term renal outcomes in adult patients. the purpose of this study was to assess longer-term trends in serum creatinine in this cohort. methods: a retrospective study was conducted of all patients admitted to an adult regional referral centre for ecmo at a uk university hospital between 2010 and 2016. those who survived for >12 months were included. demographics, baseline serum creatinine, presence of aki during icu admission, and serum creatinine at hospital discharge were determined. serum creatinine and dependence on renal replacement therapy (rrt) were assessed at 6 and 12 months post ecmo. results: 13 patients had a complete (or near-complete) data-set available. the mean age was 45.5 years, 38% of whom were male. 8/13 had aki during their critical care admission. none were dependent on rrt at 6 or 12 months post ecmo. most patients had lower serum creatinine results at hospital discharge compared to their pre-hospitalisation baseline, but creatinine concentrations at 6 and 12 months post ecmo tended to be higher than at hospital discharge ( figure 1) . conclusions: in this cohort of ecmo patients who were discharged from hospital alive, serum creatinine tended to be lower at hospital discharge compared to baseline and rose again in the following 12 months. decreased creatinine production due to deconditioning and muscle wasting may offer a biological rationale for the lower creatinine results at hospital discharge [2] . therefore, caution should be exercised in the use of serum creatinine at hospital discharge to assess renal dysfunction -further research is warranted. introduction: aki complicates more than half of icu admissions [1, 2] and is associated with development of chronic kidney disease (ckd), need for renal replacement therapy (rrt) and increased mortality [3] . we prospectively evaluated all icu admissions during a one-year period in order to determine incidence, etiology and timing of aki as well relevant clinical outcomes. methods: prospective observational study of all patients admitted from jan to dec 2017 to a multidisciplinary icu in greece. patients with end-stage renal disease and anticipated icu stay less than 24 hrs were excluded. aki diagnosis and classification was based on kdigo criteria [4] . lowest creatinine level within 3 months before admission or first creatinine after icu admission served as reference. (fig 1) . conclusions: although aki alert does not include urine output criterion or aki risk factors, it remains a helpful tool to point out patients with aki. education and diagnostic algorithms are still needed to early diagnose and treat aki patients. influence of severity of illness on urinary neutrophil gelatinaseassociated lipocalin in critically ill patients: a prospective observational study c mitaka, c ishibashi, i kawagoe, d satoh, e inada untendo university, anesthesiology and pain medicine, tokyo, japan critical care 2019, 23(suppl 2):p291 introduction: neutrophil gelatinase-associated lipocalin (ngal) is a diagnostic marker for acute kidney injury (aki). ngal expression is highly induced not only in kidney injury, but also in epithelial inflammation of intestine, bacterial infection, and cancer. however, the relationship between ungal and severity of critically ill patients has not been well understood. the purpose of this study was to elucidate whether ungal is associated with severity of illness and organ failure in critically ill patients. methods: we prospectively enrolled patients with sepsis (n=34) and patients who underwent esophagectomy with gastric reconstruction for esophageal cancer (n=39). sepsis was defined according to sepsis-3. ungal levels were measured on icu day 1, 2, 3, 4 and 7. ungal levels and aki rate in patients with sepsis were compared with those in patients who underwent esophagectomy. aki was defined according to kdigo. acute physiology and chronic health evaluation (apache) ii score and sequential organ failure assessment (sofa) score were calculated. results: median ungal level (413 ng/mg creatinine) was significantly higher in patients with sepsis than that (26 ng/mg creatinine) in patients who underwent esophagectomy on day 1. median apache ii score and median sofa score in patients with sepsis were significantly higher than those in patients who underwent esophagectomy. four patients with sepsis developed aki, and 3 out of them underwent continuous renal replacement therapy, whereas no patients who underwent esophagectomy developed aki. ungal levels were positively correlated with apache ii score and sofa score in patients with sepsis. ungal levels were remarkably elevated (> 4000 ng/mg creatinine) in urinary tract infection (n=3), loops enteritis (n=1), and obstructive jaundice due to cholangiocarcinoma (n=1). conclusions: these findings suggest that ungal level is associated with severity of illness and organ failure in patients with sepsis. ungal levels might be influenced by severity of illness and inflammation. to assess the quality of the course 15 us renal images had to be evaluated in "post-renal obstruction" (p-ro) or "no p-ro". the rate of correctness (roc farius ) was determined. in 2018 we, once again, contacted the students to attend a web-based online "follow-up". this online survey was created with "google formular". 15 new and unknown us images were presented and rated in "p-ro" or "no p-ro" (roc fup introduction: septic-induced kidney injury worsen the patient's prognosis [1] . renal resistance index (rri) is correlated with an increased mortality in septic patients [2] . the aim of this study was to describe the evolution of rri in a rat sepsis model. methods: the local ethics committee approved the study (apa-fis#9385-2016113016181432). sepsis was induced in 3-month-old male rats by caecal ligation and puncture (clp) [3] . the rri was assessed before and 24h after clp by pulse doppler on the left renal artery (rri=(peak systolic velocityend diastolic peak)/ peak systolic values expressed as % per column. abbreviations in alphabetical order: aki acute kidney injury; akin acute kidney injury network definition; ckd chronic kidney disease. there were statistical differences between subgroups with and without aki for the subgroups of patients with previous ckd (p = 0.010*), sepsis at admission (p = 0.031**), hypotension (p= 0.003***) fig. 1 (abstract p290b) . target comparing accuracy and precision of aki alert and actual aki diagnoses velocity) (fig 1) . rri were compared by a paired wilcoxon test (r software v.3.3.4). a p value < 0.05 was considered significant. results: 14 rats were included. 24 hours after sepsis induction, all rats were in septic shock with cardiac dysfunction. the rri increased after sepsis induction compared to baseline (0.61 ± 0.03 vs 0.66 ± 0.02, p<0.05) and mean renal artery velocity decreased (11.8 ± 1.41 vs 7.7 ± 0.94, p<0.05) (fig 2) . systolic and diastolic peaks velocity of the renal artery were unchanged. conclusions: sepsis induced changes in rri and mean velocity on the left renal artery whereas no changes in systolic or diastolic velocities were seen. these results are consistent with available clinical datas. the rri could be an additional tool to assess renal failure in septic rats. further studies are needed to confirm the validity of this marker during sepsis. kidney failure is one of the most common organ dysfunction during sepsis. the rri could be an additional tool in small animals to assess the effects of potential therapeutic targets on renal function induced by sepsis. (fig 2) . the egfr improved more with the heparin group (53% vs 48%; p=0.21) (fig 1) . interruptions of the filter circuit were as expected less with the citrate group (144mins vs 45mins; p=0.17). finally, inotropic requirements increased following therapy interruptions, more so with patients receiving citrate (7.2% vs 14.5%; p=0.4). conclusions: our analysis suggests that using citrate anticoagulation for rrt results in a monitoring cost saving of approximately £9 per 24 hours, alongside the other conferred savings previously reported. furthermore, results demonstrate the efficacies of both systems are similar in the initial 24 hours, although there is a suggestion that heparin systems improves renal parameters more quickly. finally, interruptions and 'filter downtime' caused an increase in the patient's inotropic requirements, however results suggestive that this is greater in the citrate group. mmol/l respectively. demographic characteristics of the study group and the main parameters of the procedure were presented in fig 1. conclusions: regional citrate is a safe and effective anticoagulation method for crrt in children, when it is applied following a protocol. it significantly prolongs circuit survival time and thereby should increase crrt efficiency. we did not find any serious adverse effects of regional citrate anticoagulation. -5) , deceased at 1 year n=67 (14%). the mdrd trend is more indicative than creatinine of decline of renal function in the post operative period (fig 1) . crrt was used in 14.4% (69 pts) and was associated to a greater los and mortality (fig 2) . preoperative bilirubin, bun and creatinine are among the greatest risk factors for its use ( table 2 . at 1 year follow up n=6 pts (1.5%) were on hemodialysis. conclusions: aki requiring crrt in after lt is associated with higher mortality and los. identify patients at risk and adopt preventive strategies in the perioperative period is mandatory. introduction: we developed a new co2 removal system, which has a high efficiency of co2 removal at a low blood flow. to evaluate this system, we conducted in vivo studies using experimental swine model. methods: six anesthetized and mechanically ventilated healthy swine were connected to the new system which is comprised of acid infusion, membrane lung, continuous hemodiafiltration and alkaline infusion. in vivo experiments consist of four protocols of one hour; baseline= hemodiafiltration only (no o2 gas flow of membrane lung); membrane lung = "baseline" plus o2 gas flow of membrane lung; "acid infusion" = "membrane lung" plus continuous acid infusion; "final protocol" = "acid infusion" plus continuous alkaline infusion. we provided an interval period of one hour between each protocol. we changed the respiratory rate of the mechanical ventilation to maintain pco2 at 50-55 mmhg during the experiment. results: the amount of co2 eliminated by the membrane lung (vco2ml) significantly increased by 1.6 times in the acid infusion protocol and our final protocol compared to the conventional membrane lung protocol, while there was statistically no significant difference observed in the levels of ph, hco3-, and base excess between each study protocol. minute ventilation in the "final protocol" significantly decreased by 0.5 times compared with the hemodiafiltration only protocol (p <0.0001), the membrane lung (p=0.0006) and acid infusion protocol (p=0.0017). we developed a novel ecco2r system which efficiently removed co2 and is easy-to-setup to permit clinical application. this new system significantly reduced minute ventilation, while maintaining acid-base balance within the normal range. further studies are needed for the clinical application of this easy setup system comprising of the materials typically used in a clinical setting. , and psychomotor agitation (10%) while the most common symptoms of hypertensive emergency were chest pain (30.4%), dyspnea (28.6%) and neurological deficit (29%). clinical manifestations of hypertensive emergency were cerebral infarction (26.4%), acute pulmonary edema (24.8%), hypertensive encephalopathy (20.6%), acute coronary syndromes (20.4%), cerebral hemorrhage (4,.5%), congestive heart failure (12%), aortic dissection (0.8%), preeclampsia and eclampsia (2.6%). conclusions: hypertensive urgencies were significantly more common than emergencies (78.1% vs. 21.9%, p<0.0001). there was no statistically significant difference in the number of patients with hypertensive urgency and emergency in relation to age, gender, duration of hypertension, except for the 60-69 age group, where urgency was statistically significantly higher (p=0.0204). introduction: emergency department (ed) crowding is a major public health concern. it delays treatment and possible icu admission, which can negatively affect patient outcomes. the aim of this study was to investigate whether ed to icu time (ed-icu time) is associated with icu and hospital mortality. methods: we conducted an observational cohort study using data from the dutch nice registry. adult patients admitted to the icu directly from the ed in 6 academic centers, between 2009 and 2016, were eligible for inclusion. for these patients nice data were retrospectively extended with ed admission date and time. ed-icu time was divided in quintiles. the data were analyzed using a logistic regression model. we estimated crude and adjusted (for disease severity; apache iv probability) odds ratios of mortality for ed-icu time. in addition, we assessed whether the apache iv probability (divided into quartiles) modified the effect of ed-icu time on mortality. results: a total of 14,787 patients were included. baseline characteristics are shown in table 1 . the median ed-icu time was 2.0 [iqr 1.3-3.3] hours. icu and hospital mortality were 18.1 and 22.2%, respectively. the crude data showed that an increased ed-icu time was associated with a decreased icu and hospital mortality (both p<0.001, figure 1a ). however, after adjustment for disease severity, an increased ed-icu time was independently associated with increased hospital mortality (p<0.002, figure 1b ). figure 2 shows that only in the sickest patients (apache iv probability >60.9%), the association between increased ed-icu time and hospital mortality was significant (p=0.019, figure 2d ). we found similar results with respect to icu mortality. conclusions: this study shows that a prolonged ed-icu time is associated with increased icu and hospital mortality in patients with higher apache iv probabilities. strategies aiming at rapid identification and transfer of the sickest patients to the icu might reduce inhospital mortality. reliability and validity of the salomon algorithm: 5-year experience of nurse telephone triage for out-of-hours primary care calls e brasseur, a gilbert, a ghuysen, v d´orio chu liege, emergency departement, liège, belgium critical care 2019, 23(suppl 2):p308 introduction: due to the persistent primary care physicians (pcp) shortage and their substantial increased workload, the organization of pcp calls during out-of-hours periods has been under debate. the salomon (système algorithmique liégeois d'orientation pour la médecine omnipraticienne nocturne) algorithm is an original nursing telephone triage tool allowing to dispatch patients to the best level of care according to their conditions [1] . we aimed to test its reliability and validity under real life conditions. methods: this was a 5-year retrospective study. out-of-hours pc calls were triaged into 4 categories according to the level of care needed: emergency medical services (amu), emergency department visit (maph), urgent pcp visit (upcp), delayed pcp visit (dpcp). data recorded included patients' triage category, resources and potential redirections. more precisely, patients included into the upcp + dpcp cohort were classified under-triaged if they had to be redirected to an emergency department. patients from the amu+maph cohort were considered over-triaged if they did not spend at least 3 resources, 1 emergency specific treatment or any hospitalization. results: 10207 calls were actually triaged using the salomon tool, of which 19.1% were classified as amu, 15.7% as maph, 62.8% as upcp and 2.1% as dpcp (fig 1) . as concerns the amu+maph cohort, the triage was appropriate in 85.3% of the calls, with an over-triage rate of 14.7%. as concerns the upcp + dpcp cohort, 97.1% of the calls were accurately triaged and only 2.9% were under-triaged. sal-omon sensitivity reached 93.9% and its specificity 92.5%. these results indicate that salomon algorithm is a reliable and valid nurse telephone triage tool that has the potential to improve the organization of pcp out-of-hours work. introduction: inappropriate visits to the emergency department (ed), such as patients manageable by a primary care physician (pcp), have been reported to play some role in the ed crowding [1] . indeed, non-urgent patients directly managed by pcps could reduce ed workload [2] . triage and diversion to alternative care facilities, eventually co-located within the ed, could offer a solution [3] provided fig. 1 (abstract p308) . distribution of different calls, their triage using the salomon algorithm and the inappropriate triages (over and undertriages) based on the preselected criteria the availability of a reliable triage tool for their early identification. we created a new triage algorithm, persee (protocoles d'evaluation pour la réorientation vers un service efficient extrahospitalier) and tested its feasibility, performance and safety. methods: after initial evaluation with a 5-level ed triage scale [4] , ambulatory self-referred patients classified as level 3 or below benefited from a simulated triage with persee identifying 2 categories of patients: ed ambulatory patients and primary care (pc) treatable patients. we collected patients data and resources. patients requiring less than 3 resources, no specific emergency treatment and no hospitalization were considered as manageable in a pc facility. results: 1999 patients were included in the study of whom 66.9% were self-referred (fig 1) . among those self-referrals, 58.6% were triaged as level 3 or below. 38.9% patients were triaged as ambulatory patients of whom 10% were as pc treatable. we noted a redirection rate of 10% of the global visits or 15% of the self-referrals, an error rate of 7%, a sensitivity of 24.6% and specificity of 97.6%. conclusions: using advanced ed triage algorithm in addition to classical ed triage might offer interesting perspectives to safely divert self-referrals to pc facilities and, potentially, reduce ed workload. introduction: generally, prehospital medical provider should minimize staying prehospital scene to reach the patient to definitive care as soon as possible in prehospital medical activity. in addition, some textbook and report saids that medical provider minimize the number of procedure or limit minimum requirement procedure because unnecessary procedure may extend the staying time in prehospital scene. however, there are few studies evaluating this hypothesis and that this "extension is significant or not. therefore, we perform this study. methods: we evaluated the operated air ambulance(doctor-heli) case from 1st april 2015 to 31st march 2018, in gifu university hospital using our mission record. we evaluated about time from landing to ready for taking off(activity time), operation doctor, mission category (i.e. trauma), number of procedure in the each activity and work load. we only focused on prehospital care and exclude transportation from hospital to hospital . in addition, we exclude the case which are not suitable for analysis. results: 1299 cases were operated in these period. 511 cases were suitable for analysis. average activity time in prehospital scene was14.32±6.09. there was weak correlation between the number of procedure and activity time. (r=0.3452) the length of the activity time did not depend on mission category. if the doctor perform 6 and over procedures, staying time was 7minutes longer, this was significantly longer than that of under 5 and under procedures. conclusions: we confirmed that we have to minimize the number of procedure or limit minimum requirement procedure in prehospital scene. and our result suggest we may have to limit appropriate number of procedures. introduction: organ failure is a critical condition, but the prevalence is largely unknown among unselected emergency department (ed) patients. knowledge of demographics and risk factors could improve identification, quality of treatment, and thereby improve the prognosis. the aim was to describe prevalence and all-cause mortality of organ failure upon arrival to the ed. methods: this was a cohort-study at the ed at odense university hospital, denmark, from april 1, 2012 to march 31, 2015. we included all adult patients, except minor trauma. organ failure was defined as a modified sofa-score > 2 within six possible organ systems: cerebral, circulatory, renal, respiratory, hepatic, and coagulation. the first recorded vital, and laboratory values were extracted from the electronic patient files. primary outcome was prevalence of organ failure; secondary outcomes were 0-7-day and 8-365-day mortality. results: of 70,399 contacts 52.1% were female and median age 62 (iqr 42-77) years. the prevalence of new organ failure was 11.8%, individual organ failures; respiratory 4.9%, circulatory 3.0%, cerebral 2.3%, renal 1.7%, hepatic 1.4%, and coagulation 0.6%. the 0-7-day and 8-365-day all-cause mortality was 11.7% (95% ci: 10.9-12.6) and 19.3% (95% ci: 18.2-20.4), respectively, if the patient had new organ failures at first contact in the observation period, compared to 1.4% (95% ci: 1.3-1.5) and 6.6% (95% ci: 6.4-6.9) for patients without. seven-day mortality ranged from hepatic failure, 5.6% (95% ci: 4.0-7.5) to cerebral failure, 33.3% (95% ci: 30.4-36.2), and the 8-365-day mortality from cerebral failure, 13.2% (95% ci: 11.2-15.4 to renal failure, 26.7% (95% ci: 23.6-29.9). conclusions: new organ failure is frequent and serious, with a prevalence of 11.8% and a one-year mortality of 31% with wide variation according to type of organ failure. results: we proceeded to a descriptive study that showed that 39% of patients were male and 62% of them were female with a sex ratio of 0.62.the average age of patients was 34 years old and ranged between 15 and 90 years old.we found that 59 patients of our population had medical background, dominated by diabetes in 12 cases, high blood pressure in 8 cases and asthma in 6 cases.the results also showed that 29.5% of patients had a history of abdominal surgery while 13% of them had history of other types of surgery.the patients were oriented according to their severity level as following: 21% care unit of emergency department, 1.5% close monitoring room .the vaspi score was ranged between 1 and 10 with an average of 4±2. it was higher than 5 in 32.5% of cases.the results of physical examination found an isolated pain in 67,5% of cases, a reactionnal pain syndrom in15% of cases, a peritoneal syndrome in 12% of cases and an occlusive syndrome in 7% of cases.the final diagnosis was mostly represented by the following causes: 45.5% of gastroenteritis 11.5% of constipation and 9% of ulcer disease.the final orientation of patients according to the diagnosis led to hospitalization in 21% of cases and to outpatient clinic in13% of cases while 66% of them did not need any more care. conclusions: appropriate diagnostic evaluation and decision for or against hospitalization is a challenge in the patient who comes to the emergency department with acute abdominal pain it need an adequate evaluation and management. introduction: we assessed patients' impressions of a selfadministrated automated history-taking device (tablet) to gather information concerning emergency department (ed) patients prior to physicians' contact. the quality of communication was compared with the traditional history-taking. methods: the algorithm content was developed by two emergency physicians and two emergency nurses through an iterative process. item-content validity index (i-cvi) was measured by five experts rating the relevance of each item (from 1: not relevant to 4: highly relevant) [1] . next, quality control was realized by research team. to assess the feasibility, we used a computerized randomization. low acuity, ambulatory adult patients presenting to the ed were assigned either to a control group (cg, n=65) beneficiating form a traditional history-taking process or to the experimental group (eg, n=66) assigned to use the tablet with further history-taking by the ed physician. communication was analyzed by the health communication assessment tool [2] and satisfaction assessed by questionnaires. results: after two rounds, validity was excellent for each item (i-cvi > 0.8). the universal agreement method was of 0.9. refusals (n=11) to participate were analyzed: they fear using an electronic device or the experimentation. content satisfaction revealed that 93% of patients understood the questions. 94% of patients indicated that the device was easy to hold and use. medical communication was not affected by the device (p=0.15). we noticed that, among the subsections, physicians significantly introduced themselves better in the eg (p=0.04). conclusions: in this feasibility study, patients were highly satisfied. the use of a self-administrated automated history-taking device does not generate miscommunications and allow physicians better introduce themselves. . a positive point we have established is the possibility for the detorsion of a twisted retention ovarian cyst after its transvaginal aspiration. we used this method only in cases when the onset of torsion did not exceed 4 hours. 28.5% of all emergency conditions associated with retention cysts were recurred by conservative therapy, and 50.4% of patients with the retention cysts rupture were successfully treated in this way. conservative management is possible in the case of a small loss of blood (up to 150.0-200.0 ml), hemodynamic stability and the absence of signs of continuing bleeding. the detorsion and resection of the cyst when torsion is not more than 180°and even longer than 4 hours, in most cases did not reveal necrosis in the appendages. conclusions: improvement of organs of preservation and reproduction in women. criteria for admission to an intensive care unit of a tertiary hospital: analysis of the decisions of the outreach intensivist and 28 day in-hospital mortality introduction: the aim of this study was the analysis of icu admission criteria and evaluation of in-hospital mortality of patients assessed by our critical care outreach team. criteria for admission to the icu should be defined to identify the patients most likely to benefit from icu admission. this triage process is complex, associated with several factors, including clinical characteristics of the patients, but also subjective factors because it depends on the judgment of the intensivist who decides whether to admit or not the patient and is obviously conditioned to the structure and size of the icu. methods: the outreach intensivist records the patient observation in a form with 5 questions (reversibility of acute illness, objective of admission in icu, comorbidities, functional reserve and intuitive prognosis of the doctor). analysis of 6 months (january 1 through june 30, 2018) of admission decisions in icu, mean delay, icu mortality, and 28 day in-hospital mortality (28hm). results: the intervention of the intensivist in "outreach" was requested on 855 occasions. the main places of observation were the emergency room (40.7%) and the wards (40.4%). the 28hm increased with the degree of comorbidity decompensation. functional reserve also influenced 28hm, reaching 42.2% in partially dependent patients and 63.4% in totally dependent patients. there was agreement between the mortality and the physician´s intuitive prognosis in 71% of the cases. conclusions: a larger sample is needed to draw sustainable conclusions, however, the evaluation algorithm correlated well with hospital mortality. decompensated comorbidities and low functional reserve have a negative impact on prognosis, regardless of acute disease. there was agreement between mortality and the physician´s intuitive prognosis. electrochemical methods for diagnosing the severity of patients with multiple trauma introduction: multiple trauma is one of the leading causes of death worldwide [1] . timely diagnosis and treatment is crucial in this state. one of the promising areas is the use of new electrochemical methods they are simple, flexible, efficient and of low cost. among these methods, attention is paid to the measurement of open circuit potential (ocp) of the platinum electrode and cyclic voltammetry (cva). the ocp is a reflection of the balance of pro-and antioxidants in the body, and the amount of electricity (q) determined by cva is proportional to the antioxidant activity of the biological environment. methods: a total of 51 patients with severe multiple trauma (38.7 ±13.5 y.o., 33 men and 18 women) were enrolled; apacheii 17.4±7.2; iss 40.9±8.3; blood loss 2356±997 ml. blood plasma was collected from patients. measurement of the ocp was carried out according to [2] , cva analysis -according to the original method on a platinum working electrode. results: a shift in the ocp towards more positive potential values (fig. 1) , while the antioxidant activity of blood plasma decreased (fig. 2) . a more significant change of ocp, as compared to the q values, may indicate not only a deficiency in the components of the antioxidant defense system of the body, but also an increase in the concentration of prooxidants (e.g., reactive oxygen species), which are involved in oxidative stress. who underwent surgical fixation). information was collected from tarn, icnarc and surgical team databases. our primary outcome was itu resource utilisation (itu los and mechanical ventilation days). our secondary outcomes were morbidity and mortality (hospital los, infection burden, inotrope use and death before discharge). data was collected and analysed in microsoft excel and r. results: 691 patients were included (group 1 = 246, group 2 = 414, group 3 = 31). mortality was significantly higher when comparing the post 2014 groups undergoing conservative (12%, 51/414) vs. surgical fixation (0%, 0/31), p-value = 0.026. regarding potential temporal changes, there was no significant difference in mortality between the non surgical groups; pre-2014 (group 1: 28/218) and post 2014 (group 2), p-value 0.683. group 3 patients did spend more time mechanically ventilated (p-value 0.019) and used more antimicrobials (p-value 0.032) ( table 1) . conclusions: patients undergoing surgical rib fixation at the rlh had significantly improved mortality with more days spent mechanically ventilated. pilot study on ultrasound evaluation of epiglottis thickness in normal adult a osman 1 introduction: as the prevalence of epiglottitis is decreasing due to immunization, the difficulty in early detection remained. the aim of this study is to determine the thickness of epiglottis in normal adult with the utilization of bedside ultrasound. methods: this was a prospective observational study of convenience selection among healthy staff in emergency department, university malaya medical centre. the identification and measurement of epiglottis were performed using a 10mhz linear transducer by trained emergency physicians and registrars in em. subjects were scanned in either standing or upright seated position with the neck neutral or mildly extended. the epiglottis, thyroid cartilage and vocal cord were visualized and the epiglottis anteroposterior(ap) diameter was measured. difference in categorical parameters were analyzed by independent-sample t-test. the relationship between height, weight and epiglottic size was analyzed using pearson's correlation. results: fifty-six subjects were analyzed with 25 males and 31 females age ranging from 18 to 50 years old. the epiglottis ap diameter ranged from 0.15cm to 0.23cm, with average of 0.18cm. there was significant difference in epiglottic ap diameter between male (m=0.19cm, sd=0.19) and female (m=0.17cm, sd=0.12; t(54)=5.27, p=<0.001, twotailed). moderate positive correlation between height and epiglottic ap diameter (r=0.49) and weight (r=0.33) was documented. conclusions: our study demonstrated the identification and visualization of epiglottis was feasible and easy with the use of bedside upper airway ultrasonography. there was a little variation in the ap diameter of epiglottis in adults. indoor vs. outdoor occurrence in mortality of accidental hypothermia in japan y fujimoto 1 , t matsuyama 2 , k takashina introduction: the impact of location of accidental hypothermia (ah) occurrence has not been sufficiently investigated so far. thus we aimed to evaluate the differences between indoor and outdoor occurrence about baselines, occurrence place, mortality, and length of icu stay and hospital stay. methods: this was a multicenter retrospective study of patients with a body temperature ≤35°c taken to the emergency department of 12 hospitals in japan between april 2011 and march 2016. we divided the included patients into the following two group according to the location of occurrence of ah (indoor versus outdoor). the primary outcome of this study was in-hospital death. secondary outcomes were the length of icu stay, and hospital stay. results: a total of 537 patients were enrolled in our hypothermia database. there were 119 and 418 patients with the outdoor and indoor occurrence. the indoor group was older (71 versus 81.5 years-old, p<0.001) and worse in adl than the outdoor group. the proportion of in-hospital death was higher in the indoor group than the outdoor group (28.2% [118/418] versus 10.9% [13/119], p<0.001). the multivariable logistic regression analysis demonstrated that adjusted odds ratio of the indoor group over the outdoor group was 2.48 (95%ci; 1.18 to 5.17) ( table 1) . as for secondary outcomes, both of the length of icu stay and hospital stay in survivors were longer in the indoor group than the outdoor group. conclusions: our multicenter study indicated that indoor occurrence hypothermia accounts for about 78% of the total in this study, and the proportion of in-hospital death was higher in the indoor group. we have to raise an alert over the indoor onset accidental hypothermia and need to take countermeasures for prevention and early recognition of ah in indoor location. conclusions: during acute asthmatic attack, arterial hyperlactatemia is frequently present at ed arrival. nevertheless, the plasma lactate level was no significant difference between ed admission and 2 hr after treatment. the introduction: this is a case series of traumatic aortic injury (tai) which was diagnosed by transesophageal echocardiography (tee) in the emergency department. the number of patients with blunt thoracic aorta injury arriving at emergency department is on the rise and survival rate is time-dependent on early diagnosis. tee offers several advantages over transthorasic echocardiography (tte) including reliability, continuous image acquisition and superior image quality. methods: all trauma patients who presented to emergency department from 1st january 2017 until 30th november 2018 at hospital raja permaisuri bainun, perak, malaysia with suspected tai were evaluated with transesophageal echocardiography. over the 2 years period, tee was performed in 30 patients. 6 patients had positive findings suggestive of tai. results: the first case was an old lady who presented after a deceleration injury in a car accident. tee was performed due to hemodynamic instability and found an intimal flap along the ascending aorta. the second case, a stanford type a (figure 1) , was complicated with pericardial tamponade. the intimal flap was visualised from the aortic arch extending to the descending aorta by tee. the third case was a case of intramural haematoma involving distal aortic arch extending to the descending aorta which survived until corrective surgery. in the fourth case, tee revealed a motion artefact which mimicked an intimal flap in the ascending aorta. in the fifth case, tee showed intimal flap at aortic isthmus which was not detected by tte. in the last case, a traumatic aortic dissection was complicated by aortic regurgitation (figure 2) . conclusions: tee can be a useful point of care tool use by emergency and critical care physicians for early diagnosis of blunt traumatic aorta injury. introduction: reboa is an endovascular intervention intended to preserve central perfusion in the context of shock due to noncompressible torso haemorrhage. more so, it is less invasive than the traditional approach of resuscitative thoracotomy (rt) and aortic crossclamping. though its use dates back to the korean war, it has not been widely adopted in trauma management, as evidence demonstrating clear benefit compared with conventional rt is lacking [1] . we aimed to evaluate feasibility, outcomes and complications after reboa for haemorrhagic shock and traumatic cardiac arrest. methods: we performed a systematic literature review, searching scopus and pubmed databases using relevant terms (july 2018). we included studies enrolling patients with haemorrhagic shock or cardiac arrest after civilian trauma who had undergone reboa and reported hospital mortality (our primary outcome). abstract-only studies and single-patient case reports were excluded. we collated and analysed data using review manager v5.3. the newcastle-ottawa scale was used to assess risk of bias. results: sixteen in-hospital studies met inclusion criteria (n=2034). ten were case series and six were cohort studies comparing reboa outcomes with those of rt. there were wide differences between studies' inclusion criteria, case-mix (including cardiac arrest), injury severity, insertion details, and reported outcomes. overall hospital mortality post-reboa was 61.4%. meta-analysis of cohort studies indicated notably lower mortality in patients undergoing reboa (or 0.41, 0.32-0.54) than rt with low statistical heterogeneity between studies (i 2 = 0%), shown in fig 1. conclusions: whilst our findings are limited by methodological differences and biases in the included studies, almost 40% of patients undergoing reboa for haemorrhagic shock and/or cardiac arrest survived to discharge. furthermore, reboa appeared to offer a consistent mortality benefit compared with rt. introduction: trauma related coagulopathy remains a primary contributor to mortality on battlefields and in civilian trauma centres. fibrinogen is considered to be the first to drop below critical level and correspondingly compromised coagulation process. however, it is unclear if fibrinogen concentrate at a very early stage is feasible and effective to prevent from coagulopathy. methods: a total of 66 acutely injured patients in austria, germany and czech republic were screened and enrolled in this controlled, prospective randomized placebo controlled double blinded multicentre and multinational trial. upon the completion of randomization, fibrinogen concentrate (50 mg/kg, fgtw©, lfb france) or placebo was reconstituted and given to the patients at the scene or during helicopter transportation from the scene to nearby hospitals. blood samples were taken at baseline (scene of accident before study drug administration), at the emergency room, three hours, nine hours and twentyfour hours after admission to the hospital as well as after three and seven days after admission, for measurements of blood gases and coagulation, together with clinical data and outcome records. results: the demographic and injury characteristics and the estimated blood loss, iss, and gcs at the scene were similar in both groups. in the placebo group, fibrinogen concentration dropped from 200 mg/dl at injury site to 160 mg/dl () at er admission and clot stability reduced from 13.5 mm (4, 21 mm) to 10 mm (p=0.013) (fig 1) . fibrinogen concentrate administration prevented the drop of fibrinogen level (baseline of 170 mg/dl to 210 mg/dl and improved clot stability from 13 mm at baseline to 16 mm at er. conclusions: pre-hospital administration of fibrinogen concentrate in traumatic bleeding patients is feasible and effective in preventing the development of coagulopathy. data from this study support the use of fibrinogen to prevent trauma related coagulopathy. fibrinogen concentrate vs cryoprecipitate in pseudomyxoma peritonei surgery: results from a prospective, randomised, controlled phase 2 study results: the per-protocol set included 43 pts (hfc, n=21; cryo, n=22). the mean total intraoperative dose of hfc was 6.5 g vs 4.1 pools of cryo (containing approx 8.8 g of fibrinogen). median duration of surgery was 7.7 h. overall haemostatic efficacy of hfc was non-inferior to cryo and was rated excellent or good for 100% of pts receiving hfc and cryo, with similar blood loss. intraoperatively, only red blood cells were transfused (median: 1 unit). intraoperative efficacy is shown in table 1 . infusions were initiated 0.4 h earlier with hfc than cryo due to faster product availability. preemptive hfc led to a greater mean increase vs cryo in fibtem a20 ( figure 1 ) and plasma fibrinogen (figure 2 ). there were 6 serious adverse events (saes) in the hfc group and 17 in the cryo group, including 7 thromboembolic events (tees; 2 deep vein thromboses, 5 pulmonary embolisms). no aes or saes were deemed related to the study drug. conclusions: hfc was efficacious for treatment of bleeding in pts undergoing surgery for pmp. no related aes and no tees occurred in pts treated with hfc. fig. 1 (abstract p326) . fib mcf t1 to t7 with 95% ci fig. 1 (abstract p327) . fibtem a20 prior to and following the preemptive dose of hfc/cryoprecipitate introduction: patients in the intensive care unit often suffer from thrombocytopenia. in dealing with this problem, we need to figure out not only the cause of thrombocytopenia but also the risk of bleeding. however, there is no reliable method for evaluating bleeding risk. methods: in this preliminary study, four thrombocytopenic patients who required platelet transfusion before undergoing invasive procedure were enrolled. written informed consent was obtained from all patients for participation in the study. bleeding was graded using the who bleeding scale. thrombogenic activity was evaluated using total thrombus-formation analysis system (t-tas), rotational thromboelastometry (rotem), and multiplate impedance aggregometry. for t-tas analysis, we prepared a novel microchip, named hd chip, which is suited for analyzing low platelet samples rather than those with normal platelet counts. , key patient groups in which it was wasted and the use of standard laboratory tests (slts) to guide its use. the purpose was to assess the potential benefit a point of care viscoelastic haemostatic assay (vha) could have on ffp transfusion and waste. the national blood transfusion committee and nhs blood and transplant committee have published data showing that up to 25% of ffp is transfused inappropriately [1] . methods: blood bank data was obtained evaluating haemorrhaging patients in whom ffp was requested across a nine-month period in 2018. patient bleeds were categorised by speciality. the mean time ffp dispensed and wasted was recorded, as were timings of slt requests. where available, the inr result was recorded. results: 66 patients were identified. 74 transfusions were requested. table 1 shows that the highest transfusion requirements are for acute medical emergencies and major trauma. 70% of transfusion were surgical specialities, it would be expected that these patients would have anaesthetic or critical care input. 242 units were wasted. acute medical emergencies wasted the highest amount of ffp (82 units). table 2 demonstrates that 29.7% of transfusions had an inr available one hour prior to ffp being dispensed. conclusions: we conclude that use of slts to guide ffp transfusion is low. this suggests transfusion decisions are being made clinically. a point of care vha could give treating physicians better access to timely haemostatic data. introduction: we developed the process for the out-of-hospital packed red blood cells (prbc) transfusion in the hems of castilla-la mancha clm according to criteria of medical indications, security, monitoring and tracking. haemorrhage is a preventable cause of death among population suffering accidents or bleeding injuries in regions with low population density where health services should reach people in remote areas. hems of clm is the first out-ofhospital emergency service in spain that provides prbc transfusion there where the accident takes place. this program has been developed jointly between hematologists of the center for transfusions ct and the hems team. methods: observational retrospective study with data collected from june 2014 to august 2018. the medical helicopter was provided with two prbc o rh(d) negative (fig 1) . shock index was selected as indication for transfusion. to achieve feasibility and preservation of the prbc it was established a prospective monitoring and microbiological culture for both groups: case group for the prbc kept in the hems and control group in the hospital (fig 2) . controls and comparison of hematologic analysis were performed immediately and 35 days after collection. statistics used spss 23.0 (signification p<0.05). results: 138 prbc were evaluated, 67 case -71 control. analyses were tested days 1 and 35 after collection. hemolysis was not observed. all cultures were negative. results obtained of the prbc after 35 days transported in the hems related to monitoring parameters were not different than those observed on prbc conserved in the ct. 35 prbc were transfused to 28 patients in out-of-hospital assistance. neither post-transfusional reactions or undesirable events have been registered. prbc units are changed every 30 days. conclusions: the process designed (collection, conservation, tracking and tests) to make prbc available in the medical helicopter has demonstrated to keep the standard conditions and properties to be transfused in critically ill patients out-of-hospital. outcomes in patients with a haematological malignancy admitted to a general intensive care unit a corner east sussex healthcare nhs trust, intensive care, eastbourne, united kingdom critical care 2019, 23(suppl 2):p331 introduction: recent published data have challenged the view that critically ill patients with a haematological malignancy have a poor prognosis [1] . reports have largely originated from tertiary centres. the aim of this audit was to evaluate the intensive care unit (icu), in hospital and one year mortality for a cohort of patients admitted to a mixed medical and surgical icu in a district general hospital. methods: details were obtained for all patients with a haematological malignancy admitted to eastbourne and hastings icu between march 2012 and august 2017. patient characteristics, type of malignancy, reason for admission, degree of organ support and survival rates at icu discharge, hospital discharge and 1 year postadmission were collected. results: 60 patients, 65% male, were identified. median (interquartile range, iqr) age was 68 (60-73) years. 55% had neutropenia. the commonest malignancies were acute leukaemia 43%, lymphoma 27% and myeloma 17%. reasons for admission were respiratory 48%, cardiac 18% and renal 10%. organ supports used were noradrenaline 68%, intubation and mechanical ventilation 42%, renal replacement therapy (rrt) 32% and dobutamine 10%. overall survival rates are shown in figure 1 . 7 patients were discharged from hospital following a period of mechanical ventilation. for these patients, median (range) age was 64 (26-72) years. all were male. median (iqr) time in hospital prior to admission was 0 (0-2) days, 7/7 patients required vasoactive support, 3/7 required rrt, median icu length of stay was 12 (3-25) days. 3/7 were admitted following surgery for an unrelated condition. to date, only 1/7 patient has survived 5 years post icu admission. conclusions: although survival rates were disappointing, particularly in those patients requiring mechanical ventilation, selected patients have the potential for a good outcome. these results outcomes have been presented to our haematology department to aid patient counselling. analyses. cox regression was used for the survival analysis. organ failure was defined as the occurrence of renal failure based on acute kidney injury network (akin)-creatinine or need for; vasopressors, invasive ventilation or continuous renal replacement therapy (crrt) the first 28 days after admission. length of stay was only analysed in survivors. results: the study included 3585 unique patients. prolonged aptt was associated with mortality with a 95% confidence interval (ci) of hazard ratio 1.001-1.010. prolonged aptt correlated also with the occurrence of renal failure and the need for vasopressor and crrt with 95% ci of odds ratio (or) 1.009-1.028, 1.009-1.033 and 1.009-1.029 (fig 2) . increased pt-inr was associated with the need for vasopressors and invasive ventilation with 95% ci of or 1.138-2.056 and 1.151-1.871. both aptt and pt-inr correlated with length of stay with 95% ci of or 1.007-1.020 and 1.034-1.438. conclusions: activated partial thromboplastin time on admission to the icu is independently associated with mortality. both aptt and pt-inr are independently associated with length of stay and the need of organ support. all regression models were adjusted for saps 3 score which means that aptt prolongation and pt-inr increase on admission represent morbidity that is not accounted for in saps 3. introduction: the goal was to assess if daily venous thromboembolism (vte) assessment was being done in our critical care (cc) unit, and if not, what changes could be made. a mortality review showed the need for a dynamic vte assessment in cc patients, who are subject to daily changes influencing vte risk. a daily risk assessment was introduced, and a 'tab' on our clinical information system, metavision(r)(mv) was created. recently published national institute for health and care excellence guidelines on vte risk assessment in cc provided us cause to assess our compliance [1] . methods: data was collected from mv. review of daily vte assessment was made and a percentage completion of daily vteassessments was calculated per patient.interventions were done using standard improvement methods through pdsa cycles. results: baseline data, of 53 patients, was collected in july,2018.compliance with daily vte assessment was 51%. the results were presented at the clinical governance forum(cgf), and posters were displayed in cc. the second cycle, of 32 patients, was collected in october. compliance had increased to 68%.following discussion from presenting results at the cgf, the vte tool was appropriately modified.the responsibility of vte assessment was also shifted to becoming more shared, including all clinical staff, rather than mainly consultants. the third cycle, of 30 patients, was collected in november. compliance had increased to 80%.introducing a nursing care bundle with vte is in progress. conclusions: despite the identification of a risk in our clinical practice and the development of an appropriate it tool to facilitate improved practice, the advent of new national guidance revealed poor compliance with agreed standards. this shows the difficulties with achieving practice change in complex multiprofessional clinical environments. a sustained effort is required focusing on dissemination and engagement across the whole team. introduction: we describe the changes in anti factor xa (afxa) activity, thrombin generation and thromboelastography (teg) in critically ill patients with and without acute kidney injury (aki) following routine administration of tinzaparin as part of venous thromboembolism (vte) prophylaxis. methods: pilot prospective observational study. 18 patients divided into those with and without aki were administered tinzaparin by subcutaneous injection as per established local guidelines. 6 patients who did not receive tinzaparin were recruited as a 'control'. plasma afxa activity and thrombin generation were measured at intervals over a 24 hour period. teg parameters were collected at t0 and t24. results: afxa activity: results are shown in figure 1 . 3/18 patients failed to achieve a prophylactic afxa level of >0.2 at any point. 14/18 patients achieved a level of >0.2 however in all cases this was at the lower end of the prophylactic range and was achieved for only a short time (median 1.5 hours). 1/18 achieved a level of >0.2 for the whole 24h period. there was no difference between the aki and no aki groups. endogenous thrombin generation: there is no significant difference in thrombin generation between the aki and no aki groups. there is a significant decrease in thrombin generation between 0h and 5h (p<0.01) and a significant increase between 5h and 24h (p<0.01) (figure 2 ). there is no significant difference between 0h and 24h (p=0.90). teg: all teg parameters for all patients were within normal range conclusions: standard vte prophylactic dose tinzaparin rarely achieves an afxa range that has been suggested for vte prophylaxis. however, as assessed by thrombin generation, a hypo-coagulable state is generated in response to lmwh. there is no difference between critically ill patients with or without aki that would suggest the need for dose reduction in this context. 2 (abstract p334) . thrombin generation at 0h, 5h and 24h. t0 = time of tinzaparin administration, with the sample taken just prior to administration. patients from aki group shown with dotted line and from no aki shown with solid line 12% which takes the third place between cpb-associated complications . current data demonstrates the importance of researching of changes in haemostatic system in paediatric patiens after cpb. provided below data is an intermediate result of our research. methods: 39 patients in age up to 11 mohth 29 days (median age -5,5 months, youngest age -2 days after birth, oldest -11 months 29 days), who underwent cardiac surgery with cpb to treat congenital heart diseases, were enrolled in this study. all patients were divided into two groups: 1stwithout tc, 2ndwith tc. protein c (pc) and fibrin-monomer (fm) plasma levels were assessed in there points: before surgery, 24-hours and 72 hours after surgery. thrombotic cases were provided by doppler ultrasound or mri. results: thrombotic complications were diagnosed in 7 chidren (18%). between all tc ischemic strokes were diagnosed in 57% (4 cases), arterial thrombosis in 29% (2 cases), intracardiac thrombus in 14 % (1 cases). in group with tc fm-mean values in points 1,2 and 3 respectively were 9.62; 37 and 108 mcg/ml, meamwhile in group without thrombosis -7.5; 36.04 and 9.25 mcg/ml .pc-mean value in 1st groupwere 50; 56 and 76%, in the 2nd group -49; 52 and 39% respectively in the points 1, 2 and 3. statistically significant differences between groups in 3rd point (p<0.05) and correlation between pc and fm (r=-0.93; p<0.05) were detected. conclusions: cpb causes hypercoagulation with increasing of pc consumtion and fm level. moreover, cp associated with a high risk of tc on the 3rd day after cardiac surgery. further studies to investigate prognostic values of fm and pc in thrombosis are required. these studies would help to asses fm and pc as markers of tc and possibility of pc-prescribing for prevention and treatment of these complications. introduction: thrombocytopenia is a common condition in critically ill patients and an independent predictor of mortality. the relevance of a supranormal platelet count remains unclear. septic patients with disseminated intravascular coagulation (dic) are also known to have a high mortality, but the influence of sepsis on mortality rates in coagulopathic patients is less well characterised. our objectives were to: 1) evaluate mortality amongst patients with sepsis and nonsepsis associated dic. 2) assess incidence of dic during the first 7 days of admission. 3) assess the relationship between platelet count and mortality. methods: records of 935 adult critical care patients admitted to the royal liverpool university hospital between 2008-2014 were retrospectively reviewed. the presence of sepsis (using the definition of sirs with infection), coagulopathy, degree of thrombocytopenia and 28 day mortality were noted. modified isth dic score was used to define dic. results: the overall mortality rate was 19%. 522 patients were identified as having sepsis (56%) and 413 non septic patients (44%). mortality rates of patients with sepsis were significantly higher than without sepsis (71% vs 29% respectively, p<0.0001). in patients with dic, their dic scores tended to be 'positive' for the first 4 days of admission. fibrin-related markers were often not available for dic scoring. mortality rates amongst patients with sepsis-associated dic were greater than patients with non-sepsis related dic. thrombocytopenia severity was associated with mortality, and patients with platelets above the upper limit of normal had lower mortality rates (11% when platelets > 400x10^9/l, 30% when platelets <50x10^9/l). conclusions: sepsis-associated coagulopathy is associated with a higher mortality rate than non-sepsis associated coagulopathy. supranormal platelet counts may be associated with a mortality benefit. introduction: deep vein thrombosis (dvt) is a major problem in icu and affects overall lethality. dvt is widespread complication in icu, especially in elderly patients, when early activisation may not be achieved. aim of this study is comparison of haemostatic potential and analgesia methods of elderly patients who underwent major urological surgery during their stay in icu. methods: a cross-sectional study was employed. participants were ≥70 y.o., underwent major urological surgery, have had normal initial hemocoagulation data (thromboelastography was performed to all of them), had received analgesia with epidural catheter or iv by opioids use and were treated in icu >3 days due to non-coagulopathy states, were included. data were collected from october 2017 till october 2018. the patients were examined with thromboelastograph "mednord" for thromboelastogramm (teg) and with esaote usg for thrombi occurrence in lower limb deep veins. the anticoagulants were prescribed under the esa guidelines 2017. results: participants (n=30) were divided in two groups -non-opioid analgesia with epidural catheter (n=12) and opioid analgesia (n=18). we received moderate decrease in anticoagulants dosage to the patients with epidural analgesia with the same teg goals compared to the patients with opioid analgesia. other factors as comorbidities may provoke dvt events, but was not evaluated in this study. the dvt events were monitored by expert with the use of usg to locate thrombi in the vein. conclusions: use of epidural catheter analgesia provides moderate decrease of anticoagulants dosage compared to opioid analgesia patients; however strict control of teg data must be presented. comorbidity need to be monitored for early detection and prevention of dvt events. introduction: patients with morbid obesity (mo) have a high risk of thromboembolic events. in patients with a bmi >35, the hypercoagulable state is due to impairment of all parts of the blood coagulation as well as anticoagulation mechanisms by obesity. methods: the hemostasis system was studied in 100 patients with a bmi> 35 kg/m2 with various pathologies that were admitted to icu. all patients were divided into 2 groups depending on the type of therapy: 1 group (n=50) received monotherapy with enoxaparin sodium 0.1% 0.2 ml sc 2 times a day every 12 h; group 2 (n=50) received combination therapy with enoxaparin sodium 0.1% 0.2 ml sc 2 times a day every 12 h and pentoxifylline 100 mg 2 times a day every 12 h. to study the hemostasis system, we used lpteg immediately after hospitalization, on 1, 3, 5 days. results: in both groups, prior to treatment: contact coagulation intensity (icc) was increased by 23.57%, intensity of coagulation drive (icd) -by more than 32.68%, clot maximum density (ma) -by 74.52%, index of retraction and clot lysis (ircl) -91.18% above normal. patients of the 1st group: icc increased by 12.62%, icd was close to normal values, ma increased by 18.63%, ircl was increased by 31.17%. patients of the 2nd group on the 5th day: icc decreased by 15.22% compared with the norm; the coagulation and fibrinolysis parameters were close to normal values and the decrease in fibrinolysis activity reaches to normal. conclusions: combined therapy of thromboembolic complications in patients with obesity sodium enoxaparin sodium and pentoxifylline is more effective than enoxaparin sodium monotherapy because it affects all parts of the hemostatic system. introduction: a laryngeal injury secondary to blunt neck trauma can lead to life-threatening upper airway obstruction [1, 2] . ultrasound enables us to identify important sonoanatomy of the upper airway [3] . the purpose of this report is to discuss role of pocus airway in blunt neck trauma and to determine airway management based on standard schaefer 5 subgroups classification. methods: three cases of blunt neck trauma presented to our centre with either subtle or significant clinical signs and symptoms. standard airway management was performed prior to pocus airway using 15mhz linear transducer and it findings were later compared to flexible fibreoptic laryngoscopy and computed tomography (ct). results: pocus airway had identified one out of 3 cases to have schaefer 2 and the remaining as schaefer 3. all pocus airway findings were confirmed with flexible fibreoptic laryngoscopy and ct scan (figs 1, 2) . based on schaefer, supportive care and early steroid administration are advisable for group 1 and 2. for groups 3 to 5, immediate open surgical repair is deemed necessary due to extension of injuries.all cases were intubated using glidescope.all including those presented with schaefer 3 were managed conservatively and discharge well with proper follow-up. conclusions: upper airway ultrasound is a valuable, non-invasive and portable for evaluation of airway management even in anatomy distorted by pathology or trauma. an organised approach using pocus airway as an adjunct can expedite care and prevent early and long term complications in facilities without flexible laryngoscope and ct. introduction: high-flow nasal oxygen (hfno) and helmet noninvasive ventilation (hniv) are increasingly used for the early management of acute hypoxemic respiratory failure (ahrf). we compared the physiological effects of hfno and hniv during ahrf. methods: in this randomized cross-over study, we enrolled patients with acute-onset (<7 days), non-cardiogenic respiratory distress (respiratory rate>25/min), pulmonary infiltrates at the chest-x-ray and hypoxemia (spo2<90% while breathing on room air). all patients received hniv (peep 10 cmh2o, pressure support adjusted to achieve a peak inspiratory flow of 100 l/min) and hfno (flow 50 l/min) for one hour each, in a randomized cross-over manner. at the end of each period, arterial blood gases, inspiratory effort (esophageal pressure) and respiratory rate were recorded. self-assessment of dyspnea and device-related discomfort ( [3] [4] [5] [6] [7] ). conclusions: as compared to hfno among critically ill patients with ahrf, hniv ameliorates oxygenation, limits inspiratory effort and relieves dyspnea, without affecting paco2, respiratory rate and comfort. introduction: pre-intubation hypoxemia is a predictor of negative patient outcomes including in-hospital mortality. while successful first intubation attempt is also an important factor of patient outcomes, little is known about whether physicians achieve successful first intubation attempt for the hypoxemic patients in the emergency department (ed). the aim of this study is to investigate the first-pass success for patients with pre-intubation hypoxemia in the ed. methods: this is an analysis of the data from the second japanese emergency airway network study (jean-2 study)a multicenter, prospective, observational study of 15 eds in japan. we included all patients who underwent intubation in the ed from 2012 through 2018. we excluded patients 1) aged <18 years and 2) patients who underwent intubation for cardiac arrest. we grouped pre-intubation hypoxemia as follows: non-hypoxemia (oxygen saturation [spo2], ≥97%), moderate-hypoxemia (spo2, 96%-90%), and severehypoxemia (spo2, <90%). primary outcome was the first-pass success rate. to demonstrate the association between pre-intubation hypoxemia and the first-pass success in the real-world setting, we fit two unadjusted logistic regression models 1) using grouped preintubation hypoxemia as a categorical variable and 2) using the preintubation spo2 as a continuous variable. results: among 10,144 patients who underwent intubation in the ed (capture rate, 97%), 5,463 patients were eligible for the analysis. compared to the non-hypoxemia, the first-pass success rate was low in moderate-hypoxemia (72% vs 67%; or=0.77 [95%ci, 0.67-0.89]) and severe-hypoxemia (72% vs 69%, or=0.85 [95%ci, 0.72-0.99]). additionally, there was a linear association between pre-spo2 and lower first-pass success rate (or for the success, per one pre-spo2 decrease, 0.99 [95%ci, 0.98-0.99]). conclusions: based on the large, multicenter data, the first-pass success rate was low in hypoxemic patients compared to nonhypoxemic patients in the ed. introduction of rapid-sequence induction guideline to reduce drug-associated hypotension in critically unwell patients introduction: the aim of this project was to assess whether the introduction of a rapid sequence induction (rsi) agent guideline changed drug choice and the incidence of peri-intubation vasopressor use at st john's hospital, livingston. it is well documented that emergency airway management in the critically ill can be a source of significant morbidity and mortality [1, 2] and the choice of induction agent matters [3] . methods: an rsi agent guideline was instituted for all critically ill patients being intubated in icu and the ed [ figure 1 ]. following this, we set up an intubation registry to collect data from all intubation events. this data was then compared to a previous audit of intubations completed in 2012. results: the choice of agent used pre-and post-intervention are summarized in figure 2 . forty-five intubation events were included in the initial audit in 2012, of which, 7 (16%) required vasopressor support immediately following intubation. of the 41 intubation events following the guideline's introduction, 2 (5%) required vasopressors. ketamine use changed from 0% to 51%, propofol use from 43% to 29% and midazolam from 14% to 0%. thirty-eight of these intubation events (93%) were compliant with the guideline. conclusions: the introduction of the rsi guideline dramatically affected the choice of induction agent and reduced the incidence of significant hypotension requiring vasopressors (5% versus 16%). overall compliance with the guideline was excellent (93%). introduction: the purpose is to test the feasibility of using the i-gel® device for airway maintenance during bronchoscopic-guided percutaneous dilatational tracheostomy (pdt). usually pdt is accomplished via the tracheal tube. failure to position the endotracheal tube correctly can result in further complications during the procedure. the alternative implies extubation and reinsertion of an i-gel® airway device. methods: the pdt was performed using the blue dolphin method in 5 patients in intensive care unit. before undertaking bronchoscopicguided percutaneous dilatational tracheostomy (pdt), the patient's tracheal tube (et) was exchanged for i-gel®, as a ventilatory device for airway maintenance. the insertion of the i-gel®, the quality of ventilation, the blood gas values, the view of the tracheal puncture site, and the view of the balloon dilatation were rated as follows: very good (1), good (2), barely acceptable (3), poor (4), and very poor (5) [1] . results: the i-gel® successfully maintained the airway and allowed adequate ventilation during percutaneous tracheostomy in all patients. the ratings were 1 or 2 in 100% of cases with regards to ventilation and to blood gas analysis, for identification of relevant structures and tracheal puncture site, and for the view inside the trachea during pdt. conclusions: the i-gel® successfully maintained the airway and allowed adequate ventilation during percutaneous tracheostomy in all patients. the ratings were 1 or 2 in 100% of cases with regards to ventilation and to blood gas analysis, for identification of relevant structures and tracheal puncture site, and for the view inside the trachea during pdt. no damages to the bronchoscope, reports of gastric aspiration or technical problems were detected. the bronchoscopic view obtained via an i-gel® seems to be better than that obtained through an endotracheal tube (et) or through traditional laryngeal mask [1] . introduction: the purpose of this study was to investigate the efficiency of nasal airway inserted in the oral airway (on airway) in securing the airway patency during mask ventilation [1] (fig 1) . methods: fifty eight patients undergoing general anesthesia were randomly assigned to either oral airway group (group o) or on airway group (group n). in both group, 2 mg/kg of propofol was infused intravenously and mask ventilation was performed in the sniffing position without head extension or jaw thrust. the patients were ventilated with a volume-controlled ventilator with o2 flow of 10 l/min, tidal volume of 10 ml/kg (ibw), and respiratory rate of 10 /min. before the start of mask ventilation, airway was placed in the oral cavity. oral airway was used in group o and on airway was used in group n. peak inspiratory pressure (pip), tidal volume and etco2 were compared between the two groups. the location of airway tip was graded by fiberoptic bronchoscope as; 0: airway obstructed by tongue, 1: epiglottis visible, 2: airway touches epiglottis tip, 3: airway passes beyond epiglottis tip [2] . methods: a prospective uncontrolled observational study in 2017-18 in 4 ukrainian hospitals. 10 sma-pts from 6-18 mo were involved. all pts. ready for extubation: afebrile, no infiltrations on chest x-ray, normal wbc. however, each sma-pts. failed sbt (t-tube or psv). we evaluated: extubation success (no reintubation in 48 hours), icu los, one year survival. three pts. were excluded: two pts. by staff decision, 1 family have choosen tracheostomy. 7 sma-pts. included. a cuff leakage test performed -with a negative, dexamethazone 1mg iv was administered. after extubation niv was started by ventilogik ls in st mode via nasal mask giraffe. the epap and ipap settings were titrated to reach the chest excursion and target levels of spo2 (92-96%) and etco2 (40-45 mmhg). a sputum was draining by mechanical insufflation-excuflation (mie) and aspirator results: all pts, were extubated successful. the mean icu los was 8.5 days (7-10 days), one year survival rate was 100%, respiratory failure fully compensated by niv, there was no icu admission. every sma-pts. are in good condition, gaining weight introduction: aerosol delivery has previously been assessed during simulated adult hfnt, delivered by various stand-alone humidification systems [1] . the objective of this study was to evaluate aerosol delivery during simulated hfnt delivered by a mechanical ventilator, across three clinically relevant gas flow rates. methods: 2ml of 2 mg/ml salbutamol was nebulised using an aerogen solo nebuliser (aerogen, ireland). an adult head model was connected to a breathing simulator (asl5000, ingmar, us), vt 500 ml, bpm 15 and i: e, 1:1 (fig 1) . hfnt was supplied via the servo-u ventilator (maquet, getinge, sweden), using the integrated nebulisation option. tracheal dose was recorded at two nebuliser positions; a (after the humidification chamber) or b (before of the cannula), at three gas flow rates (10lpm, 30lpm and 60lpm) (n=3). the mass of drug captured on a filter placed distal to the trachea (tracheal dose) was quantified using uv spectroscopy at 276 nm. results: presented in table 1 . conclusions: to our knowledge, this is the first study to successfully demonstrate aerosol delivery during simulated hfnt, delivered by a mechanical ventilator. increasing gas flow rate was associated with a reduced tracheal dose (p= <0.0001). at 10lpm, a significantly greater tracheal dose was observed when the nebuliser was positioned before the nasal cannula (p= <0.0001). at 60lpm, a greater tracheal dose was yielded when the nebuliser was positioned after the humidifier (p= <0.0001). introduction: tracheotomies are often performed in critically ill patients who are in need of prolonged mechanical ventilation and respiratory care. our aim was to evaluate the possible effect of percutaneous and surgical tracheotomies on thyroid hormone levels. methods: eighty seven adult patients were included in our study from january 2017 to september 2018. patients were in need of prolonged mechanical ventilation and tracheotomies were performed after consent was taken. we have excluded patients with preexisting thyroid diseases. forty five patients were undergone percutaneous tracheotomies and forty two patients were undergone for surgical. thirty eight female patients and forty nine male, age range 18-85. we studied tsh, t3 and ft4 serum levels using chemiluminescence immunoassay method before either procedure and 2 hours post each procedure.: statistical analysis was performed using spss 15. significance was estimated at the level of p< 0.005 results: tsh levels were increased in surgical group compared to percutaneous group at 2 hours post procedure but the difference was not found statistically significant (p> 0.005). the rise in post operative levels of t3 compared to preoperative was found statistically significant for surgical tracheotomy group (p< 0.005).elevated ft4 levels for both groups have shown statistically significant difference between preoperative and postoperative period for the surgical tracheotomy group (p< 0.005) conclusions: we analyzed the effect of surgical versus percutaneous tracheotomy on thyroid hormones and it was found that both introduction: insertion of a tracheostomy for weaning purposes is associated with prolonged critical length of stay (los) and several adverse patient outcomes [1] . previous work has suggested that protocolised weaning may reduce weaning times [2] . we aimed to assess the impact of protocolised weaning on los following introduction of a standardised weaning protocol in 2017. conclusions: introduction of a standardised weaning protocol for patients with a tracheostomy in our unit has had a beneficial effect on several patient outcomes, notably duration of weaning and length of critical care admission. introduction: delirium is a relatively frequent neurologic complication in liver transplantation (lt) recipients, which is an important cause of increased morbidity, mortality, extended icu stay, and increased cost of medical care. extubation of the endotracheal tube at an appropriate timing is an essential part of intensive care after lt, suggested to improve graft perfusion and systemic oxygenation, and thus decrease intensive care unit (icu) stay and positively affect prognosis. the aim of this study was to compare the incidence of delirium between early and late extubation groups after lt. methods: medical records from 247 patients who received lt from january 2010 to july 2017 in a single university hospital were retrospectively reviewed. patients were divided into 2 groups: those who underwent early extubation after lt (group e, n = 52) and those who underwent extubation within few hours of icu admission after surgery (group c, n = 195). the data of patients´demographics, perioperative management, and postoperative complications were collected. early extubation was defined as performing extubation in the operating room after lt. a propensity score matching analysis was performed to minimize the effects of selection bias. results: postoperative delirium occurred in 4/52 (7.69%) in group e and 30/195 (15.38%) in group c, respectively (p = 0.15). after propensity score matching, there was no difference in icu stay (p = 0.96), time to discharge after surgery (p = 0.12), and incidence of delirium between groups (p = 1.00). conclusions: although this study is retrospective in nature, limited by small sample size, early extubation did not affect the incidence of delirium after lt. further prospective studies on this area are required. weight estimation and its impact on mechanical ventilation settings in queen elizabeth hospital intensive care unit a nasr, a iasniuk, a roshdy queen elizabeth hospital, icu, london, united kingdom critical care 2019, 23(suppl 2):p353 introduction: documented weight in the intensive care unit (icu) can be the total, ideal, adjusted or predicted body weight (pbw). lung protective ventilation depends on tidal volume (vt) delivery which is based on accurate calculation of patients´weight [1] . the weight is most probably documented on admission to the icu using estimation or one of many available equations. the aim of this study is to assess the documented versus the pbw and its impact on tidal volume delivery for mechanically ventilated patients in queen elizabeth hospital icu. methods: data was collected prospectively from all ventilated patients over a period of 2 weeks in june 2018. vt delivered in the first hour was calculated for each patient. documented body weight and height of each patient was obtained from the nursing chart. pbw was calculated and compared with the documented weight. the difference in vt attributable to the difference in weight has been subsequently calculated. results: 29 ventilated patients were included (17 males). the mean tidal volume delivered according to the documented body weight was 7.16 ml/kg versus 8.28 ml/kg based on pbw. vt more than 8 ml/ kg was delivered in 31% of patients based on documented weight versus 48% when correcting the weight according to the pbw equation. conclusions: inaccuracy in documenting weight on patients´admission to the icu is a potential cause of delivering unsafe tidal volume [2] . the harm can extend to drug dosage, nutrition provision and renal replacement therapy. introduction: ventilator-associated pneumonia (vap) is the leading cause of death among mechanically ventilated critically ill patients [1] . chest radiography (cxr) is essential in the diagnosis of vap. in the past decade lung ultrasonography has proven to be a valuable tool in the diagnosis and monitoring of lung diseases. the aim of the study is to assess sensitivity and correlation between cxr, lung ultrasound and clinical pulmonary infection score (cpis). methods: in this retrospective, non-randomized study seven patients with proved vap were enrolled. in all patients cpis and lung ultrasound score (lus) [2] were assessed. comparison of patients that had lus≥18 and cpis≥6 points was performed. the correlation between lus and cxr was done using the pearson model. results: we found significant difference between positive cxr patients with lus≥18 and cpis≥6 (100% vs 57%, p<0.05). there is a very high correlation between cxr and lus. these results render lung ultrasound as a highly sensitive tool in the diagnosis of vap. conclusions: our study shows that lung ultrasonography could be used as a reliable supplementary method in the diagnosis of vap. the benefits of lung ultrasound include the ability to perform it at the patient´s bed without need for transportation, no radiation exposure and repeatability. the high correlation between cxr and lung ultrasound makes echography a valuable adjunct in the diagnosis of vap. color introduction: it is difficult to differentiate between pneumonia and atelectasis as cause of lung consolidation in intensive care unit patients. tools like the clinical pulmonary infection score are of little help (sensitivity 60% and specificity 59% for detecting pneumonia) [1] . the objective of this study was to determine the accuracy of ultrasound assessed vascular flow within the consolidation to distinguish these causes. methods: adult patients with pulmonary symptoms and lung consolidation on lung ultrasound that were scheduled for chest-ct were included. vascular flow was analyzed with color doppler imaging (flow velocity scale was chosen at 0.25m/sec.). the final diagnosis made by the treating physician was regarded as the gold standard. results: 20 patients were included of which nine (45%) were diagnosed with pneumonia. vascular flow in the consolidation was present in seven (78%) out of nine patients with pneumonia, compared to three out of 11 (27%) patients with atelectasis (p = 0.07). the diagnostic accuracy in differentiating between pneumonia and atelectasis was 75%. the sensitivity and specificity were 78% and 73% respectively. the positive predictive value was 70% while the negative predictive value was 80%. conclusions: vascular flow in lung consolidations assessed by lung ultrasound in icu patients aids in differentiating between pneumonia and atelectasis. it outperforms the frequently used clinical pulmonary infection score. methods: three intubated patients for various causes of respiratory distress undergoing mechanical ventilation were subjected to tee. at the level of mid-esophagus, the descending aorta short-axis view (0°) the imaging plane is directed through the transverse axis of the descending aorta. sector depth was increased to image the left pleural space beneath the aorta. for the right lung, the tee is rotated to the right at the level of atria until lung is seen or until the image of the liver is seen and the probe was withdrawn until the right lung is seen. recruitment manoeuvres were performed after identifying pbl atelectasis. atelectatic lungs were visually observed to open up during and after the recruitment manoeuvres. results: the time to acquire the image of pbl atelectasis from the time of insertion by tee is short. the images of posterior lung and the effect of lung recruitments is successfully viewed (fig 1) . no immediate complication seen. conclusions: tee provides an excellent view of pbl atelectasis and able to directly monitor the success and failures of recruitment manoeuvres. introduction: high respiratory driving pressure (δ prs) is strongly associated with increased risk of lung injury and increased mortality during mechanical ventilation. δ prs consists of the pressure required to distend the lung the transpulmonary driving pressure (δ pl) and the pressure required to distend the chest wall. δ pl is the pressure that increases the risk of lung injury. data on δ pl is limited because its measurement requires an esophageal catheter. we aimed to assess changes in δ prs and δ pl during proportional assist ventilation (pav+) at different experimental conditions. methods: we retrospectively analyzed patients ventilated with pav+ who had esophageal pressure measurements before and after dead space or chest load addition. we calculated end-inspiratory plateau pressure (pplateau), δ prs, respiratory system compliance (crs) and δ pl during occluded breaths in pav+ (figure 1 ). data were compared with wilcoxon signed rank test and p value<0.05 was considered significant. results: 16 patients were analyzed. dead space increase (9 patients) did not affect the studied parameters. chest load (7 patients) significantly increased pplateau (p=0.03) and δ prs (p=0.02) and decreased crs (p=0.02) but δ pl remained the same (p=0.4). median (iqr) changes were 9.5 ml/cmh2o (7.7-13.2) for crs, 2.9 cmh2o (2.4-5.1) introduction: particle flow in exhaled air from mechanically ventilated patient's mirrors the opening and closing of small airways and can be detect by optical particle counter [1] . we hypothesized that this particle flow is affected by cardiac function. methods: exhaled air from 20 mechanically ventilated patients was analyzed using a customized optical particle counter pexa, figure 1 . introduction: we assessed the diagnostic accuracy of mechanical power (mp) and driving pressure (dp) alone and combined with stress index (si) to identify ventilator settings likely to produce ventilator induced lung injury caused by tidal hyperinflation [1] [2] [3] . methods: secondary analysis of a previous database of ards patients [1] . computerized tomography markers of tidal hyperinflation (were used as a "reference standard". analysis of the area under the receiver-operating characteristics curve (auc) was used using a two-fold cross-validation. results: in a cluster of 44 patients, a "training set" of 28 not hyperinflated patients was compared with a "validation set" of 14 hyperinflated patients. (figure 1-2) . conclusions: si seems to be more accurate than mp and dp in identifying tidal hyperinflation in patients with ards. specificity and sensibility were not improved combining si with mp or dp. the introduction: the pao 2 /fio 2 (p/f) ratio is widely used to assess the severity of lung injury. conceptually, the p/f ratio should be independent of the fio 2 and solely depend on the pulmonary condition. however, effect of fio 2 modulation on the p/f ratio has not been well characterized in ventilated intensive care (icu) patients. the purpose of the present study was to investigate the relationship between fio 2 and the p/f ratio in icu patients on mechanical ventilation. methods: in a prospective, interventional study 10 patients with a swan ganz catheter in situ were included. the p/f ratio was calculated at fio 2 levels ranging from 0.21 to 1.0 with 10 minute intervals. during the study other ventilator settings were not modulated. to understand the physiological effects of fio 2 modulation on gas exchange and hemodynamics, mixed venous oxygen saturation and cardiac output were assessed. shunt fraction was calculated as described by west [1] . results: patient characteristics and ventilator settings are reported in table 1 . all patients were admitted to the icu after elective cardiac surgery. modulation of fio 2 did have a significant effect on the p/f ratio, following a u-shaped pattern (p < 0.05) (figure 1 ). the shunt fraction varied with altering fio 2 levels, also exhibiting a u-shaped pattern (p < 0.05) (figure 2 ). cardiac output was not affected by fio 2 . conclusions: in contrast to current thinking, the p/f ratio varied substantially with altering fio 2 levels in mechanically ventilated icu patients. this is an important novel physiological observation. in addition, it demonstrates that the assessment of the severity of respiratory failure by using the p/f ratio should be standardized to a fixed fio 2 level. conclusions: in patients undergoing prolonged mechanical ventilation, we must take into account all the factors that may affect our patients. the assessment of diaphragmatic dysfunction is key to preventing weaning failure. an optimal level of consciousness as well as a good management of secretions are key to a successful weaning. prognostic value of the minute ventilation to co 2 production ratio as a marker of ventilatory inefficiency in the icu r lopez 1 , r pérez 1 , á salazar 1 , i caviedes 2 , j graf 1 introduction: ventilatory inefficiency for co2 clearance may provide better severity stratification in acute respiratory failure than oxygenation [1] . ventilatory inefficiency (vi) is best assessed by the bohr-enghoff physiological dead space [2] . we recently reported that the minute ventilation to co2 production ratio (ve/vco2), a simplified vi index from exercise testing that obviates the paco2 measurement, correlates better than other vi indices to physiological dead space in mechanically ventilated patients [3] . here we report the prognostic performance of this index using a survival analysis. mean±sem ve/vco2 was higher in patients who died than those who survived (58±8 vs 43±1, p<0.001, figure 1 ). we found a ve/ vco2 cutoff value of 45. mortality was higher in patients with high-ve/vco2 (≥45) as compared to those with low-ve/vco2 (21% vs 4%, p=0.021) with an odds ratio of 6.7 [95%-ci 1.2-35.8]. cumulative mortality was higher in the high-ve/vco2 than in the low-ve/vco2 group (log-rank p=0.015, figure 2 ). conclusions: in this unselected cohort of mechanically ventilated patients an early high ve/vco2 ratio was associated to 28-days mortality. the ve/vco2 ratio may be a simple and non-invasive vi index with prognostic value in this population. introduction: sodium thiosulfate (sts) is a clinically relevant and safe hydrogen sulfide donor that improved acute lung injury (ali) and brain ischemia/reperfusion injury in previous studies [1, 2] . methods: in a prospective, controlled, randomized, and doubleblinded trial, twenty adult, anesthetized, mechanically ventilated and surgically instrumented swine with preexisting coronary artery disease [3] underwent 3 h of hemorrhagic shock (hs; removal of 30% of the calculated blood volume and subsequent titration of mean arterial pressure to 40mmhg). post-shock resuscitation (72h) comprised re-transfusion of shed blood, crystalloids, and norepinephrine. animals were randomly assigned to "placebo" or "sts" (0.1g·kg -1 ·h -1 for 24h). before, at the end of and every 24h after shock, hemodynamics, blood gases, and lung function were recorded. results: survival rates did not differ between groups. sts-infusion attenuated the hs-induced impairment of lung mechanics and pulmonary gas exchange (table 1 ,2), resulting in a significantly higher horovitz/peep-ratio ( figure 1 ). conclusions: sts during acute resuscitation from hs may protect comorbid swine against hs-induced ali. introduction: alveolar epithelial cell (aec) death is a main mechanism of severe respiratory failure in acute respiratory distress syndrome (ards). classically, cell death is classified into necrosis or apoptosis. recent studies have reported that not only apoptosis but also certain types of necrosis are molecularly regulated and that these regulated necrosis can be therapeutic targets for various diseases. however, the relative contribution of necrosis and apoptosis to aec death in ards has not been elucidated. our study aimed to elucidate which type of cell death is dominant in aec death and to evaluate whether the regulated necrosis is involved in lps-induced experimental ards. methods: we established ards model by instilling 25μ g of lps intratracheally to mice. to estimate the relative proportion of apoptosis and necrosis in aec death, we measured cytokeratin18 m65 level (total cell death marker) and m30 level (apoptosis maker) in bronchoalveolar lavage fluid (balf) by elisa, and quantified propidium iodide-positive necrotic cells and tunel-positive apoptotic cells in the lung sections. moreover, we performed pathway enrichment analysis of gene expression data from pcr array to evaluate whether regulated necrosis pathway is associated with the ards model. results: both m65 and m30 levels were increased in the ards mice. the m30/m65 ratio (an indicator of the proportion of apoptosis to total cell death) in the ards mice was significantly lower than that of healthy controls. moreover, the number of propidium iodidepositive necrotic cells was significantly higher than that of tunelpositive apoptotic cells in ards mice. in the pathway enrichment analysis, the necroptosis pathway, a regulated necrosis pathway, was associated with lps-induced experimental ards. conclusions: aec necrosis is more dominant than apoptosis in lpsinduced ards model. moreover, necroptosis may contribute to ards pathogenesis. aec necrosis including necroptosis is a potential therapeutic target for ards. clinical ards diagnosis is not associated with a unique circulating neutrophil cell surface phenotype t craven 1 , s duncan 1 , s johnston 2 , c haslett 1 , k dhaliwal 1 , t introduction: acute respiratory distress syndrome (ards) is a form of non-cardiogenic oedema due to alveolar injury secondary to an inflammatory process. the clinical diagnosis is defined by the berlin criteria but this may not reflect the underlying biological process. the activated neutrophil is central to the pathogenesis of ards, characterised by altered cell surface markers. methods: three cohorts of seven participants were recruited. the first cohort suffered from mild, moderate or severe ards as defined by the berlin criteria [1] . the second cohort was composed of ventilated patients on the intensive care unit with acute inflammatory lung disease (diagnosis of clinical suspicion) but did not meet the berlin criteria for ards. a third cohort was composed of age and sex matched healthy volunteers. procurement of human tissue was approved by a regional ethics committee (14/ss/1074 or 08/s1103/38 or amrec: 15-hv-013) and with the informed consent of the participant or their personal legal representative. patients were excluded if aged under 16 or over 80 years of age, were expected to survive for less than 24 hours, if the attending physician refused, due to the absence of suitable indwelling vascular catheter, if the haemoglobin concentration was below 6.5 g/dl, or if the patient was enrolled in a trial of novel anti-inflammatory agent. whole blood (lysed erytocytes) underwent flow cytometry to determine cd11b, 63, 66b, 88, 62l and 16. results: a description of the enrolled cohorts can be found in table 1 . there were no significant differences between the mechanically ventilated, critically ill cohorts for any cell surface molecule in the multiplicity adjusted p values (fig 1) . the results support the conjecture that clinical diagnostic criteria should not be used as a surrogate to stratify patients according to biological changes, with implications for the testing of biological therapies. introduction: aim of the present study was to compare the global and regional diagnostic accuracy of lung ultrasound (lus) compared to lung computed tomography (ct) scan in patients with the acute respiratory distress syndrome (ards). ards is characterized by a diffuse, inhomogeneous, inflammatory pulmonary edema. lung ct scan is the reference imaging technique, but requires transportation outside the intensive care and exposes patients to x-rays. lung ultrasound (lus) is a promising, inexpensive, radiation-free, tool for bedside imaging. methods: lung ct scan and lus were performed at peep 5 cmh2o. lus was performed using a standardized assessment of 6 regions per hemithorax: superior and inferior; anterior, lateral and posterior. each region was classified for the presence of normally aerated, alveolar-interstitial syndrome, consolidation regions and pleural effusion. agreement between the two techniques was calculated, and diagnostic parameters were assessed for lus using lung ct as a reference. both a global and a regional analysis were performed. results: thirty-two sedated and paralyzed ards patients (age 65±14 years, bmi 25.9±6.5 kg/m2 and pao2/fio2 139±47) were enrolled. global agreement between lus and ct was 0.811±0.032. the overall sensitivity and specificity of lus are shown in table 1 . similar results were found with regional analysis (anterior/lateral/posterior lung regions is a common practice in our icu. during the interruption eit belt was positioned. when the presence of spontaneous breathing activity was evident by clinical assessment and ventilator traces analysis, nmba were administered to reach full paralysis, in accordance with the treating physician. eit tracing were analyzed offline and the change in eeli after nmba bolus, as compared to before nmba administration, was measured. respiratory mechanics and arterial blood gas (abg) data were collected results: we enrolled 5 ards patients, undergoing controlled mechanical ventilation with muscle paralysis. baseline respiratory mechanics and abg data are shown in table 1 . in 4 out of 5 patient the bolus of nmba led to an increase of eeli. in 1 case, the nmb administration led to no changes in eeli. the mean change in eeli was 159 ±152ml conclusions: in our small population of ards patients, the administration of a bolus of nmba after the regain of spontaneous breathing activity led to an increase in eeli in 4 out of 5 patients. further study are needed to 1) correlate this increase to global and regional respiratory system compliance and 2) correlate this increase to the time needed to wean the patient from nmba introduction: to analyze the use of the orthostatic board as an auxiliary device for the treatment of severe ards by assessing its risks and benefits. methods: we selected 91 patients, 43 females and 48 males, hospitalized in a neurological icu, between june 2014 and july 2018, in a physiotherapeutic follow-up with diagnosis of severe ards. the patients were submitted to orthotics assisted for 40 to 60 minutes and monitored hr, pam, fr, sato2 at 30°and 60°of inclination and the pao2 / fio2 ratio after the procedure. the mean number of sessions per patient was 6.6. all patients were undergoing anticoagulation in rass -5, in the treatment of the cause of ards. the mean time of mechanical ventilation was 8.5 days. results: among the patients selected, 36.3% presented tachycardia above 115 bpm, requiring intervention in 12.1% and interruption of the procedure in 6.6%. pam arterial hypotension <65 mmhg was observed in 34.1%, requiring intervention (increase of vasopressor dose and / or change of plank angulation) in 22% and interruption of the procedure in 14.3%. hypoxemia sato2 <92% was observed in 8.8%, without interruption, but an improvement in pao2 / fio2 was observed in only 95.6% of the patients. conclusions: assisted orthostatism as an auxiliary device for the treatment of severe ards was shown to be an alternative, with improvement of pao2 / fio2 in 95.6% of the patients, safe and without significant hemodynamic repercussions that could lead to interruption of the procedure. introduction: the eolia trial found that vvecmo compared to conventional mechanical ventilation (cmv) did not improve mortality in patients with severe ards [1] . the cmv strategy consisted of airway pressures below 30cmh 2 o. in patients with severe ards higher airway pressures are required to maintain lung aeration. grasso et al. measured the transpulmonary pressure (p l ) in patients with severe ards and increased peep until p l was 25cmh 2 o, accepting airway pressures above 30cmh 2 o. fifty percent of patients responded to an increase in airway pressure and did not require vvecmo [2] . we hypothesized that a p l guided open lung concept (olc) improves oxygenation and prevents conversion to vvecmo in patients with severe ards. methods: a retrospective study was conducted in a tertiary referral icu. the records of patients referred to our icu for advanced medical care were reviewed. inclusion criteria were severe ards according to the berlin definition and the eolia trial inclusion criteria for vvecmo. results: mechanical ventilation was limited to a p l of <25cmh 2 o instead of plateau pressures below 30cmh 2 o. the p l guided olc resulted in an increase in p/f ratio and none of the patients required vvecmo. during the first 6 hours peak airway pressure was increased, but was reduced within 24 hours while peep was maintained ( fig. 1 ). at 72 hours both peak airway pressures and peep were reduced to baseline values while p/f ratio remained stable. only one patient (12.5%) died of disseminated invasive aspergillosis. conclusions: the p l guided olc improved oxygenation and none of the patients required vvecmo. these findings support a ventilation strategy guided by transpulmonary pressures instead of plateau pressures in patients with severe ards. introduction: the mortality benefit conferred by early prone positioning in the treatment of acute respiratory distress syndrome (ards) has been well established. we also know that aprv improves oxygenation, and more recently has been shown to reduce ventilator dependent days and icu length of stay [1, 2] . however, controlled ventilation remains the mainstay mode of ventilation used during prone position. literature looking at combined aprv and prone positioning is scarce. we aim to explore and report our institutional experience with respect to feasibility and outcomes in combining aprv and prone positioning, and perform a literature review in this area. methods: we undertook a single-centre retrospective cohort study within a surgical icu of a tertiary hospital in singapore between jan 2013 -oct 2017. patients with ards who received combined prone positioning and aprv were reviewed retrospectively. a literature review of patients with ards who received combined intervention was also performed. results: 5 adult patients aged 21-77 years old diagnosed with ards received a combination of aprv and prone positioning for a duration of 16-45 h ( table 1 ). all the patients tolerated aprv with prone positioning well. our patients saw an improvement of p:f ratio ranging from 59-225 upon completion of combination therapy. 3 out of 5 patients were extubated within 72 hours of turning supine, 1 was weaned to tracheostomy mask after 14 days and 1 died while on the ventilator. only 1 case report and 1 randomized clinical trial were found on this topic upon literature review, which corroborated our findings. conclusions: in our experience, aprv is a practical and feasible alternative mode of ventilation that can be employed in the prone position, yielding significant p:f ratio improvements. the synergistic effects on improving oxygenation herald potential, especially in the subset of severe ards patients with refractory hypoxemia, where extracorporeal membrane oxygenation is unsuitable or unavailable. introduction: the recirculation during veno-venous extracorporeal membrane oxygenation (vv ecmo) had been a drawback, which could limit sufficient oxygenation. purpose of this study is to compare the short-term oxygenation in acute respiratory distress syndrome (ards) patients under vv ecmo according to their cannula configurations, especially in the national environment of the absence of newly developed double-lumen, single cannula. introduction: vv-ecmo is most commonly used in severe potentially reversible respiratory failure. this report looks at two patients in whom vv-ecmo was used to facilitate surgical airway stenting. methods: case 1-a 56-year-old with recurrent respiratory arrests, on a background of neurofibromatosis type 1 and kyphoscoliosis. he had complex airway pathology, including, airway neurofibromas and granulation tissue, tracheobronchomalacia, severe kyphoscoliosis and a permanent tracheostomy tube. rigid bronchoscopy was performed and following debridement of granulation tissue, a trouser-leg stent was deployed. case 2-a 75-year-old with progressive stridor due to recurrence of a malignant melanoma, which was causing mid-lower tracheal compression. three tracheal stents were deployed via a rigid bronchoscope. in both cases, percutaneous bi-femoral vv-ecmo was established prior to general anaesthesia and decannulation took place the following day. results: in these cases, vv-ecmo provided stable extracorporeal gas exchange without conventional tracheal intubation. cardiopulmonary bypass and veno-arterial ecmo have been described in patients at risk of compression of the heart and distal airway [1] . however, if the major threat is airway collapse, vv-ecmo can provide cardio-respiratory support without the problems associated with arterial cannulation and with lower anticoagulation requirements. introduction: ecco2r facilitates the use of low tidal volumes during protective or ultraprotective mechanical ventilation when managing patients with acute respiratory distress syndrome (ards); however, the rate of ecco2r required to avoid hypercapnia remains unclear. methods: we determined ecco2r requirements to maintain arterial partial pressure of carbon dioxide or co2 (paco2) at clinically desirable levels in ventilated ards patients using a six-compartment mathematical model of co2 and oxygen (o2) biochemistry [1] and whole-body transport [2] with the addition of an ecco2r device for extracorporeal veno-venous removal of co2. the model assumes steady state conditions and is comprehensive from both biochemical and physiological perspectives. o2 consumption and co2 production rates were assumed proportional to predicted body weight (pbw) and adjusted to achieve pao2 and paco2 levels at a tidal volume of 7.6 ml/(kg of pbw) as reported in lung safe [3] . clinically desirable paco2 levels during mechanical ventilation were targeted at 46 mm hg for a ventilation frequency of 20.8/min as previously reported [3] . results: model simulated paco2 levels without and with an ecco2r device at various tidal volumes are tabulated in tables 1 and 2 , respectively. table 1 shows a substantial increase in paco2 at a tidal volume of 6 ml/(kg of pbw) that is more pronounced when further reducing the tidal volume. additional simulations showed that predicted ecco2r rates were significantly influenced by ventilation frequency. conclusions: the current mathematical model predicts that ecco2r rates that achieve clinically acceptable paco2 levels at tidal volumes of 5-6 ml/(kg of pbw) can likely be achieved with current technologies; achieving such paco2 levels with ultraprotective tidal volumes of 3-4 ml/(kg of pbw) may be challenging. figure 1a ). pulmonary infections for each subtype of immunosuppression are shown in figure 1b . conclusions: ards vv-ecmo patients with underlying immunosuppression have higher mortality rates and higher rates of ecmo weaning failure. immunosuppressed patients suffer from a different spectrum of pulmonary infections in comparison to not immunosuppressed patients. introduction: acute asthma attack in children is a life-threatening emergency that requires urgent medical intervention. in the present study, we aim to clarify the effect of non-invasive ventilation (niv) on the heart rate (hr), respiratory rate (rr), and fraction of inspired oxygen (fio2) in children with acute severe asthma (asa) who failed to respond to standard medical treatment; and to evaluate the associated complications and length of stay (los) at the pediatric intensive care unit (picu). methods: this is a retrospective descriptive study of prospectively collected data. it was carried at the picu of a tertiary university hospital, saudi arabia. the study included children ≤14 years old with asa admitted to the picu from november 2011 to november 2015 and required niv. outcome measures include the effect of niv on the hr, rr, fio2, and los. the study included 118 children with asa and 52 (44%) of them required niv. of those 52 patients, 12 (23%) were excluded due to incomplete data, and 40 (34%) patients were included in the final analysis. they were 22 (55%) male and 18 (45%) female with a mean age of 66 months and a median pediatric index of mortality 2 (pim2) score of 6.3%. of them, 28 (70%) had moderate asthma scores (≥5-9) and 12 (30%) had severe asthma scores (≥9). the median duration of niv was 18 hours and the median los in the picu was three days. at 6 hours, only rr showed a significant decrease compared to initiation of niv (p-value <0.001) (fig 1) ; while hr, rr, and fio2 were significantly improved at 24 hours from initiation of niv (p-value <0.001) (fig 2) . conclusions: non-invasive ventilation, in association with standard medical treatment, was associated with clinical improvement in children with asa not responding to standard medical treatment alone. niv was not associated with significant complications or side effects. neurally adjusted ventilatory assist (nava) is a partial support ventilatory mode which triggers and tailors the level of assistance delivered by the ventilator to the electrical activity of the diaphragm. the objective of this study was to compare nava and pressure support ventilation (psv) in patients who were difficult to wean. methods: a total of 99 difficult-to-wean patients who were able to sustained psv in the critical care medicine unit (icu) of the zhongda hospital, southeast university were enrolled in the study (fig 1) . patients were classified according to the reason for weaning failure and were randomly assigned to receive nava or psv during weaning ( table 1 ). the primary outcome was the duration of weaning. secondary outcomes included the proportion of successful weaning and patient-ventilator asynchrony. results: there were 17% (8/47) and 33% (17/52) patients in the psv and in the nava group never weaned from mechanical ventilation (p = 0.073). the duration of weaning was significantly shorter in the nava group [2.4 (1.1-5.3) days], than in that in the psv group [4.1(1.1-7.7) days] (p = 0.041). the proportion of patients with successful weaning was 70% (n=33/47) in nava group which was much higher than that in psv group (48%, n=25/52) ( table 2) . compared with psv, nava improved the rate of successful weaning in patients with single reason (74% vs. 49%, p = 0.019) but not in patients with multiple reasons for difficult weaning (50% vs. 45%, p = 0.656). nava decreased ineffective efforts and improved the trigger and cycling-off delays when compared with psv. mortality was similar in the two groups (fig 2) . in patients who were difficult to wean, nava decreased duration of weaning and increased the probability of successful weaning. nava which improved patient-ventilator asynchrony, is safe, feasible and effective over a prolonged period of time during weaning. conclusions: only mrc score is independently associated with sbt failure and difficult or prolonged weaning. hgs is also associated with these two outcomes related to mv weaning and may serve as a simple tool to identify icuamw. introduction: there is evidence to support that in patients with hypoxemic respiratory failure (ahrf) under non invasive ventilation (niv), high tidal volume (tv) and high respiratory rate (rr) are associated with niv failure and possibly poor prognosis. we postulated that high minute ventilation (mv); or tv x rr; is associated with mortality in ahrf, when niv is initiated. methods: single-center, prospective and observational study. we included consecutives ahrf adults requiring niv. ahrf was defined as acute dyspnea with new pulmonary infiltrates on chest radiography and paco2 below or equal to 45mmhg. we registered demographic and clinical parameters (including rr, mv, arterial blood gases, heart rate and blood pressure) at baseline and after 6 hours of first session of niv, apache ii score, diagnosis, need for intubation and icu mortality. we performed a multivariate analysis to assess independent factors associated with mortality and roc .000) and (auc = 0.7; p =0.019), respectively for mortality, future exacerbations and readmissions. the optimal cut-off point for the 6mwt ratio to predict mortality was 0.23 and to predict future exacerbations and readmissions was 0.4. the 6mwt ratio performed at icu discharge reveals interesting discriminative properties to predict early mortality, future exacerbations and readmissions in ae/copd patients. diffuse alveolar haemorrhage in an intensive care unit -search and you will find m matias 1 , e ribeiro 2 , j baptista 3 , p martins 3 introduction: the incidence of diaphragmatic ruptures after thoracoabdominal traumas is 0.8-5% [1] and up to 30% diaphragmatic hernias present late [2] when there is a complication. we report two cases of delayed traumatic diaphragm rupture to highlight the diagnostic difficulties. methods: case 1 (image 1) presented left diaphragmatic hernia containing the stomach, spleen, bowel and pancreas. the patient reported a motor vehicle accident dating 4 months. he had thoracoabdominal trauma with several broken ribs on the left side. he then reported occasional pain in his left shoulder and occasional dyspnoea. case 2 (image 2) showed right diaphragmatic hernia containing right hemicolon, right hepatic lobe and gallbladder, he reported occasional dyspnoea and recent right chest pain. he had a 25 years car accident in which three ribs broke on the right side. results: almost 88% of the patients with delayed diaphragmatic rupture presented with complications between 9 and 12 months after trauma, singh [3] reported a diaphragmatic rupture presenting 50 years after the traumatic event. the physical examination is often not helpful. conclusions: those cases emphasizes on the delayed presentation, patients may be asymptomatic or produce only mild, nonspecific symptoms, such as vague abdominal pain, chest pain or recurrent dyspnoea for months or years. the best tool to guide the clinician toward the appropriate diagnosis is a high index of suspicion whenever there is a history of high velocity trauma, regardless of how remote. factors associated with asynchronies in pressure support ventilation (psv), a bench study introduction: critically ill patients frequently have increased risk of ocular surface disorders (osds) due to poor eyelid closure and reduced tear production due to sedation during mechanical ventilation. we conducted a study to look at the incidence of osds in our icu with the current eye care practices and the impact of a protocolised eye care on the incidence and outcome and to determine the correlation of risk factors with the incidence of osds methods: this study was done in our mixed medical surgical icu. it had a prospective cohort design and was done as before and after study in two phases (phase i and phase ii). in phase i existing eye care practices were continued. in phase ii protocolised eye care was implemented and incidence of osds was noted in both phases. introduction: both fentanyl and morphine are known as opioid analgesics, which blocks the brain from receiving pain signals, the route of administration and the adverse effects affect their use. we compare the efficacy of intranasal fentanyl versus intravenous morphine adults population presenting to an emergency department (ed) with acute post traumatic severe pain. methods: we conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in a tertiary emergency department between october 2016 and june 2017. adults with severe post traumatic was included to receive either active intravenous morphine (3 mg immediately and then 1 mg every 3 min if persistence of severe pain maximum 10 mg) and intranasal placebo or active intranasal concentrated fentanyl (2 μ g /kg maximum 200 μ g) and intravenous placebo. exclusion criteria: significant head injury, allergy to opiates, nasal blockage, or inability to perform pain scoring, pain scores were rated by using a digital scale at 0, 5, 10, and 30 minutes. routine clinical observations and adverse events were recorded. conclusions: iscs were related to k over-use in our bicu. burnt patients are at risk of hepatic injury [2] , but k related hepatic injury likely occurred. its not clearly understood mechanisms may involve a cumulative dose effect. although involvement of concomitant medications is being investigated, k restriction policy seemed to contain hepatic disorders. introduction: in november 2016, our institution switched from using alfentanil to fentanyl for analgesia and sedation in adult patients receiving ecmo. there is no published evidence comparing the clinical use of alfentanil vs fentanyl for sedation in ecmo patients, although some reported increased fentanyl sequestration into the circuit [1] . for these reasons, we conducted a retrospective observational study to explore whether there were any significant differences in patient outcome or adjunctive sedation before and after the switch. methods: outcome data and total daily doses of alfentanil or fentanyl as well as adjunctive sedation/analgesia for each patient where obtained from our clinical information system (philips icca®). data was included from ecmo patients who were sedated with alfentanil or fentanyl from 1/1/16 to 31/10/2017 until ecmo decannulation. patients not requiring either opiate or who were switched between the two during ecmo therapy were excluded. all medicines prescribed for the management of sedation or agitation were included. for each patient an average total daily dose of each drug, was calculated. data was analysed using stata®. results: both groups were found to be statistically equivalent for mode of ecmo, age, apache 2 score and charlson score (p=0.202) except for bmi (p=0.007). no difference in patient outcomes were found between groups (table 1) . patients in the alfentanil group were found to have received significantly higher median average total daily dose of quetiapine and midazolam (table 2) . conclusions: no differences in patient outcomes were found between patients sedated with alfentanil compared to fentanyl. we introduction: the european society of intensive care medicine consensus statement recommends that for comatose survivors of cardiac arrest 12 hours without sedation is the minimum acceptable before neurological assessment. they highlighted the need to investigate the pharmacokinetics of opioid drugs in post-cardiac arrest patients, especially those treated with controlled temperature [1] . methods: following approval by research ethics committee, we measured the blood concentration of fentanyl in 24 post-cardiac arrest patients treated with ttm following cessation of continuous infusion. the fentanyl was discontinued when the patients were rewarmed to a temperature of 36.5 degrees celsius and a blood sample taken 12 hours later. the blood was analysed using a commercial elisa kit (neogen corporation). using the total dose of fentanyl administered, the half-life of fentanyl was calculated for each patient. patient physiological data, cyp3a4 and abcb1 polymorphism and drug history were compared with half-life. results: the median fentanyl concentration at 12 hours was 0.82 mcg/l with a very wide range (0.07-8.29 mcg/l). the results for calculated half lives are shown in figure 1 . there was no correlation between fentanyl level and bmi, illness severity (saps ll), creatinine clearance, transaminase or lactate level. there was no correlation between co-administration of drugs of metabolised by the cyp3a4 and abcb1 enzyme systems or genotype. conclusions: there is marked variation in the concentration of fentanyl at 12 hours in patients managed with ttm following cessation of fentanyl infusion. the calculated clearance of fentanyl in some patients is greater than 48 hours and a 12 hour cut off is not safe. introduction: objective of this study was to compare the effects of three analgesic regimens, one opioid and two multimodal ones, on cardiovascular stability and pain intensity in patients undergoing elective surgery under general endotracheal anesthesia during the 24 h postoperative period. methods: sixty elderly patients, asa ii, undergoing elective knee sugary were assigned to receive 1) morphine 5 or 10 mg iv q6h, depending on body weight, and paracetamol 1 g iv q6h (mp group), or multimodal nerve block: 2) femoral nerve block, single shot (fnb group) or 3) fascia iliaca compartment nerve block single shot (ficnb group). measurement of pain intensity was performed with numerical introduction: opioids are frequently used in the intensive care unit (icu) to relieve pain and facilitate tolerance of life-support technologies. when discontinued abruptly, patients may develop a cluster of symptoms known as opioid-associated iatrogenic withdrawal syndrome (oiws). this phenomenon is poorly described in critically ill adults although it is associated with unfavourable outcomes, such as prolonged icu stay. the objective of this study was to describe the signs and symptoms of oiws in adult icu patients. methods: a prospective observational study was conducted in two tertiary care centres in patients requiring mechanical ventilation and regular opioids for more than 72 hours. after an opioid dose reduction of at least 10%, patients were assessed daily for signs and symptoms of withdrawal using a standardized form. concomitantly, the presence of oiws was assessed daily by a physician using modified dsm-5 criteria. all physician evaluations were blinded and performed independently. inter-rater reliability for dsm-5 evaluations was assessed with the kappa coefficient. results: a total of 1128 patients were screened and twenty-nine enrolled. the majority were male (72.4%) with a median age of 65. the median apache ii score was 27. withdrawal occurred in 20.7% of patient within a median of three days (iqr 3 to 9 days) from opioid weaning. according to investigator assessment, restlessness, agitation, anxiety, hallucinations, insomnia/sleep disturbance, mydriasis and elevated blood pressure were more prevalent in oiws-positive patients. dsm-5 evaluations identified dysphoric mood, muscle aches, lacrimation/rhinorrhea, pupillary dilation/piloerection/sweating, diarrhea and yawning more frequently in oiws-positive patients. the kappa coefficient showed good agreement (0.64). conclusions: oiws in critically ill adults presents with a large spectrum of signs and symptoms that occur within a median of three days from onset of opioid weaning. further studies are needed to confirm these preliminary findings. withdrawal reactions after discontinuation or rate reduction of fentanyl infusion in ventilated critically ill adults s taesotikul introduction: propofol is a well-known sedative, commonly used in intensive care units (icu s), that on rare occasions has been reported to cause green urine and has also been associated with pink or transient white urine discoloration. it can cause several adverse effects, such as low blood pressure, pain on injection, apnea, hypertriglyceridemia and when administered in high doses it may lead to the "propofol infusion syndrome". methods: we present two examples of interesting urine discolorations observed unexpectedly in our icu in patients under propofol sedation requiring mechanical ventilation. results: dark green urine discoloration as presented in fig.1 is the result of a phenolic metabolite of propofol that is produced in the liver and is subsequently excreted in the urine, thus changing its color. it is considered a reversible phenomenon that resolves after propofol discontinuation.respectively, pink urine discoloration as presented in fig.2 can also be the result of propofol infusion. the increase in urine excretion of uric acid caused by propofol, in combination with a low urinary ph can lead to the formation of uric acid crystals and turn the urine pink. discontinuation of propofol and urine alkalization can reverse the phenomenon. conclusions: green or pink urine discoloration due to propofol is generally a benign, reversible condition. its presence should not compel the physician in charge to perform unnecessary testing, although other causes of discoloration should be considered. as far as green urine discoloration is concerned, other factors such as drugs, dyes, certain nutritional supplements or even a pseudomonas urinary tract infection may be at fault. on the other hand, pink urine syndrome due to propofol infusion seems to be even rarer. although its presentation is not alarming, it may well increase the risk of uric acid lithiasis, a fact that the physician in charge should always keep in mind. conclusions: hepatic changes related to propofol are frequently observed and should be systematically monitored to ensure patient safety. fig. 1 (abstract p405) . dark green urine discoloration introduction: clevidipine (clev) and propofol (prop) are lipid-based medications used in the intensive care unit (icu) for hypertension and sedation, respectively. no data exists regarding potential adverse effects of concurrent therapy with this combination. this study aims to evaluate the incidence of hypertriglyceridemia (htg) and pancreatitis in icu patients using concurrent clev and prop. methods: this was a single-center, retrospective chart review in patients utilizing clev and prop concurrently from february 2015 to november 2018. patients were included if they were 18 years and older, on clev and prop concurrently for at least 24 hours with no more than 2 hours of interruption at a time, had at least one triglyceride (tg) level during concurrent therapy, and admitted to the medical or surgical icu. the incidence of htg (defined as tg equal to or greater than 500 mg/dl) and pancreatitis (provider assessment based on 2013 american college of gastroenterology guidelines) was evaluated. patients with and without htg were compared to identify risk factors for the development of htg. results: of 145 patients screened, 30 patients were included which comprised 36 observations. the incidence of htg was 13.9% with no patients developing pancreatitis. patients with htg had a higher median age compared to without htg (64.5 vs. 38), p=0.015. in patients with htg the median dose of clev and prop were 16 mg/h and 42.3 mcg/kg/min, respectively, which was higher but not statistically significant when compared to patients without htg. cumulative lipid load (g/kg/d) was non-significantly higher in patients with htg (2.6 vs. 1.9), p=0.599. conclusions: the incidence of htg was comparable to what is cited in literature for prop alone. patients with htg were older, had higher median clev and prop doses, and a larger cumulative lipid load compared to patients without htg. introduction: the 2013 society of critical care medicine guidelines for pain, agitation and delirium suggested use of nonbenzodiazepine sedatives like dexmedetomidine which is associated with a reduced duration of mechanical ventilation, shorter length of hospital stay and a lower incidence of delirium [1] . enteral clonidine represents a potentially less costly alternative for agitated patients with prolonged dexmedetomidine infusion. limited literature exists examining this transition for management of agitation [2] . methods: the critical care management initiated an action plan on the transition of patients with prolonged dexmedetomidine infusion to oral clonidine. a protocol was prepared with clinical pharmacist's assistance. risk factors were assessed and inclusion criteria were applied as per protocol. dexmedetomidine infusion rate was reduced gradually with oral clonidine administration in selected patients. other rescue managements were implemented as per protocol. oral clonidine was then tapered down by reducing frequency of administration over few days. results: post intervention data in 2017 showed significant decrease of dispensed doses and cost of the injections compared to 2016. the annual cost saving was 24% equating to 61,249 usd (table 1, figure 1 ). conclusions: transitioning to clonidine may be safe and less costly method of managing agitated critically ill patients on prolonged dexmedetomidine infusion. more studies are needed to evaluate the efficacy and safety of this practice. incidence of dexmedetomidine associated fever at a level 1 trauma center na beaupre, jt jancik hennepin county medical center, pharmacy department, minneapolis, united states critical care 2019, 23(suppl 2):p409 introduction: we evaluated the incidence of dexmedetomidine associated fever (daf) in a level 1 trauma center's medical intensive care unit (micu). hypotension and bradycardia are the most commonly reported adverse effects associated with dexmedetomidine (dex) infusion. case reports suggest dex can cause fevers and the clinical trials that led to the approval of dex demonstrated fever rate to be 4-5% [1] . methods: this was a single-center, retrospective chart review of patients admitted to the micu at hennepin county medical center between march and july of 2018 that were started on a dex infusion. patients were included if they were 18 years and older, on a dex infusion for at least 12 hours, and had temperature data available. fever was defined as >38.3c and other causes of fever including infections, medications, withdrawal, recent surgery, thromboembolic disease, thyroid disorders and seizures were excluded from analysis. results: of the 246 patients screened, 120 were included. the mean age was 50 years and 63.3% were males. of all the patients included, the mean change in temperature after initiation of dex infusion was +1.1c from baseline. the mean initial dose was 0.3 mcg/kg/hr. four of 120 patients (3.3%) had a daf. of those that had a daf, the median initial dose was 0.3 mcg/kg/hr; the median time of infusion was 43.5 hours; and the median cumulative dose was 0.57 mcg/kg/hr. the median time to fever after initiation of dex was 7 hours, with a range of 5 to 20 hours. the median time to fever cessation after discontinuation of dex was 3 hours. conclusions: in our population, the incidence of dexmedetomidine associated fever was relatively rare at 3.3% and similar to current literature rates. the results obtained showed a statistically significant fact that fewer points on the test, from 11 to 20 points, received older patients who underwent an urgent surgical procedure, over 60 years of age, of which 27% . also statistically significant data were obtained that patients who used a higher amount of sedatives during emergency surgery, 47% had a worse test result than under 20 points due to increased preoperative anxiety. the older population is more susceptible to postoperative delirium, especially in emergency surgery situations, which they carry, unpreparedness for surgery, increased use of medication for fig. 1 (abstract p411) . flowchart of enrolled patients calm, unpredictability of the duration of surgery, and therefore anesthesia as well the use of anticholinergics, which is sometimes impossible to avoid in operative procedures such as gall bladder surgery. the results of the study suggest that in cases of emergency surgery, the use of protocols for postoperative delirium should be planned regularly to prevent or at least mitigate the clinical picture of delirium that can lead to complications postoperatively. introduction: delirium is a serious and often underestimated condition with implications for morbidity, mortality and healthcare costs. as it presents in a wide range of settings from admission to discharge, early prediction and risk assessment are essential. e-pre-deliric is a delirium prediction score which has been validated in itu patients but not in other populations, and we conducted a quality improvement project using this score to assess its utility in other settings. methods: data was gathered from three patient categories: those undergoing elective surgery (es), admissions to the emergency observation unit (eou) in the a&e, and patients with fractured neck of femur (nof). clinical notes were reviewed to collect data to calculate e-pre-deliric score at admission, along with a number of other clinical variables including incidence of delirium, and statistical analysis performed. results: a total of 103 patients were included, with 52 in the es group, 32 in the eou group, and 19 in the nof group respectively, with an overall average e-pre-deliric score of 17.5%. es had a 5.4% average e-pre-deliric score, a mean age of 56 and no cases of delirium. the eou group had an average age of 63, a 20.5% average e-pre-deliric score and no incidence of delirium. the nof group had a mean age of 84 and an average e-pre-deliric score calculated on admission of 45.3%. this was the only group in which 5 patients developed delirium. a 50% cut off was demonstrated to be the most accurate to predict delirium in this population with a sensitivity of 0.80 and a specificity of 0.78. conclusions: despite the limitation of a small sample size, this project has shown that e-pre-deliric score could be a useful tool to predict patients at high risk of delirium in a non-itu setting, with a 50% cut off in hip fracture patients. further investigation should be conducted into the potential use of e-pre-deliric in non-itu patients. comparison of long-term mortality between patients with and without delirium during admission in medical intensive care units in a university hospital n kongpolprom king chulalongkorn memorial hospital, pulmonary unit, bangkok, thailand critical care 2019, 23(suppl 2):p415 that delirium is linked with preoperatory comorbidities. the complexity of surgery has a big influence on the development of delirium, especially in the cases of aortic dissection. delirium was associated with intraoperatory blood transfusions. finally, our data point to a bridge between postoperatory electrolytic disturbances, as well as inflammation as factors potentially triggering delirium onset. introduction: we did a retrospective case note study of mortality due to sepsis of our unit over three months as observational study in which we noted the causes of deaths, origin of sepsis, organism, patient characteristics and icnarc physiology scores and icnarc h2015 model predicted risk of acute hospital mortality percentage. methods: icnarc data base was used to gather the data and coding was used to identify the patients with sepsis for three months. patients mortality attributed to sepsis were identified from mortality list.causes of death were noted from patients notes and death certificates.cyber lab was used to access the data and case note were ordered for review.patients characteristics were noted including dnacpr orders and treatment withdrawal orders. scores (apache scores, icnarc physiology scores, icnarc h2015 predicted risk models of acute hospital mortality percentage) were noted. results: mortality percentage was found to be 17% as per codig which was reduced to 12% as 5% deaths were attributed to other causes. 44% patient had dnacpr in first 24hrs. average length of stay was 5.58 days with median of 2.53 days.median age was 66yrs in surviving age group and 78years in other. icnarc physiology score 23 with predicted risk of 56.8%. commonest cause was found pneumonia 49% followed by urine tract infection. 20% patients were with no source identification. conclusions: conclusion was made that we do need to improve the coding as significant percentage was mentioned as sepsis as cause of death where clinicians differed. pneumonia was found to be the commonest killer in critical care followed by urine tract infection. it was pointed to be useful to carry out further audit targeting pneumonia .review of icnarc case mix program, development of icnarc physiology score, which provides excellent local use with downside of lacking international comparison was done also. introduction: hospitals vary widely in the quality of care they provide for septic patients. since many septic patients present to their nearest hospital, local variations in care quality may lead to geographic disparities in access to optimal sepsis care. we sought to better understand geographic access to high quality sepsis care, taking advantage of publicly reported data on sepsis management and outcomes in a large us state. methods: we performed a cross-sectional analysis of geographic access to high quality sepsis care, taking advantage of a 2013 new york state initiative that mandates public reporting of sepsis quality data to the state government. we linked these data to the locations of hospitals in new york state from the us centers for medicare and medicaid services and population data from the us census bureau for 2016. we defined hospital sepsis performance using self-reported risk-adjusted mortality rates (ramr) and defined high-performing hospitals as those with a ramr <20%, which represents the lower end of short-term mortality typically observed in sepsis. we used arcgis to generate drive-time estimates and assess population access to high performing acute care hospitals for sepsis care. results: 161 hospitals publicly reported treating 47,081 cases of sepsis from a population of 19,569,040 persons. overall access to an acute care hospital was excellent at the 45-minute drive threshold (99.3%), good at the 30-minute threshold (95.6%), and marginal at the 15-minute threshold (84.4%). we classified 46 hospitals (28.6%) as high-performing based on a ramr <20%. high-performing hospitals reported 12,666 (26.9%) of the total sepsis cases. high-performing hospitals were geographically dispersed across the state, although population access diminished substantially with increasing drive times (92.6% at 45-minutes, 83.5% at 30-minutes, and 59.8% at 15minutes; figure 1 ). conclusions: one in six people do not have timely access to a high performing hospital for sepsis care using a 30-minute threshold. [1] . this poses a significant safety risk. a previous study found that the implementation of a multidisciplinary medication safety group in intensive care increased reporting of errors and near misses [2] . the purpose of our work was to set up a multidisciplinary group to provide a forum to review and improve medication safety at all stages of the process. here we discuss some of the initiatives and outcomes implemented in the last 12 months. methods: ccmsg was formed in 2013, under the leadership of the critical care pharmacy team, with representation from medical and nursing disciplines. the group meet fortnightly to analyse trends in medication errors, implement changes to local practice and review outcomes to improve patient safety. the cohesive, multidisciplinary nature of the group allows medication safety initiatives to be delivered in the most effective way. results: on average, ccmsg reviewed 21 medication errors per month. the most common high risk drug classes involved are seen in table 1 . medication safety initiatives implemented were based on these trends and included writing guidelines and policies, bedside education, teaching and training, informatics optimisation and operational changes. examples are seen in table 2 . conclusions: initiation of a ccmsg provides a cohesive approach to facilitate the implementation of targeted safety initiatives, which are proven to reduce some of the most common medication errors in critical care. in addition, these often result in optimisation of operational and financial inefficiencies. introduction: cis/hospital electronic medical records downtime can cause major disruptions to workflow, patient care, key communication and information continuity [1] . here we describe the consequences of deploying a business continuity plan (bcp) designed to support a critical care clinical informatics system (cis) failure, during an 8-hour unplanned downtime in a large central london icu. the institutional bcp was developed through an iterative process based on cis provider recommendations and internal workflow knowledge. it consisted of a web offline chart (woc) that is accessible at every computer connected to the network (in the event of a cis server fault), and via hard copy from designated back up computers connected to a printer (in the event of whole network loss). operational and clinical consequences were recorded during informal and formal debrief of the informatics team. the decision making around´drop-to-paper´was reviewed. -the bcp permitted´drop-to-paper´, service continuity and controlled uptime -patchy network loss and lack of a general institutional bcp delayed initial system failure diagnosis (network vs primary server); reduced reliability of´read-only´data and delayedd rop-to-paper-day-to-night handover during downtime led to loss ofḿ emory´of key patient data/events, and should have accelerated decision to´drop-to-paper-transfer of prescriptions was time consuming, distracting (occupied cis team) and prone to error conclusions: previous end-to-end testing of the bcp had not identified many of the observations and recommendations that came from the analysis of an actual period of unplanned downtime. we recommend sharing of similar experiences and scheduled high-fidelity simulated downtime in other institutions to replicate real world conditions, particularly in a critical care setting. .001) were predictors of icu transfer. we developed a simple score to predicting icu transfer from previous variables and performed analysis of auc of roc, which was compared to that of apa-che ii. the result showed the auc of roc of a new score was slightly higher than the apache ii, namely 0.797 vs. 0.720 respectively. conclusions: the immunocompromised patients take two times higher risk than the immunocompetent ones regarding icu transfer. the other risk factors are lower gcs, lower sbp, and higher rr. a newly developed score may be a promising tool for predicting and triaging site of care in patients who require imcu admission. introduction: this research aims to explore the role of situation awareness in the decision-making of patient discharge from the intensive care unit (icu). the discharge of these patients is a complex and, moreover, a challenging transition of care. readmissions are undesirable given the association with a more extended hospital stay and a possible chance of higher mortality. little is known on how the decision-making process takes place and accordingly, the role of situation awareness of patient discharge from the icu. in order to improve the quality of care of patient discharge from the icu, further research is necessary. methods: this research concerns a qualitative study in which various health care providers, working in an icu adults of a large teaching hospital, were interviewed. through purposive sampling, six nurses, two physician assistants, two intensivists and a physiotherapist were included. on the obtained data a thematic analysis was applied, based on the principles of the grounded theory. results: the discharge decision of icu patients seems mainly based on the team´s situation awareness, with the initiating role of the intensivist and the guiding role of the nurse. furthermore, there is an additional role for the physician-assistant and a consultative role for physiotherapy in the process of the decisionmaking. worries of patients and family seem not to affect the decision-making directly. in the decision-making process, the well-being of the patients and the possibility to provide the most suitable and best possible care were central. organizational factors, such as an urgent demand for icu beds do count but seem not to push the decision to transfer patients from the icu to the regular hospital ward. conclusions: the decision to dismiss icu patients is a complex process with different disciplines and a variety of factors involved. obtained knowledge and insights into the role of situation awareness provide starting points for improving the quality of the discharge process of icu patients. conclusions: despite the fact that older people was more severe illnes, and similar frequency of respiratory failure, the use of mechanical ventilation, the use of central venous catheter and arterial catheter was less frequent. the addition of a simulation fellow within the intensive care team and introduction of in situ simulation n bhalla, d hepburn, g phillips royal gwent hospital, intensive care unit, newport, united kingdom critical care 2019, 23(suppl 2):p429 introduction: traditionally, simulation based medical education has been carried out in off site simulation centres, however, we trialled the addition of a simulation fellow, within our intensive care team, to run an in situ simulation (iss) program on our intensive care unit over a 3 month period. methods: our multi-disciplinary iss program, led by a simulation fellow, incorporated participants, observers and facilitators including doctors (junior trainees up to consultants of varying medical specialties), nursing staff, healthcare support workers, operating department practitioners, physiotherapists and medical students. we ran simulated emergency scenarios and technical skills sessions. with every scenario, we collected data on participant and observer feedback using the world health organisation participant feedback form and conducted a satisfaction survey at the end of our trial period. results: our results, highlighted in table 1 , show participants found iss led by a simulation fellow realistic, well structured and organised. it was useful for testing and understanding our response systems, fig. 2 (abstract p426) . patient journey of group 2: those patients discharged home 2 days after step down from critical care identifying strengths and gaps and establishing individual roles/functions within emergencies; overall leaving us feeling better prepared for critical care emergencies. from our satisfaction survey, 100% of participants found the simulation fellow a useful addition to the intensive care team and expressed the need for more in situ simulation. conclusions: the addition of a simulation fellow allowed for numerous disciplines within the critical care team to be involved in challenging emergency scenarios (fig 1, 2) , with the additional realism of being on the intensive care unit playing the role they would in real life; as well as having opportunity for spontaneous discussion and learning. from this they reported great benefit and satisfaction. following our initial success with this program, we plan to have a simulation fellow as an ongoing role within our critical care team. impact of multidisciplinary team in readmission in a brazilian cardiac intensive care unit c bosso 1 , p introduction: the aim of this study is to determine the importance of the multidisciplinary team at readmission rates in a cardiac intensive care unit (cicu). methods: retrospective study with analysis of 2945 patients in a cicu of a medium size brazilian hospital. the years of 2012 and 2013 represent the reduced team (physician, nurse and physiotherapist) and 2015 and 2016 the complete multidisciplinary team (additional presence of phonoaudiologist, psychologist, pharmacist, dentist and nutritional professional). the risk of mortality was determined by saps3 score. in order to compare the teams, it was utilized odd ratio of a logistical sample to the discrete data, and t-student test to the continuous data. the data analysis was executed from the software rstudio (1.1.456), and the significance level adopted was 5%. results: the number of patients was of n=2945 (1422 from the reduced team and 1523 from the multidisciplinary team). the age, sex and bmi didn`t present significant difference between groups. the average age of the sample was 68±13 years old (p=0.13). the male sex represented 58% (p=0.93), and the bmi was around 29.2±23.3 (p=0.12). the main diagnoses were similar in both groups -coronary angiography with stent (16%), unstable angina and non st elevation myocardial infarction (9%). table 1 shows the average, standard deviation, p-value to t-student test to saps 3 score and lengh of stay (days), according to both reduced and multidisciplinary teams. table 2 exposes the mortality rate and readmission for both teams. the figure shows the odds ratio and its ic 95% to the comparison of the mortality, readmission, 24 hours readmission and 48 hours readmission rates between the teams. conclusions: the multidisciplinary team performance reduced the number of hospital readmissions in 24 and 48 hours in a cicu. methods: during the initial audit 24 hours' worth of waste from one itu bed was manually divided into the categories above. results: based on these figures it was estimated that a saving of £1745 per year would be made (£87.25 per bed space) over the course of a year should domestic waste bins be placed across the 20 bed icu/hdu. a business case was made, and every bay had a domestic waste bin installed with poster signs for explanation.the reaudit in which all domestic waste across the unit was weighed produced an even greater figure of a saving of £205 per bed space (£4100) per year. conclusions: introducing a domestic waste bin may save approximately £200 per year per bed. in a typical itu such as lewisham (10 itu beds/10 hdu beds) that may mean a saving of £4000 per year (with 100% capacity). there are also environmental benefits, burning of plastics releases harmful dioxins. the authors wish to make intensive care units and indeed all areas of the hospital aware of the cost and environmental impact associated with disposing of waste in incorrect categories. we hope that our quality improvement project demonstrates how easily money may be saved and environmental footprint reduced. association between resilience and level of experience in intensive care doctors in india j gopaldas, a siyal manipal hospital, bangalore, critical care medicine, bangalore, india critical care 2019, 23(suppl 2):p433 introduction: attrition of doctors in intensive care unit (icu) is one of the highest amongst all medical specialities globally, and is strongly associated with stress and burn out syndrome (bos). factors that contribute to bos are low pre-morbid resilience and low level of icu experience. studies from india have shown high levels of stress in intensive care doctors (>40%), but there are no published studies measuring pre-morbid resilience and risk of burnout in relation to years of experience amongst icu doctors. our main aim was to measure cross sectional resilience levels in icu doctors compared between those with less than 5 years of experience to those with 5 years or more. a secondary aim was to assess the impact of other factors that may contribute to low scores. methods: an anonymised survey was conducted involving 125 doctors in icus across 6 different states in india, using the connor-davidson resilience scale (cd-risc 25), which is validated in indian population. results: a statistically significant correlation was found between low levels of resilience in icu doctors with under 5 years of experience 1.456) , and the significance level adopted was 5%. a logistic regression model was used to test the difference between the mortality and readmission rates in <90 and ≥ 90 groups, which enabled the calculation of odds ratios. chi-square test was used to evaluate categorical variables and t-student test to some quantitative variables. the roc curve was constructed to verify the sensitivity of prediction of mortality through different saps 3 scores. results: among the <90 and ≥ 90 groups, respectively 59% and 37% was male (p = 0.0001). mean weight of the> 90 years was 76 ± 16 kg and <90 years was 61 ± 11 (p <0.0001). odds values indicated a significant difference only for the mortality rate, which was more than double among ≥ 90. readmissions in any time, 24h and 48h as well the mortality is shown in table 1 and odds in figure 1 . there was a significant difference in saps 3 points between groups ( table 2 ). the ≥ 90 group presented an average of 10 points higher on the severity scale when compared with those in the <90 group. there was no significant difference in lengh of stay. the highest amount provided by saps3 scores was 63% and a specificity of 86% for hospital mortality not group <90 years. in ≥ 90 group the highest sensitivity was 53% and the specificity was 84%. roc curve for saps3 is shown in figure 2 . conclusions: the extremely elderly patients of a cicu is more severe, with higher mortality and have the same lengh of stay and readmission rates. introduction: the purpose was to assess the prevalence and impact of non-urgent interruptions (nui) within critical care (cc).a root cause analysis of a never event in our cc discussed nui as a contributory factor, paralleled by learning from serious incidents.the negative impact of nui is well evidenced, resulting in delayed task completion, increased stress, and affecting patient safety. methods: any nui during a consultant ward round (cwr) or invasive procedure (ip), not relating directly to the current clinical episode, was included. qualitative data was collected by a survey, assessing the cc multidisciplinary teams(mdt) perception of nui. results: one third of reviews during the cwr, and 40%of ips, had a nui. adverse effects included prescription omissions, delayed cwr, near-miss with a cvc, and failed picc insertion. overall, 86% of staff considered nui a problem; 95% had experienced nui that led to distraction in train of thought. 45% felt that nui had led to an error: 83% of doctors, versus 20% of nurses. 86% overall felt nui contributed to stress at work. reasons for interruptions included: feeling overloaded, needing to resolve concerns before forgetting/being distracted, unable to prioritise, and to shift responsibility.lack of leadership or clinical supervision providing a point of contact for problems during shifts was mentioned as contributory. senior staff raised that whilst attempts have been made to level hierarchy, allowing a voice for all to express concerns contributes to interruptions. potential solutions included awareness on impact of nui, jobs book,´sterile cockpitd uring ips, and increased clinical supervision during shifts. conclusions: we have demonstrated the prevalence and consequences of nui within cc is significant.the impact on staff is significant, both for contribution to errors and also the negative impact on stress in the workplace. identified potential solution will be implemented. the impact of an education package on the knowledge, skills and self-rated confidence of medical and nursing staff managing airway & tracheostomy/laryngectomy emergencies in critical care l o´connor 1 , k rimmer 2 , c welsh methods: the factors affecting the delivery of intensive care was elucidated by a comprehensive review of the intensive care literature. a further understanding of intensive care delivery in south africa was obtained by "making sense of the mess" with eight workshops and 20 interviews using a systems approach. systemic intervention served as the meta-methodology and methods and techniques from interactive planning, critical systems heuristics, soft systems methodology and the viable system model were employed. results: making sense of the mess emphasised the complexity of intensive care delivery, on both a situational and a cognitive level. it became clear that a single methodology would not suffice, but that a pluralist methodology was required to guide improvement in intensive care delivery. based on this understanding, nine principles were formulated to guide the development of a framework. systemic intervention was again used as the meta-methodology. interactive planning was identified as the key methodology, incorporating methods and techniques used in the making sense of the mess phase to build a systemic framework for the improvement of intensive care delivery. embedded in the proposed framework are matters relating to systemicity, complexity, flexibility, empowerment, and transformation of intensive care delivery. the proposed framework allows for multiple-perspectives, including that of marginalised stakeholders, the mitigation of multivested interests and power relationships (fig 1) . it is both flexible and adaptable to promote learning about the complex problems of intensive care delivery and it accommodates the strengths of various relevant approaches to complex problem solving. conclusions: the proposed framework aims to facilitate sustainable improvement of intensive care delivery and to ensure the "just-use" of resources to foster distributive justice. the perioperative management of adult renal transplantation across the united kingdom: a survey of practice c morkane 1 , j fabes 2 , n banga 3 , p berry 4 , c kirwan 5 introduction: there is a limited evidence base to guide perioperative management of patients undergoing renal transplantation and no national consensus in the uk. we developed an electronic survey to provide an overview of uk-wide renal transplant perioperative practice and determine the need for future guidelines on patient management. methods: a 29-question survey was developed to encompass the entire renal transplant perioperative pathway with input from clinicians with expertise from renal transplant surgery, anaesthesia, nephrology and intensive care. the survey was sent to lead renal anaesthetists at each of the 23 transplant centres across the uk. results: twenty-two centres (96%) returned complete responses. there was limited evidence of guideline-based approaches to preoperative work-up, with marked variety in modality of preoperative cardiorespiratory function testing performed. questions regarding intraoperative fluid management (fig 1) , blood pressure targets and vasopressor administration (fig 2) identified a broad range of practice. of note, the routine use of goal-directed fluid therapy based on cardiac-output estimation was reported in six (27%) centres whilst nine centres (41%) continue to target a specific central venous pressure (cvp) intra-operatively. a dedicated renal ward was the most common postoperative destination for renal transplant recipients (62% of centres), whilst a renal or transplant-specific hdu provided postoperative care in 8 (38%) centres. the need for care in an icu setting was decided on a case-by-case basis. conclusions: this questionnaire highlighted a high degree of heterogeneity in current uk practice as regards the perioperative management of renal transplant recipients. development of evidence-based national consensus guidelines to standardise the perioperative care of these patients is recommended. fig. 1 (abstract p437) . framework for the improvement of intensive care delivery introduction: postoperative care of high risk patients in the icu used to be considered the gold standard of care in terms of reducing perioperative mortality [1] . new evidence comes to question this practice [2] . the primary objective of our study was to detect any benefit of postoperative icu care after elective surgery in terms of patient's outcome, length of hospital stay, complications and cost. methods: a 6-month retrospective analysis of high perioperative risk patients who were about to be subjected into an elective operation were included into the study. subsequently they were allocated into two groups. group i patients were those admitted into the icu for postoperative care while those admitted into the standard ward consisted group ii. demographic data, length of hospital stay, outcome, need of mechanical ventilation, complications and total cost were recorded. results: a total of 78 patients were recorded, 39 in each group. there was no statistical difference regarding the demographic data between the two study groups. seven patients died before hospital discharge (5 in group i and 3 in group ii, p>0.005). there was no impact of icu admission on length of hospital stay (p=0.03) which is primarily affected by the need of mechanical ventilation (p=0.04) and reoperation (p<0.05). the total cost and the postoperative cost of hospital care did not statistically differ among study groups. conclusions: according to our study the need of postoperative care of high risk patients in the icu is rather questionable in terms of perioperative mortality, length of hospital stay and cost of care. introduction: tivap is a preferred vascular access device for patients with solid tumors and radiological-guided insertion is a standard of care. however, many hospitals have no access to interventional radiology service. our study aimed to determine whether it is safe to place tivaps in icu for immediate administration of chemotherapy. methods: we analysed prospectively maintained database of our department and collected data for adult pts with tivaps implanted between 02/2008 and 10/2018. the median age was 55 (range 18-82) years, 59% were women. all procedures were performed by 3 trained physicians with experience in ultrasound (us). puncture technique was used and tip location was controlled with electrocardiographic (ecg) and us with subsequent chest x-ray confirmation. pts were followed up for at least 30 days after the procedure for complications, functioning of tivap and surgical wound healing. results: all 277 tivaps were successfully implanted in 276 pts. infraclavicular route was used in 231 cases (83.3%). difficulties with indwelling guide wire were observed in 11 (4.76%) pts but did not precluded implantation. placement complications included pneumothorax (n = 3), catheter malposition (n = 3) and artery bleeding (n = 1). these complications required additional therapy but were managed successfully and resolved without consequences. in the rest 46 cases internal jugular vein (jv) was used. complications were not observed. ecg and us navigation provided optimal tip location control in these situations. surgical wound healed after 10-14 days and chemotherapy initiation did not affect healing. all tivaps had adequate functioning 30 days after placement. conclusions: it is feasible to implant tivaps in icu. these devices can be used on the implantation day without jeopardizing patient safety. jv catheterization seems to be optimal approach and us navigation and ecg are sufficient methods for placement control. introduction: there is increasing use of clinical information systems to improve patient safety and quality of care in critical care. with all these systems, a rigorous business continuity access (bca) plan needs to be in place so patient safety is not compromised [1] and ensure continuity of care. here we evaluate the types of medication errors that occurred during a period of unscheduled downtime; potential contributory factors [2] and the number of errors involving critical medicines [3] were analysed. methods: during the unscheduled downtime, all prescribing and administration of medicines were transferred to a paper based system using the patients' web offline chart (woc -philips healthcare). pharmacists at the time double checked the paper charts that were transcribed, to mitigate errors but this was not consistent due to the timing of the event. we retrospectively compared the paper drug charts against the electronic prescriptions and noted all errors for 47 patients. results: in total 26 medication errors were identified & 1 allergy omission ( table 1) . pharmacists double checked 68% of the paper charts. conclusions: our data highlights the risks associated with unscheduled electronic patient management system downtime and the heterogeneity of the types of errors & potential contributory factors. it underscores the need for robust local bca plan implementation, critical review of the woc document and regular staff training around potential unscheduled system downtime. introduction: the transfer of patient care (toc) between the intensive care unit (icu) and hospital ward is associated with a high risk of medical errors [1] .according to uk national data between 30-70% of patients have an error or unintentional medication change made when moving between care settings [2] . currently different prescribing systems without interoperability are used between icu areas & ward settings in our institution, resulting in medications needing to be re-prescribed on transfer. we aimed to evaluate the time delay in medication re-prescribing, number of unintentional omissions of drug doses and reasons, as well as percentage of critical medicines [3] omitted in the first 24h following discharge. methods: over a 2 month period, 79 discharged patients (50% of all discharges) from two icu units were included. the icu discharge letter which contained the medication list on transfer was compared against the ward based electronic drug chart to identify all unintentional omitted medication doses during the first 24 hours. the starting time point was when the patient physically left icu. results: 13/79 (16%) of patients had their medication prescribed more than 4 hours post discharge. there were a total of 269/1,145 (23%) unintentional omitted doses (table 1) . of these 104/269 (39%) were considered critical medicines ( table 2) . conclusions: this data confirms the risk associated with toc especially around medicines. the need of interoperable electronic prescribing systems is one solution and could improve patient safety by streamlining the process. introduction: staff perceptions of safety may contribute to workforce stress and be organisationally important [1] . this study explored the feasibility of capturing perceptions of safety with a bedside professional reported (bpr) shift safety score, and explored relationships between bpr and measures of staffing and workload. methods: uk health research authority approval was obtained (id249248). data were collected for 29 consecutive days at imperial college healthcare trust (70 general critical care beds on 3 sites).the bpr asked all icu staff to rate each shift as "safe, unsafe, or very unsafe". responses were described and correlated with data on organisational staffing (care hours per patient day chppd) and nursing intensity (total number of organs in failure/ total number of nurses). results: a total of 2836 bpr scores were recorded (response rate 57%). we noted heterogenous responses between sites and days, and within shifts, only 14 % of shifts were unanimously rated. whilst 34% of shifts were rated by staff as "unsafe" or "very unsafe", organisational metrics recorded only 5% as 'unsafe'. we did not find a correlation between measures of staffing (chppd) and perceptions of safety ( figure 1 ). preliminary analyses suggest that staff perceptions of safety are not well correlated with nursing intensity (figure 2 ), although these numbers commonly inform staffing metrics. conclusions: completing the bpr tool was feasible and acceptable to staff. responses showed variations in perceptions of safety and a gap between organisational metrics and individual perceptions. introduction: delivery of intensive care (icu) is complex because of multiple stakeholders with varied perspectives and conflicting goals that interact and are interdependent. to inform the development of a framework for the improvement of icu delivery in south africa, it was essential to first understand icu delivery or "make sense of the mess". a systemic approach such as systems thinking is required to holistically explore and understand the complexity of icu. no methodology is perfect and methodological pluralism as proposed by systemic intervention, a systems thinking approach, was used for a more flexible and responsive intervention. the methods used was the making sense of the mess phase of interactive planning, stakeholder analysis as describe by critical systems heuristics, rich pictures from soft systems thinking and viable systems model diagnosis. making sense of the mess was done in 2 phases: first the mess was formulated with rich pictures generated in 8 workshops and 20 interviews. the discussions of the rich pictures by the respective stakeholders were transcribed and analysed using braun and clark's thematic analysis. secondly, based on the data generated from phase 1 a diagnosis of the viability of the icu system was made. results: the data from the 2 phases were very rich and complex and 6 themes emerged (figure 1 ). these themes were interdependent and resulted in disorganised icu delivery with limited opportunities for learning to improve icu delivery with dichotomies that existed at various levels of icu. it was a problem to present the complex data in the traditional linear manner due to the interdependence of the themes. the analysis is presented as 6 stories, a known approach in the complexity discipline, where the themes of the analyses are portrayed. the making-sense-of-the-mess phase confirmed the complexity of icu delivery, at both a situational and a cognitive level and with this understanding a framework for the improvement of icu delivery could be developed. introduction: improving prescribing practice involves changing prescriber behaviour. education is assumed to change behaviour but other approaches may be more effective (figure 1 ) [1] . changes to the presentation of information and the configuration of choices have potential to rectify common prescribing errors through subtle 'nudges' [2] . the implementation of clinical information systems (cis), including electronic prescribing, provides an opportunity to deploy strategies such as standard orders, dose limits, and product level prescribing. with an infinite number of configuration options available, clinical leaders need to know which interventions are most effective. we evaluated several of these strategies in a before and after observation study methods: interventions, utilising cis nudges, were chosen to improve four areas of prescribing practice in a tertiary critical care unit using methods matched to the top 4 levels of the hierarchy. data were collected for 2 months before and after interventions to map changes in compliance with a pre-defined standard except for the standardisation intervention where 4 months' data were collected due to low prescription numbers. no education on changes was given during the baseline data collection so any change in performance after the go-live date is entirely attributable to the intervention. results: the change in performance for each level ranks the intervention levels in the order (highest first) forced function, automation and standardisation ( table 1 ). the use of point of prescribing reminders was not associated with a significant difference in performance. conclusions: the effectiveness of intervention levels seen in practice is consistent with that of the model. further studies could be undertaken to strengthen these conclusions but in the meantime the approach to changing practice using cis nudges should focus on standardisation or above. introduction: intensive care unit (icu) sound pressure levels (spl) are persistently above world health organisation recommendations for clinical areas [1] . this may impact patient recovery. standard spl monitoring records single values for each 24h period (laeq24). we hypothesise this reporting rate is unsuitable for icu. methods: we measured spl october 2016 -may 2018, logging frequency (hz), spl (db), and loudness (perception of sound) every second [2] . the resulting dataset was of a size that conventional statistics programs would require computational resources not easily obtainable on standard university commodity hardware. we processed the full dataset without sampling by using distributed task dispatching, parallelism and scheduling of a cluster computing framework (apache spark). we created a system consisting of a single workstation (6 cores; 32gb ram) running ubuntu 18.04 lts, oracle java 1.8, apache spark 2.3, scala 2.11, r core 3.5, r studio 3.5 and sparklyr 0.8.4. we utilised the sparklyr library in r studio to run arbitrary r code using the dplyr library. we analysed aggregate data in r core & used ggplot (v3) to create visuals. results: we achieved more complex analysis than standard spl reporting with relatively modest computing resources. specifically we identified lower spl peaks in the early hours & loudness levels considerably higher than parallel spl. conclusions: simple laeq24 do not facilitate reflection on practice thus impetus for change is limited. loudness data highlight the patient experience of spl in the icu is more intrusive than laeq24 indicates due to high sensitivity to sounds~2-4khz, a common frequency range for alarms. higher fidelity increases understanding of spl which can lead to targeted interventions to reduce patient disturbance. introduction: survivors of critical illness face significant long term impairments in mental and physical function. early mobilisation (em) in the intensive care unit has been suggested to improve functional outcomes and reduce delirium in the icu. we hypothesized that implementing a protocol for em in the icu would improve mobilisation rates while remaining safe. methods: design: prospective non-blinded observational cohort study, based on a quality improvement project. data was collected conclusions: only 6 of 10 variables in boyd criteria were significant associated with morbidity or mortality. the physiologic score and operative score were significant higher in the patient on mortality and morbidity after sicu admission. effects of structural hospital characteristics on risk-adjusted hospital mortality in patients with severe sepsisanalysis of german national administrative data d schwarzkopf 1 introduction: the quick sequential organ failure assessment (qsofa) score is a simple tool used to identify severe patients with infection. as this score is calculated from three variables that can be measured at the scene of trauma-systolic blood pressure, respiratory rate and consciousness-the prehospital qsofa score may also be a good predictor of mortality in trauma patients. so we evaluated the discriminative ability of the prehospital qsofa score in patients with trauma for in-hospital mortality. methods: this is a retrospective multicenter study using the data from nationwide trauma registry in japan. we included 42722 patients with trauma aged ≥18 years old transferred to hospitals from scene. primary outcome is in-hospital mortality. results: the mean age was 59.4±21.5 years old and 27069 patients (63%) were male. in-hospital mortality occurred in 2612 patients (6%). in-hospital mortality in each qsofa score was 105/11783(0.9%), 941/17839(5%), 1280/11132(12%) and 286/1968(15%) in qsofa score 0, 1, 2 and 3, respectively (p<0.0001 for trend). area under receiver operating characteristics curve (auroc) of the aqsofa score for inhospital mortality was 0.70(95% confidence interval 0.69-0.71). if we use the cutoff ≥1, sensitivity and specificity of the qsofa score were 0.96 and 0.29. conclusions: in patients with trauma, the prehospital qsofa score was strongly associated with in-hospital mortality. we can identify patients with very low risk of death by using the cutoff ≥1 of the prehospital qsofa score. introduction: only one prospective study is available of the validation of the diagnostic and prognostic role of qsofa (quick sofa score) in the emergency department (ed). a prospective study was conducted in greek eds. methods: the prompt study (clinicaltrials.gov nct03295825) run in the ed of six hospitals in greece among patients with suspected infection and presence of at least one of fever, hypothermia, tachycardia, tachypnea and chills. clinical data were collected and the 28-day outcome was recorded. sepsis was defined by the sepsis-3 criteria. results: the sensitivity and the specificity of at least 2 signs of qsofa for the diagnosis of sepsis was 78.4% and 96.8% respectively and for the prognosis of 28-day mortality 45.7% and 94.2% respectively. the odds ratio for 28-day mortality when qsofa was equal to or more than 2 was 59.67 among patients with charlson's comorbidity index (cci) equal to or less than 2; this was 7.45 among patients with cci more than 2 (p: 0.038 between the two ors by the breslow-day's test; p: 0.040 by the tarone's test). conclusions: data validated the sensitivity of qsofa for the diagnosis of sepsis. cci was an independent predictor of severity. qsofa could better predict unfavorable outcome among patients with low cci. comparative accuracy between two sepsis severity scores in predicting hospital mortality among sepsis patients admitted to intensive care unit n sathaporn, b khwannimit prince of songkla university, internal medicine, hat yai, thailand critical care 2019, 23(suppl 2):p455 introduction: recently, the new york sepsis severity score (nysss) was developed to predict hospital mortality in sepsis patients. the aim of this study was to compare the accuracy of nysss with the sepsis severity score (sss) and other standard severity scores for predicting hospital mortality in sepsis patients. methods: a retrospective analysis was conducted in a medical intensive care unit of a tertiary university hospital. the performance of severity scores was evaluated by discrimination, calibration, and overall performance. the primary outcome was in-hospital mortality. results: overall 1,680 sepsis patients were enrolled, 895 patients (53.3%) were classified to septic shock by sepsis-3 definition. hospital mortality rate was 44.4%. the nysss predicted hospital mortality 34.6+/-21.5%, which underestimated prediction with smr 1.28 (95%ci 1.19-1.38) . however, the sss predicted hospital mortality 47 +/-22.2%, which slightly overestimated mortality prediction with smr 0.94 (95%ci 0.88-1.01). the nysss had the moderate discrimination with an auc of 0.772 (95% ci 0.750-0.794), in contrast to the sss presented good discrimination with an auc of 0.889 (95%ci 0.873-0.904). the auc of sss was statistically higher than that of nysss (p<0.0001). nevertheless the apache iv and saps ii showed the best discrimination with auc of 0.937. the auc of the nysss and sss was significant lower than that of apache ii, iii, iv, saps ii and saps 3 ( figure 1 ). the calibration of all severity scores was poor with the hosmer-lemeshow goodness-of-fit h test < 0.05. the nysss was the lowest overall performance with brier score 0.201. the apache iv present the best overall performance with brier scores 0.107. conclusions: the sss indicated better discrimination and overall performance than the nysss. however the calibration of both sepsis severity scores and another severity score were poor. furthermore, specific severity score for sepsis mortality prediction needs to be modified or customized to improve the performance. introduction: metabolic markers, especially lactate, have been shown to predict mortality in acutely unwell patients. we hypothesised that early changes in metabolic markers over time would better predict mortality and length of stay, with patients who correct their metabolic derangement having lower risk of death and reduced length of stay (los). methods: single centre, retrospective cohort study in a 31 bed icu. we included all patients who had an arterial measurement of lactate, paco2, base excess (be) and ph on admission and at 6 hours after admission to icu between 01/01/2016 and 31/12/2017. the 'clearance' of these markers was calculated using the equation ((value at admissionvalue at 6 hours)/value at admission). clearance calculations only included those patients with deranged results on admission (lactate>2mmol/l, be<-2mmol/l, ph<7.35, paco2>6.0kpa). roc analysis was used to predict in-hospital mortality and length of stay, using both the initial admission values, and using the clearance value, as well as icnarc and apache ii scores for comparison. if a patient was admitted twice in the time period, only the first admission was included. results: 1506 patients were included (sex ratio 1.5, mean age 61.6). table 1 ). none of the values tested had a auc greater than 0.6 for predicting length of stay. conclusions: the clearances of metabolic markers over the initial 6 hours after icu admission does not provide better prognostic information than the value at admission. initial lactate level was the best predictor of mortality, but compared poorly to icnarc score. metabolic markers do not accurately predict length of stay. 8.0-22.8) vs 9.1 (iiq 9.6-9.9), p=0.005]. the other hemogram parameters did not differ between groups (table 1) . when adjusted for severity score, in patients submitted to emergent surgery, the mpv value was still independently associated with mortality (or 1.146 ci 1.057-1.243, p=0.042), and its roc curve (auc) was 0.861 to mortality (figure 1 ). conclusions: mpv is a cheap and easily accessible marker which can add prognostic value in this specific population. in the future, we will validate it in a larger cohort of cancer pts admitted to intensive care. haematological malignancy in critical care: outcomes and risk factors c denny 1 introduction: about 7% of patients admitted to hospital with a haematological malignancy will become critically ill [1] . life expectancy in these patients is poor with a 6 month mortality of 60% or more in specialist units [2] . in contrast, patients without critical illness can expect a 5 year survival rate exceeding 60% for many cancers. this disparity results in differences of opinion on the best strategy for such patients among haematologists and critical care physicians. we conducted a local quality improvement project to quantify mortality and risk factors in critically ill patients with a haematological malignancy in our hospital. methods: patients admitted to the critical care unit of broomfield hospital, a district general hospital with tertiary specialist services, from january 2011 to december 2017 with haematological malignancy were included in the analysis. patients in remission for more than 20 years and patients admitted following elective surgery were excluded from analysis. death in critical care or in hospital after critical care discharge were the primary outcomes. mortality was correlated with demographic data using simple statistical measures and regression analysis. results: 93 patients were included in the analysis. overall mortality was 45%(n=42). survivors tended to be younger (65 vs 71 years) but had similar clinical frailty scores. early critical care admission (within 24 hours) was associated with better survival (72.5 vs 35.7%). nonsurvivors had a greater incidence of sepsis and respiratory failure, and required more ventilatory and vasopressor support. mortality was higher in patients requiring more than one organ support. conclusions: the overall mortality in our data is lesser than previously published data but supports the conclusion that mortality is determined primarily by the number of organs supported with the effects of malignancy playing a secondary role. (figure 1 ). increasing levels of frailty were associated with increasing risks of death at 1 year (p<0.001) (figure 2 ). frailty significantly increased 1-year mortality hazards in unadjusted analyses (hr 1.96; 95%ci; 1.41-2.72; p<0.001) and covariate-adjusted analyses (hr 1.41; 95%ci 1.00-1.98; p=0.0497) ( table 2) . conclusions: frailty was common and associated with greater age, more severe illness and female gender. frailty was significantly associated with heightened mortality risks in both unadjusted and covariateadjusted analyses. frailty scoring may encapsulate variables affecting mortality which are omitted in current predictive systems, making it a promising risk stratification and decision-making tool in icu. fig. 1 (abstract p461) . unadjusted survival curves stratified by frailty status. frail patients were statistically significantly less likely to survive to 1 year plateau at day 4=18, delta peak=2 and hpr=0.34. were assigned respectively a point value of 1, 1, and 2 to these predictors based on their beta coefficient in the predictive model. the score yielded a roc-auc: (auc=0.79; 95%ci, [0.72-0.86]; p=0.000). using the validation data set (n=104), the score had an roc-auc=0.8 and similar estimated probabilities for mortality. conclusions: the paw-mps seems to demonstrate interesting discriminative properties to predict mortality. what is the role of the pulmonary embolism severity index (pesi) and rv/lv ratio as clinical risk assessment tools for patients undergoing ultrasound-assisted catheter-directed thrombolysis (uacdt)? introduction: to evaluate if the pulmonary embolism severity index (pesi) score correlates with rv/lv ratio, biomarkers of cardiac injury, fibrinogen and length of stay(los). also to evaluate the correlation between rv/lv ratio with biomarkers of cardiac injury, fibrinogen and los for patients who underwent uacdt. methods: a retrospective review of patients with sub-massive pulmonary embolism (pe) who underwent ultrasound-assisted catheterdirected thrombolysis (uacdt) was performed. pesi score, rv/lv ratio, length of stay(los), fibrinogen levels, troponin levesl, and brain natriuretic peptide(bnp) levels, were calculated and collected prior to uacdt. spearman's rank correlation coefficient was calculated for all non-parametric variables. results: 31 patients, 17 males and 14 females, were included in the study. the mean (±sd) age was 54±17 years. the mean pesi score was 93±38. mean rv/lv ratio was 1.34±0.35. a significant correlation between the rv/lv ratio and both fibrinogen and troponin level (p=0.0013, p=0.0167) was noted. no significant correlation existed between pesi score and rv/lv (p=0.85). no significant correlation existed between both rv/lv ratio and pesi score with length of stay (p=0.1649) after uacdt. there were no noted mortality or complications. conclusions: pesi score is used as a prognostic factor for the patients with pe, however, our study shows that pesi score does not correlate with rv/lv ratio or length of stay after the uacdt. there was inverse correlation between rv/lv ratio and fibrinogen. there was also positive correlation between rv/lv ratio and troponin for patients with and without heart failure. according to our data, there may be limited use of pesi score and rv/lv ratio for risk stratification of pe patients undergoing uacdt. introduction: conventional scores for prediction of risk and outcome, such as sapsii and sofa, have not been validated for patients admitted to level ii critical care units (intermediate level or imcus). we compared the performance of sapsii and sofa scores with the intermediate care unit severity score (imcuss) in a general population admitted to imcu. methods: we conducted a prospective observational cohort study in a 31-bed level ii-iii icu from a university-affiliated hospital, during a three-month period. we applied sapsii, sofa day one and imcuss to all patients admitted during that period. primary outcome was a composite of hospital mortality and need to increase level of care. additionally, we tested the relevance of each variable within each score to predict the outcome. results: we included 108 patients with a mean age of 61.7±18.6 years. 63 patients were considered "step-down" (transferred from our level iii beds), and the remaining originated from the emergency conclusions: 12 months after completion, the primary care management intervention had no effect on mental health-related quality of life and physical function among survivors of sepsis. increase in ptsd symptoms in the control group may suggest a possible protective effect of the intervention. introduction: critically ill patients and their families are often confronted with an overwhelming amount of clinical information shortly after hospital admission. their reliance on internet resources for additional information is increasing, particularly for unfamiliar medical terminology. yet, little is known about whether these online resources meet the recommended reading level and complexity appropriate for the average reader. methods: an online search of 40 websites containing four common critical care diagnoses in the icu (respiratory failure, renal failure, sepsis and delirium) was performed. a total of 6 readability formulas were used. the flesch-kincaid grade reading level (grl) and flesch reading ease (fre) were used in the final analysis. document complexity was evaluated using the pmose/ikirsch formula. results: websites on respiratory failure were written at the 13th grl with fre of 29.6. renal failure resources had a 9th grl with fre of 54.7. sepsis websites had an 8th grl with fre of 48.3. delirium websites had a 12th grl with fre of 31.6. when comparing website types (government, non-profit and private), anova showed a difference in fre across all 3 groups and government websites had a conclusions: online resources used by intensive care unit patients and families tend to be written at higher than the recommended 6th grl, with government sites better meeting this target than nonprofit and private organizations. online resources should be improved to lower this unfortunate barrier to patient education. introduction: the recent enactment of the data protection act 2018, the general data protection regulations, and a series of data breaches in the healthcare sector, have renewed interest in how our patients' information is collected, used and shared. the complex framework of laws and regulations governing the use and disclosure of personal data may lead to professional and financial consequences if information is disclosed inappropriately. disclosures to the police when they concern incapacitous patients are particularly challenging, as the disclosure may have no direct benefit to the patient and may cause the patient considerable harm. methods: we have reviewed the relevant laws and regulations to identify the circumstances in which doctors must release information regarding incapacitous patients to the police. the laws and regulations are examined to identify the extent of the disclosure required, and any requirements for the disclosure to be lawful. we have also identified laws which confer a power to disclose information about incapacitous patients, and the circumstances in which these powers can be used. results: in conjunction with a local police constabulary we have developed an information request form which makes it easier for those requesting and disclosing information to understand the legal basis of the disclosure. we have also developed guidelines to allow practitioners to understand where a disclosure is obligatory or discretionary. conclusions: the next stage of the project is to audit disclosures of information in the intensive care unit, and identify whether information is being released lawfully and following the correct procedure. introduction: family members are affected both physically and psychologically when their relative is admitted to icu. there is limited knowledge describing their experiences and structured interventions that might support them during their relative's critical illness. the aim of this review is to describe published literature on the needs and experiences of relatives of adult critically ill patients and interventions to improve family satisfaction and psychological well-being. methods: design: scoping review. standardised processes of study identification, data extraction on study design, sample size, sample characteristics and outcomes measured (figure 1) . results: from 469 references, 43 studies were identified for inclusion four key themes were identified: 1) different perspectives on meeting family needs 2) family satisfaction with icu care 3) factors impacting on family health and well-being and capacity to cope 4) psychosocial interventions conclusions: family members of patients in icu experience unmet information and assurance needs which impacts on their physical and mental health. structured written as well as oral information show some effect in improving satisfaction and reducing psychological burden. icu's who are able to support interventions based on meeting family information needs, in addition to reducing psychological burden and increasing satisfaction will enable each family to provide more support to their relative within the icu. introduction: unmet informational needs lead to dissatisfaction with care and psychological distress. identifying interventions to help meet specific needs is a crucial and necessary step in providing family centred care in icu. we aimed to implement and evaluate the impact of delivering a structured communication strategy on levels of anxiety, uncertainty and satisfaction with care and decision making in families of critically ill adults. methods: a quasi experimental study with pre and post test design. a convenience sample of 52 family members were recruited from july 2016 to february 2018. the intervention group (n=26) received both oral and printed information to guide them in preparing for a structured family meeting. the control group (n=26) received usual fig. 1 (abstract p476) . article selection process for scoping review routine care and existing family informational support. anxiety, uncertainty and family satisfaction were measured in the two groups on icu admission and icu discharge. results: mean anxiety, uncertainty and satisfaction with care and decision making scores pre and post intervention were compared. there were no significant differences in mean anxiety, uncertainty or satisfaction scores between the two groups before the intervention (p>0.05). mean scores on anxiety (45.5vs 46.9), and uncertainty (72.4 vs 76.7) were lower post intervention, but not significantly so ( figure 1&2 ). total satisfaction, satisfaction with care and satisfaction with decision making mean scores were similar in both groups before and after the intervention (p.0.05). conclusions: providing relatives with a combination of targeted written and oral information delivered by nursing and medical staff reduced anxiety and uncertainty with this reduction being evident through to discharge from icu. although not statistically significant, there was what may be seen as a suggestion of a clinically significant drop in anxiety and uncertainty following the intervention introduction: clinical studies in intensive care unit (icu) patients are warranted in order to improve healthcare. the aim of this study was to analyse barriers and challenges in the process of achieving informed consent from icu patients. methods: we analysed patients considered for inclusion in a prospective observational study of venous thromboembolism in the icu, i.e. the norwegian intensive care unit dalteparin effect (norides) study. data were collected from the screening log, consent forms and associated research notes of the norides study. results: we observed that 58 of 279 (20%) eligible patients according to inclusion and exclusion criteria were omitted from the nor-ides study due to barriers and challenges in the process of receiving informed consent. 21 were categorized as psychiatric diseases consisting of known psychosis or recent suicide attempt, 19 likely or actual treatment withdrawals and 18 due to language barriers among non-norwegians. among the 70 patients included in the norides study, 29 (41%) consents were from patients and 41 (59%) obtained from their next of kind. from the patient consents, 11 (38%) consents were oral and 18 (62%) were written. 6 patients were physically unable to sign, and 7 patients did not recognize their own signature. the study further pointed at some specific challenges in the process of consent, herein questionable competence to give consent, failure to remember being asked/included, inability to separate research from treatment etc. there were also difficulties in evaluating who was next of kin and how to reach them. conclusions: barriers and challenges in obtaining informed consent from icu patients led to exclusion of one fifth of the eligible patients in our study. informed consent directly from patients was obtained from less than half of the included patients. obstacles in the process of achieving informed consent were practical, medical, ethical and/or legal. determinants of end-of-life decision-making in the intensive care unit p eiben, c brathwaite-shirley, s canestrini king´s college hospital nhs foundation trust, london, united kingdom critical care 2019, 23(suppl 2):p479 introduction: although the majority of intensive care unit (icu) deaths follow the decision to forgo life sustaining treatment (lst), variability in patterns is commonly observed [1, 2] . we reviewed end of life (eol) practice at our institution in order to explore: (i) patient characteristics affecting eol decision-making, (ii) communication among surrogate decision-makers, and (iii) eol management. methods: we retrospectively analyzed data from consecutive patients who died in our ten-bed icu over 16 months (study period). patient demographics, apache ii, functional status, diagnosis on admission, icu length of stay (los) were collected; family/next-of-kin (nok) involvement and rationale for lst limitation were recorded ( conclusions: our analysis shows that in our institution eol deliberations follow a shared decision-making process. lack of family/nok involvement and incomplete documentation was exceptional. the significant difference in los between w-group and nw-group, in the face of similar apache ii, warrants further investigation. vae calculator rheumatology review 2. van der jagt m. crit care consensus on circulatory shock and hemodynamic monitoring. task force of the european society of intensive care medicine cardiac output monitoring: how to choose the optimal method for the individual patient perioperative cardiovascular monitoring of highrisk patients: a consensus of 12 guidelines for nutrition support therapy in the adult critically ill patient references 1. nice guideline for aki: prevention, detection and management 2 serial creatinine results pre-and post ecmo references 1. polit et al. research in nursing & health reference 1. sherliker et al national blood transfusion committee, nhs blood and transplant arch otolaryngol head neck surg fig. 1 (abstract p343). rsi agent guideline references 1. nuckton tj nejm 2018 icm 2012 baseline characteristics reference elso guidelines for cardiopulmonary extracorporeal life support s3-leitlinie invasive beatmung und einsatz extrakorporaler verfahren bei akuter respiratorischer insuffizienz 1.auflage p387 handgrip strength does not predict spontaneous breathing trial failure or difficult or prolonged weaning of critically ill patients g friedman 1 total burn care introduction: we aimed to evaluate safety and efficacy of light sedation with dexmedetomidine (dex-ls) in acute brain injury (abi) patients. methods: retrospective analysis on icu patients with traumatic/medical abi, out of the neuroprotection window and undergoing dex-ls. data of pre-infusion and infusion periods were compared. results: 101 patients (age 51±24, males 83.2%) were included. traurespectively. conclusions: dex-ls among icu patients affected by abi turned out to be feasible and safe. it enabled discontinuation from mv and maintenance of spontaneous breathing in the majority of cases 88%) delirious patients and 93 of 114 (81.58%) non-delirious patients could be discharged from the hospital. we evaluated the 2-year mortality in the hospital survivors. results: totally, 153 patients participated in our study. the majority of them (55.1%) were male with the median age of 64[45, 76.25] years and the median apache ii score on the first day of icu admission of 13 risk of delirium was associated with preoperatory euroscore ii (p=0.028) and history of previous cardiac surgery (p=0.042). moreover, in the intraoperatory period the risk of delirium was associated with red blood cell transfusion, intervention for aortic dissection (p=0.013), hypothermic circulatory arrest (hca) with anterograde cerebral perfusion (acp) (p=0.036) (table 1). in the postoperatory period risk of delirium was associated with levels of creatinine clearance (p=0.035) and c-reactive protein (crp) (p=0.029). conclusions: delirium is relatively frequent in the cardiac surgical icu patient journey of group 1: those patients discharged directly home from critical care unit poor compliance with co-signing in icca (66%, n=161) compared to paper (93%, n=183) (figure 2) and the reported difficulty in co-signing (8%, n=85) reveals significant usability concerns and potential safety issues. 40% (n=85) found icca intuitive, though 16% (n=85) found navigating the interface difficult and reported concerns with losing saved work (19%, n=85). conclusions: this study highlights important usability issues that may impact staff satisfaction 4th national audit project of the royal college of anaesthetists and the difficult airway society. major complications of airway management references 1. guidelines for provision for intensive care services (gpics), version 2 medicines optimisation: the safe and effective use of medicines reducing harm from omitted and delayed medicines. a tool to support local implementation p444 understanding the delivery of intensive care in south p448 mobilising ventilated patients early with interdisciplinary teams (move it) singapore general hospital, department of respiratory and critical care p451 validation of boyd criteria and possum-score on mortality and morbidity in general surgical intensive care unit k chittawatanarat, y chatsrisuwan faculty of medicine pts with central nervous system neoplasms or submitted to elective surgeries were excluded. descriptive analysis and χ test, pearson´s, wilcoxon rank-sum, uni and multivariate logistic regressions were used when appropriate. results: from a total of 105 pts identified, 57.1% (n= 60) were admitted after emergent surgery and 42.9% (n=45) for medical reasons. global icu mortality was 25.7% (n=25). in comparison to survivors, the patients that died had a similar age were recorded data regarding demographics, clinical variables, paw (at admission and at day 4), high pressure ratio (hpr = number of days with high pressures: peak ≥40 and/or plateau ≥30; and/or driving pressure ≥14; and/or auto-peep ≥6; divided by los), trends of paw (paw at day 4 -paw at admission) and outcomes. the patients were divided into two groups: a construction group (n=200) and a validation group(n=104). the paw-mps was developed and validated by analyzing in a multivariate regression model the different paw ±0.1; pco2, 49±21 mmhg paw were respectively for peak, plateau, driving, and auto-peep at admission: 32 01±10, 20.7±7, 13.6±5 and three independent mortality risk factors were identified centro hospitalar do porto p469 five-year mortality and morbidity impact of prolonged icu stay n van aerde 1 , g hermans laboratory of cellular and molecular medicine we investigated differences in mortality and morbidity after short (<8 days) and prolonged (≥8 days) icu-stay. methods: prospective, 5-year follow-up study of former epanicpatients (clinicaltrials.gov:nct00512122, n=4640). mortality was assessed in all. for morbidity analyses, all long-stay and a random sample (30%) of short-stay survivors were contacted. primary outcomes were total and post-28-day 5-year mortality in multivariable cox regression analysis, icu-risk factors comprised hypoglycaemia, corticosteroids, nmba, benzodiazepines, mechanical ventilation, new dialysis, new infection, liver dysfunction, whereas clonidine may be protective. among 276 long-and 398 short-stay 5-year survivors hgf, 6mwd and pf sf-36 were lower in long-stayers 6mwd: 85% (95%ci:69%-101%) vs 94% (95%ci:76%-105%) multivariable regression identified associations with benzodiazepines (hgf and pf-sf36), vasopressors (pf-sf36) and opioids (6mwd) ptsd related symptoms were accessed with the post traumatic stress syndrome 14 questions inventory (ptss-14) at the post icu follow up clinic, six months after the acute stress event. the post icu consultation was carry out by an icu doctor and an icu nurse. exclusion criteria: previous severe psiquiatric disorders, not able to respond the questionnaire medical 67%, surgical 24% and trauma 9%. 60 patients (57%) were on imv and the median ventilation days was 7. ptsd scores ranged from 14 to 70. delusional memories were conclusions: in this study the rate of ptsd was lower 2.8% and related with a lower saps ii and the presence of memories of the icu stay. no relation was found with delusional memories, imv or superior icu length of stay. patients with lower illness severity and without imv, should be elective to the follow up-clinics. p471 long-term effects of a sepsis aftercare intervention k schmidt 1 united states; 4 jena university hospital patras general university hospital, intensive care unit, patras, greece; 4 patras general university hospital, division of infectious diseases results: 60 (41.6%) patients were readmitted within 72 hours and 84 (58.4%) in 4 to 60 days. the two groups didn't differ in age, gender, charlson comorbidity index and length of stay on both admissions. elective surgery was the most common type of admission (34.7%) followed by medical (28.4%), emergency surgery (27%) and trauma (9.7%). the mean time to readmission in the late group was 17.9 (±17.8) days. patients in the late group had higher apache ii score on their first and second admission, (17.3±5.5 vs 14.2±6.1; p=0.008) and (18.7±6.9 vs 14.4±6.7; p=0.002) respectively. respiratory insufficiency was the most common cause of readmission in both groups followed by sepsis and cardiac arrest. finally in the early group p480 introduction: in intensive care units, perceived inappropriate treatments (pit) have been associated with negative impact on caregivers univariate analysis revealed that burn-out, pit and intention to leave were greater in units where nurses´teams included no activity in the icu, compared to "shared" work in icu and idtcu. in multivariate analysis, perception of non beneficial treatment of patients with life support witholding was associated with: bad collaboration with other units p481 profile of intensive care unit (icu) patients on whom life-sustaining medical treatment were withdrawn or withheld s chatterjee 1 variables collected-age, sex, apa-che iv score, diagnostic-category and co-morbidities. primary outcomes were icu and hospital mortality. secondary outcomes included icu and hospital length of stay(los) female sex, n (%) 34 (46.6%) diagnosis on admission: medical, n (%) rrt at time of wlst, n (%) 28 (38.4%) dnr order, n (%) 61 (83.6%) organ donation services involved, n (%) 26 (35.6%) introduction: high flow nasal cannula(hfnc) is a new modality in respiratory failure management [1] . this study objectively held to compare the physiological outcomes in the non-invasive ventilation(niv) treatment of cardiogenic acute pulmonary oedema(apo) patient in the emergency department(ed) delivered by helmet cpap(hcpap) and hfnc. methods: single-centre randomized controlled trial on patients presenting with cardiogenic apo. primary endpoint was a heart rate reduction.secondary endpoints included: improvement in subjective dyspnoea scales, respiratory rate, blood oxygenation, intubation rate and 28 days mortality rate. results: 188 patients were enrolled and randomized (94 patients to hcpap; 94 to hfnc) ( 89 to 271.83±73.63). intubation rate was lower in hcpap (6.9% for hcpap versus 10.48% for hfnc) and 28 days mortality rate is lower in hcpap (9.6% for hcpap versus 14.9% for hfnc). conclusions: both hcpap and hfnc significantly improved patient condition in patient presenting to the ed with cardiogenic apo. however, hcpap was better than hfnc in improving physiology outcomes, lower intubation rate and mortality rate in patient introduction: the aim of the study was to compare the confusing assessment method of the intensive care unit (cam-icu) and the nursing delirium scoring scale (nu-desc) for assessment of delirium in the icu. furthermore we wanted to test the interpersonal variation of the nu-desc. delirium is proved to be associated with increased mortality [1] . nu-desc is an observational five-item scale that does not require patient participation and is adapted to the fluctuating nature of delirium. each item can be scored from 0 to 2. delirium is defined with a score > 2. the nu-desc has recently been translated into danish (nu-desc dk) but has not been validated.methods: icu patients, who met the inclusion-criteria for the cam-icu were scored with both cam-icu and nu-desc dk. patients were scored of two independent nurses at approximately the same time every day.results: a total of 24 patients were enrolled, and 54 comparisons between cam-icu and nu-desc dk were registered ( figure 1 ).there was agreement between nu-desc and cam-icu in 46 of registrations (hereof 44 registrations were delirium negative). in interpersonal variation, 14 registrations were made. the conclusion was identical in 86% of registrations, but only 57% agreed in all 5 scoring-scale items (all negative).conclusions: a high agreement between nu-desc and cam-icu was found however the comparison was based on predominately patients with negative delirium score. the interpersonal variation of nu-desc scoring was substantial. a future validation of the nu-desc dk as a screening tool in the icu requires thorough training and instructions to minimize interpersonal variation. introduction: an increasing number of patients are being discharged directly home from critical care units and this is currently viewed as a negative quality indicator [1] . the purpose of this audit was to characterise a cohort of patients who can be safely discharged directly home from adult critical care at st thomas´hospital (sth). methods: retrospective observational study of two groups of patients; 1) those discharged directly home from critical care, 2) those discharged within two days of step down to a ward from critical care (admissions 1st june-31st october 2017). the clinical notes of these patients were reviewed via online systems. results: baseline demographics of the 58 patients in group 1 and 90 patients in group 2 were similar (mean age of 51 years, versus 46 years, p=0.34); average length of stay in critical care was also similar (2.9 days versus 2.5 days respectively p= 0.72). in group 1, 24 of 168 icu days were after considered fit for step down versus 40 of 222 days in group 2, p=0.32 (fig 1, 2) . in group 1, drug related presentations were more common (27% versus 13% p=0.03), fewer patients had specialist follow up post discharge (36% versus 87%, p<0.001). in group 1, 7 patients (12%) were readmitted within 28 days, 3 to critical care. in group 2, 7 patients (8%) were readmitted, 1 to critical care (p=0.38 and 0.14 respectively); none of these readmissions were felt to have been preventable.conclusions: there is a cohort of patients suitable for discharge directly home from critical care who did not spend significantly longer in icu awaiting discharge than those who were stepped down to the ward. identifying these patients early, potentially by their diagnosis, and creating a pathway including access to specialist follow up clinic could allow prompt discharge directly from critical care, thus improving patient satisfaction and reducing hospital-acquired morbidity healthcare costs [1] . the evaluation of the usability of a critical care information system ( introduction: critical care information systems (ccis) support clinical processes by storing and managing data, but poor usability can lead to staff dissatisfaction and increased workload, promoting workarounds that may compromise patient safety [1] . the purpose of the study was to evaluate the usability of a philips intellispace critical care and anaesthesia (icca) ccis, recently implemented in 51 beds across three critical care units of a large uk teaching hospital. methods: a prospective, mixed method observational study conducted in may 2018, comprising of (1) an audit assessing the ease of linking bedside devices to icca, (2) an audit assessing the usability of co-signing medications in icca compared with a non-icca paper factors that commonly drive workforce metrics may not correlate with staff perceptions of safety. the bpr is a pragmatic, staff driven, tool to augment other measures of safety and is applicable to various icu settings. further research is needed to explore staff perceptions in order to understand the importance of this organisationally, and for staff stress. ventilator-free duration in icu, central venous catheter duration, urinary catheter duration, rates of deep vein thrombosis (dvt) and stress ulcer prophylaxis, rates of de-escalation antibiotic therapy, dvt prophylaxis duration, stress ulcer prophylaxis duration, icu and hospital mortality, 28-day mortality, rate of central venous catheter infection, length of stay in icu and hospital between two groups were analyzed. results: rate and duration of dvt prophylaxis in the intervention group were 81.3% and 3(2,6) days respectively, in the control group were 67.7% and 5(3,10) days, the differences between two groups were statistically significant(p<0.05) ( table 1 ). there were no differences in ventilator-free duration in icu, central venous catheter duration, urinary catheter duration, rate of stress ulcer prophylaxis, rates of de-escalation antibiotic therapy, stress ulcer prophylaxis duration, icu and hospital mortality, 28-day mortality, rate of central venous catheter(cvc) infection, length of stay in icu and hospital between two groups ( table 2) . conclusions: electronic checklist in ward rounds can increase the rate of dvt prophylaxis and reduce the duration, but it cannot improve the prognosis of critically ill patients. introduction: the goal of the project "i see you" is family-centeredcare based on family meetings that improve the experience of the patient´s family members during hospitalization in the icu. the meetings focus on relaying information, raising knowledge and addressing the social and emotional needs of families. providing support along with information was found to be the strongest predictor of family satisfaction and could lead to improve cooperation between family and staff [1] .methods: meetings and questionnaire: family meetings consist of a multidisciplinary team, a group facilitator and combined with a multimedia presentation about the unit and equipment. in addition, they focus on social and emotional needs: managing daily routine, sharing problems, fears and anxieties and more. at the end of the session a questionnaire was given to assess the impact of the intervention. sharing data: at the end of the first quarter, the data from meeting was summarized and sent to the staff alongside tools for effective communication.results: the project began in february 2018. to date, 162 family members of 74 patients have attended the sessions. the topics discussed by the participants include: contact with the patient, prevention of infections, procedures, visits, conversations with doctors, medical confidentiality; guardianship; tracheotomy and social issues (fig 1) . a sample of questionnaires was transferred to 57 participants report satisfaction at a very high level.conclusions: the meeting received a very positive feedback from the participants. the project has achieved its goals and therefore it has been decided to be continued.introduction: possum score and boyd criteria are used to predict the outcome for high risk surgical patients. the aim of this study was to validation of these two measurement tools on mortality and morbidity in a university-based surgical intensive care unit (sicu) in thailand.methods: nine hundred and fifty two patients were enrolled onto this prospective review. all patients who had been admitted to sicu in a university-based hospital were included. all patients were collected for boyd criteria and possum score and outcomes and morbidity during sicu admission and discharge. introduction: aromatic microbial metabolites (amm), such as phenyllactic (phla), p-hydroxyphenylacetic (p-hphaa), and phydroxyphenyllactic (p-hphla) are involved in the pathogenesis of septic shock and are associated with mortality [1] . according to previous studies, amm have a high prognostic value in patients with abdominal infection [2, 3] . we hypothesize that amm have the prognostic value in patients with pneumonia in icu. methods: data of patients with community-acquired pneumonia was obtained on admission to icu. the levels of amm (phla, p-hphla and p-hphaa) were measured in blood serum using gas chromatography with flame ionization detector and compared in 2 groups of patients: with favorable and with lethal outcome (mann-whitney utest). spearman's correlations between amm and clinical and laboratory data were calculated. using method of logistic regression and roc analysis, we measured the prognostic value of amm. (table 1) . it was revealed, that some amm have similar prognostic characteristics in comparison with sofa and curb-65 scales; high level of amm is associated with high risk of death (roc-analysis fig. 1) .conclusions: serum concentrations of amm can be used as independent and practical criteria for the assessing of prognosis in patients with infection in icu. introduction: frailty in the critically ill is associated with increased morbidity and mortality but the optimal timing of frailty assessment, how to best measure frailty, reasons for adverse outcomes and how critical illness impacts frailty are unknown [1] . in preparation for a multi-center study designed to address these knowledge gaps, we conducted a pilot study whose aim was to assess feasibility as determined by recruitment rates, ability to assess frailty at icu admission and hospital discharge, ability to measure icu and hospital processes of care and ability to conduct 6-month assessments. conclusions: a multi-center study is feasible but follow-up losses due to mortality and inability to return for assessment will require sample size adjustment. frailty characterization is method dependent, can be done on hospital discharge but varies with time of assessment. these findings will need to be confirmed in our larger study currently in progress. introduction: given the ageing of the world´s population, the demands of critical care resources for elderly patients has increased during the past decade. however, little is known about quality of life and outcomes of elderly icu survivors. the aim of the study is to assess outcomes of elderly icu survivors at least 6 months after discharge: quality of life and mortality. methods: it is a retrospective study performed in a medical adult icu between january 2016 to december 2017. the study included all elderly survivors ( ≥65 years) after icu admission. outcomes were assessed by telephone interviews at least 6 months after icu discharge. the primary outcome was assessing the quality of life after icu stay, measured by euro qol 5d questionnaire. the eq-5d descriptive system contains five dimensions (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression). for each dimension, there are five levels (no problems, slight problems, moderate problems, severe problems and unable to/extreme problems figure 1 . conclusions: most elderly survivors patients showed a good health related quality of life using the euroqol 5d-5l after icu discharge. fig. 1 (abstract p468) . quality of life (euroqol 5d) scores after icu discharge introduction: sepsis survivors face mental and physical sequelae even years after discharge from the intensive care unit (icu). effects of a primary care management intervention in sepsis aftercare were tested. exploratory analyses suggest better functional outcomes within the intervention group compared to the control group at six and 12 months after icu discharge. longer term effects of the intervention have not been reported. methods: a randomized controlled trial was conducted, enrolling 291 patients who survived sepsis (including septic shock), recruited from nine german icus. participants were randomized to usual care (n=143) or to a 12-months intervention (n=148). the intervention included training of patients and their primary care physicians (pcp) in evidence-based post-sepsis care, case management provided by trained nurses and clinical decision support for pcps by consulting physicians. usual care was provided by pcps in the control group. the primary outcome of the trial was the change in mental healthrelated quality at 6-months after icu discharge. secondary outcomes included measures of mental and physical health. data were collected by telephone interviews using validated questionnaires at the 24-months follow-up (12 months after the 1-year intervention).results: 186 [63.9%, 98 intervention, 88 control] of 291 patients completed the 24-months follow-up. unlike the intervention group, the control group showed a significant increase of posttraumatic symptoms (diff. ptss-10 to baseline, mean (sd) 3.7(11.8) control vs.-0.7(12.1) intervention; p=0.016). there were no significant differences in the mcs and all other secondary outcomes between intervention and control group.introduction: survivors of sepsis often show symptoms of posttraumatic stress disorder (ptsd). only few studies report on courses of more than 12 month after discharge from the icu. the aim of this study was to identify predictors for changes in ptsd symptoms over time up to 24 month. methods: follow-up data of the smooth triala rct to evaluate a primary care management intervention on sepsis survivorswere analyzed. included patients were surveyed by phone for ptsdsymptoms at one, 6, 12 and 24 months after discharge from icu using the post-traumatic-stress-scale (ptss-10). scores changes between follow-up periods were analyzed using latent-change scores in structural equation models. predictors were clinical and sociodemographic baseline characteristics as well as physical, cognitive and functional sepsis sequelae assessed by validated questionnaires.results: 291 patients were included of which 186 participated in the 24 month follow-up. a decrease of ptsd symptoms between 6 and 12 months was predicted by higher education (b=-0.32, p=0.04), while higher pain intensity at one month predicted an increase (b=0.01, p=0.041). increasing ptsd symptoms between 12 and 24 months were predicted by reporting more than two traumatic memories at one month (b=0.44, p=0.004), more sleep problems (b=0.22, p=0.08) and worse cognitive performance at 6 months (b=-0.03, p=0.043) as well as more neuropathic symptoms at 12 months (b=0.04, p=0.015).conclusions: sepsis patients that suffer from physical, cognitive and functional impairments after icu discharge may be at increased risk for developing late-onset ptsd. these predictors need to be replicated by future studies. early versus late readmission to the intensive care unit: a ten-year retrospective study v karamouzos 1 , n ntoulias 2 , d aretha 3 , a solomou 3 , c sklavou 3 , d logothetis 3 , t vrettos 3 , m papadimitriou-olivgieris 4 , d velissaris 5 , f fligou 3conclusions: icu patients whose life-sustaining treatment was withdrawn or withheld had higher illness-severity scores, were older, had longer icu los and higher mortality than those in active-treatment group. healthcare introduction: caring for the critically ill patient is a complex task and becomes tougher when a death process takes place. a number of needs and coping strategies emerge from the healthcare providers before these issues but are mostly displayed out of individual skills and intuition. if those approaches are unappropriate and the needs are not met, patients' death process may be burdensome for caregivers. this could affect the quality of care for patients and families during the whole end-of-life care process. the aim of our study was to explore the different needs and coping strategies used by icu healthcare providers when facing patients in the dying process. methods: qualitative and collective case study. ten semi-structured interviews were conducted in icu personnel (3 physicians and 7 nursing professionals). a thematic analysis was done using nvivo 11 software. local ethics committee approved the study. results: respondents were 70% women, had 36.7 ± 8.2 years-old and 11.1 ± 8.2 years of icu experience. main needs identified in icu healthcare providers refer to a lack of tools for doing emotional containment when delivering bad news to families, handling personal mourning, the need to perceive consistency regarding end-of-life care management across the icu team, and a wish of having regular training from a psychologist. main identified coping strategies included closing rituals, finding quiet spaces to spend time, and asking for counselling with more expert colleagues. a need for systematic, although basic training on these issues from qualified professionals is demanded. conclusions: usually, basic needs from patients and families in the process of dying are well addressed, but healthcare providers' needs are underrecognized and coping strategies mostly unknown. visibilization of those needs and basic but formal training in emotional containment, self-care and coping strategies are greatly desired. introduction: in the intensive care unit (icu), patients often exhibit cognitive impairments that prevent them from participating in decisions related to therapeutic options at the end of life. consequently, their families are often asked to speak for them when difficult decisions must be made. the main of this study was to determine the frequence in wich family want to share in end of life decisions and factors associated with this desire.methods: a prospective study was conducted in one mixed icu in montevideo. relatives of patients were invited to participate in this study after 72 hours in the icu and completed a survey that included the hospital anxiety and depression scale. results: we analized 135 relatives from 96 patients hospitalized in the intensive care unit. the relationship with the patient was as follows: 23% spouses, 23% siblings, 21% grown children, 14% parents, and 19% other family members and friends. of them, 41.5% reported a desire to share in end of life decisions. anxiety and depression symtoms were present in 60% and 41% respectively. factors asociated with the desire of involvment in end of life decisions by bivariate analysis were: female sex (48% vs 29%, p=0.03), presence of anxiety (51% vs 28%, p=0.008) and patient ecog 2-4 (70% vs 34%, p=0.05). multivariate analysis shows that the presence of anxiety is the only independent factor associated with the desire to participate in end of life decisions (or 2.20, ic 95% 1.02-4.73; p=0.04). conclusions: have a loved one in icu is often associated with anxiety and depression after 72 hours of admission. only 41% of the relatives want to participate in end of life decisions. the presence of anxiety is independently associated with the want to share in decisions making process. introduction: intensive care aims to treat failure of vital organ systems. sometimes, a patient's condition is of such a degree that intensive care is no longer beneficial, and decisions to withdraw or withhold intensive care are made. this means that life-sustaining treatments are terminated or not initiated. we aimed to identify variables that are independent factors for the decision to withdraw or withhold intensive care. methods: registry study using extracted data from a national quality registry the swedish intensive care registry (sir) 2014-2016. data are delivered to the registry by nurses and doctors daily, during each patients' stay in the intensive care unit (icu). a total of 97,095 intensive care cases reported to the sir from 2014-2016. results: data regarding each patient´s age, sex, diagnoses, condition at admission (expressed as simplified acute physiology score version 3, saps 3), comorbidities and registered decisions to withdraw or withhold intensive care were analyzed. of the 97,095 cases reported, 41.9% were women and 58.1% men, and 47.1% were 61-80 years old. a total of 15.4% received a decision to withdraw or withhold intensive care, accounting for 16.2% of all women and 14.8 % of all men, p<0.001. independent variables associated with increased odds of receiving a decision to withdraw or withhold intensive care were older age, worse condition at admission, and female sex. female sex was associated with an increased odds of receiving a decision to withdraw or withhold intensive care by 18% (ci 13.4-23.0%) after adjustments for condition at admission and age. conclusions: older age, worse condition at admission and female sex was found to be independent variables associated with an increased odds to receive a decision to withdraw or withhold intensive care.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-014464-m5n250r2 authors: sole-violan, j; sologuren, i; betancor, e; zhang, s; pérez, c; herrera-ramos, e; martínez-saavedra, m; lópez-rodríguez, m; pestano, j; ruiz-hernández, j; ferrer, j; rodríguez de castro, f; casanova, j; rodríguez-gallego, c title: lethal influenza virus a h1n1 infection in two relatives with autosomal dominant gata-2 deficiency date: 2013-03-19 journal: crit care doi: 10.1186/cc11953 sha: doc_id: 14464 cord_uid: m5n250r2 nan introduction acute myocardial depression in septic shock is common [1] . myocardial depression is mediated by circulating depressant substances, which until now have been incompletely characterized [2] . the aim of our study was to observe the eff ects of tnfα on the model of perfused rat heart. methods after profound anesthesia with pentothal, the wistar rats were killed by exsanguination. after sternotomy, the heart was taken and connected to the langendorf column. the apex of the heart was hooked to a strength sensor. biopac student laboratory software was used to record and analyse heart contractions. contractions were recorded every 5 minutes during periods of 20 minutes. control measurements were fi rst recorded. we measured four parameters: heart rate, contraction force, speeds of contraction and relaxation for control, during tnfα (20 ng/ml) exposure and after removal of tnfα. we express the variations of parameters as percentage of the control ± sem. a paired t test was used to compare heart rate, contraction amplitude, speeds of contraction and relaxation with tnfα and control measurements and after removal of tnfα. results eight rat hearts wistar (weight = 325 ± 23 g) were studied. see table 1 . heart rate 78 ± 6* 91 ± 5 introduction traditional whole blood experiments suggest that sepsis causes abnormal red blood cell (rbc) deformability. to investigate this at the cellular level, we employed a novel biophysical method to observe individual rbc membrane mechanics in patients with septic shock. methods we collected blood samples from patients with septic shock until either death or day 5 of admission. thermal fl uctuations of individual rbcs were recorded allowing a complete analysis of rbc shape variation over time. mean elasticity of the cell membrane was then quantifi ed for each sample collected. we recruited nine patients with septic shock. table 1 shows mean rbc thermal fl uctuation and sofa scores. conclusion rbc thermal fl uctuation analysis allows variations in rbc elasticity during sepsis to be quantifi ed at a cellular level. we could not identify any specifi c trend between sepsis severity and erythrocyte elasticity. cells demonstrated both increases and decreases in fl uctuation independent of sofa score. this is contrary to current evidence that suggests rbc deformability is reduced during sepsis. reference introduction whole blood experiments suggest that cardiopulmonary bypass (cpb) causes red blood cell (rbc) trauma and changes in deformability that may contribute to postoperative microcirculatory introduction neutrophil gelatinase-associated lipocalin (ngal)/ lipocalin2, known as a sensitive biomarker of acute kidney injury, prevents bacterial iron uptake, resulting in the inhibition of its overgrowth [1] . we previously demonstrated that this protein was discharged into gut lumen from crypt cells in septic conditions, and inhibited the growth of escherichia coli [2] . however, it remains unclear which pathway is associated with the upregulation of ngal. we therefore designed the present study to reveal whether the patternrecognition receptor of bacteria, the toll-like receptor (tlr) family, plays a pivotal role for ngal secretion from gut crypt cells. methods with our institutional approval, the ileum and colon of male c57bl/6j mice (6 to 7 weeks) were everted and washed by ca 2+ and mg 2+ free pbs buff er fi ve times. tissues were incubated with ca 2+ and mg 2+ free pbs containing 30 mm edta for 1 hour to isolate crypt cells of gut. the cell suspension was fi ltered through a cell strainer (40 μm) twice, and deposited the crypt cells by centrifugation at 700×g. the isolated crypt cells were resuspended in pbs and stained with 0.25% amido black for labeling paneth cells. the 5×10 5 crypt cells were resuspended in 50 ml hbss containing 2.5% fetal bovine serum and 1% penicillin-streptomycin. the crypt cells were incubated at 37°c with or without tlr ligands: lipopolysaccharide (tlr4 ligand, 10 μg/ml) and cpg-dna (tlr9 ligand, 8 μg/ml). after a 2-hour incubation period, the crypt cells were deposited and eluted mrna to measure the expression of both ngal and tlr mrna using real-time pcr. results more than 70 to 80% of collected cells were stained by amido black. lps signifi cantly upregulated the expression of ngal and tlr4 mrna in ileum and colon crypt cells (p <0.05). although the cpg-dna did not upregulate ngal and tlr9 mrna in ileum crypt cells, the apparent expression of ngal and tlr9 mrna was found in colon crypt cells (p <0.05). conclusion bacterial stimulation of tlr4 and tlr9 pathways plays a pivotal role in the expression of ngal mrna in gut, suggesting that ngal, derived from gut crypt cells, could contribute to the regulation of the intraluminal microfl ora in the critically ill. references introduction most individuals infected with the 2009 pandemic h1n1 infl uenza a virus (iav) (h1n1pdm) experienced uncomplicated fl u. however, in a small subset of patients the infection rapidly progressed to primary viral pneumonia (pvp) and a minority of them developed ards. inherited and acquired variability in host immune responses may infl uence susceptibility and outcome of iav infection. however, the molecular nature of such human factors remains largely elusive. methods we report three adult relatives with the autosomal dominant gata-2 defi ciency. p1 and his son p2 had a history of myelodysplastic syndrome and a few episodes of mild respiratory infections. they developed pvp by h1n1pdm which rapidly evolved to ards. they died at the age of 54 and 31, respectively. results patients were heterozygous for a novel r396l mutation in gata2. like other patients with gata-2 defi ciency, the three relatives had absence of peripheral nk and b cells and monocytopenia. however a high number of plasma cells, which were found to be pauciclonal, were observed in peripheral blood from p1 during h1n1pdm infection. p1 and p2 had normal levels of immunoglobulins and igg antibodies against common viruses. microneutralization test showed that p1 produced normal titers of neutralizing antibodies against h1n1pdm and against the previous annual h1n1 strain. our results suggest that a few clones of long-living memory b cells against iav expanded in p1; and that these cells produced cross-reactive antibodies against h1n1pdm, similar to those recently described. during the fl u episode p1 had a strong increase of ifnγ-producing t cells and of ifnγ production. the th1-related chemokines cxcl10 and cxcl9, as well as ifnγ, mcp-1 and il-8, were strongly elevated in serum from p1 and p2 in the course of h1n1pdm infection. conclusion gata-2 defi ciency is the fi rst described mendelian inborn error of immunity underlying severe iav infection. primary immunodefi ciencies predisposing to severe iav infections may debut, even in adults without a history of previous severe infections. the massive ifnγ-mediated cytokine storm may explain the fatal course of h1n1pdm infection in our patients. introduction adenosine exerts anti-infl ammatory and tissue protective eff ects during systemic infl ammation. while the anti-infl ammatory properties may induce immunoparalysis and impede bacterial clearance, the tissue protective eff ects might limit organ damage. the eff ects of a common loss-of-function variant of the adenosine monophosphate deaminase 1 gene (ampd1), which is associated with increased adenosine formation, in patients with sepsis are unknown. methods in a prospective cohort, genetic-association study, the eff ects of the presence of the ampd1 gene on immune function, multiorgan dysfunction and mortality in septic patients was studied. pneumosepsis patients (n = 402) and controls without infection (n = 101) were enrolled. results in pneumosepsis patients and controls, a similar prevalence of the 34c>t (rs17602729) mutation in the ampd1 gene was found. univariate logistic regression analysis showed a tendency of increased mortality in patients with the ct genotype, compared with patients with the cc genotype (or 1.53; 95% ci 0.95 to 2.5). moreover, carriers of the ct genotype tended to suff er more from multiorgan dysfunction, or 1.4 (0.84 to 2.3) and 3.0 (0.66 to 13.8), for ct and tt, respectively (p = 0.07). in septic carriers of the ct genotype, the ex vivo production of tnfα by lps-stimulated monocytes was attenuated (p = 0.005), introduction hypogammaglobulinemia has been frequently found in adult patients with severe sepsis and septic shock. furthermore, it seems that at least a low serum level of igm is correlated with higher mortality in sepsis. the mechanisms of hypogammaglobulinemia in septic shock have not yet been explained. it has been hypothesized that outfl ow of immunoglobulins into the extravascular space due to increased capillary permeability could reduce immunoglobulin serum concentrations. angiopoietin-2, which directly disrupts the endothelial barrier, is markedly elevated in sepsis and other infl ammatory states and its serum level has been correlated with microvascular leakage, end-organ dysfunction and death in sepsis. methods in the prospective, noninterventional study, we assessed the correlation between the capillary leakage marker angiopoetin-2 and serum levels of igg and igm in 41 patients with community-acquired severe sepsis or septic shock on admission. blood samples were obtained during the fi rst 12 hours after admission to hospital. results mean age of patients (17 females) was 70 years. median apache ii and sofa scores at admission were 24 and 11, respectively. the mortality rate was 45%. thirty-four percent of all patients had level of igg <650 mg/dl. the median concentration of angiopoietin-2 in the hypo-igg group was 11,958 pg/ml, which was not statistically diff erent (mann-whitney; p >0.05) than in the rest of patients with normal levels of igg (15,688 pg/ml). the concentration of igm <40 mg/dl was found in only four patients (10%) and all died. pearson's correlation test showed that the correlation between the concentrations of angiopoietin-2 and igg (correlation coeffi cient 0.191) or igm (correlation coeffi cient 0.0408), respectively, were not statistically signifi cant (p <0.05). conclusion at present the hypothesis that increased microvascular leakage is responsible for hypogammaglobulinemia in septic patients could not be accepted. studies on larger number of patients are needed. in addition, it is necessary to further explore other possible mechanisms, such as increased catabolism and consumption of antibodies or inadequate synthesis of immunoglobulins, which could also be responsible for hypogammaglobulinemia in sepsis. introduction septic encephalopathy is a frequent complication in severe sepsis but its pathogenesis and mechanisms are not fully understood. oxygen supply and utilization are critical for organ function, especially for the brain, a tissue extremely dependent on oxygen and glucose. disturbances in oxygen utilization are common in sepsis and a number of mitochondrial dysfunctions have been described in diff erent tissues in septic animals as well as in septic patients. our group described mitochondrial dysfunctions in the brain during experimental sepsis. methods experimental sepsis was induced by endotoxemia (lps 10 mg/ kg i.p.) in sprague-dawley rats and by polymicrobial fecal peritonitis in swiss mice. brain glucose uptake was observed in vivo in endotoxemic rats using positron emission tomography with [ 18 f]fl uorodeoxyglucose and autoradiography with 2-deoxy-14 c-glucose. results mice with polymicrobial sepsis present hypoglycemia, hyperlactatemia and long-term cognitive impairment. we observed a rapid increase in the uptake of fl uorescent glucose analog 2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose in brain slices from septic mice in vitro. a similar increase in brain glucose uptake was observed in vivo in endotoxemic rats. remarkably, the increase in glucose uptake started 2 hours after lps injection, earlier than other organs. the brains of mice with experimental sepsis presented neuroinfl ammation, mitochondrial dysfunctions and oxidative stress, but mitochondria isolated from septic brains generated less ros in vitro in the fi rst 24 hours. this led us to investigate the role of nadph oxidase, an enzyme induced during innate immune response, as a potential source of reactive oxygen species in experimental sepsis. inhibiting nadph oxidase with apocynin acutely after sepsis prevented cognitive impairment in mice. our data indicate that a bioenergetic imbalance and oxidative stress is associated with the pathophysiology of septic encephalopathy. we are observing a new metabolic phenotype in the brain during sepsis, characterized by a rapid increase in glucose uptake and mitochondrial dysfunctions that may be secondary to infl ammation and hypoxia. introduction pathophysiology of brain dysfunction associated with sepsis is still poorly understood. potential mechanisms involve oxidative stress, neuroinfl ammation and blood-brain barrier alterations. our purpose was to study the metabolic alterations and markers of mitochondrial dysfunction in a clinically relevant model of septic shock. methods twelve anesthetized (midazolam/fentanyl/pancuronium), invasively monitored, and mechanically ventilated pigs were allocated to a sham procedure (n = 5) or sepsis (n = 7), in which peritonitis was induced by intra-abdominal injection of autologous feces. animals were studied until spontaneous death or for a maximum of 24 hours. in addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdialysis were assessed at baseline, 6, 12, 18 and 24 hours after sepsis induction. after death, brains were removed and brain homogenates were studied to assess markers of mitochondrial dysfunction. introduction identifying a group of patients at high risk of developing infectious complications is the fi rst step in the introduction of eff ective pre-emptive therapies in specifi c patient groups. quantifying cytokine gene expression also furthers our understanding of trauma-induced immunosuppression. our group has already demonstrated that a predictive immunological signature derived from mrna expression in elective thoracic surgical patients accurately predicts pneumonia risk [1] . methods in total, 121 ventilated polytrauma patients were recruited. mrna was extracted from paxgene tubes collected within 2 hours of the initial insult, at 24 and 72 hours. t-helper cell subtype specifi c cytokines and transcription factors mrna was quantifi ed using qpcr. ten healthy controls served as a comparator. results the median injury severity score (iss) was 29. time 0 bloods demonstrated a reduction in tnfα † , il-12 § , il-23 ‡ , rorγt* and t bet § , and an increase in il-10* and il-4 † mrna levels in comparison with the control group (*p <0.0001, † p <0.001 to 0.0001, ‡ p <0.01 to 0.001, § p <0.05 to 0.01). there was a positive correlation between iss and il-10 ‡ whilst both il-23 § introduction measurement of biomarkers is a potential approach to early assessment and prediction of mortality in septic patients. the purpose of this study was to ascertain the prognostic value of proadrenomedullin (padm), measured in all patients admitted to the icu of our hospital with a diagnosis of severe sepsis or septic shock during 1 year. methods a cohort study of 117 patients >18 years with severe sepsis according to the surviving sepsis campaign, in an icu of a university hospital. demographic, clinical parameters and padm, c-reactive protein and procalcitonin were studied during 1 year. descriptive and comparative statistical analysis was performed using the statistical software packages statistica stat soft inc 7.1 and medcalc 9.2.1.0. results we analyzed 117 consecutive episodes of severe sepsis (15%) or septic shock (85%) in the icu. the median age of the patients was introduction sepsis results from complex interactions between infecting microorganisms and host responses, often leading to multiple organ failures and death. over the years, its treatment has been standardized in early goal-oriented therapies, which may benefi t from circulating biomarkers for early risk stratifi cation. we aimed to evaluate the prognostic value of presepsin (scd14-st), a novel marker of bacterial infection. methods we performed a nested case-control study from the randomized controlled albumin italian outcome sepsis (albios) trial, enrolling patients with severe sepsis or septic shock from 100 icus in italy. fifty survivors and 50 nonsurvivors at icu discharge were selected, matched for age, sex, center and time of enrollment after inclusion criteria were present. edta-plasma samples were collected at days 1, 2 and 7 after enrolment for presepsin (immunechemiluminescence assay pathfast presepsin, url 320 pg/ml, cv 5%; mitsubishi chemicals) and procalcitonin assay (pct, elecsys brahms cobas® pct, url 0.046 ng/ml, cv 8.8%; roche diagnostics). results clinical characteristics were similar between the two groups, except for a worse sofa score at day 1 in decedents. presepsin at day 1 was signifi cantly higher in decedents (2, 268 (1,145 to 4,305) pg/ ml, median (q1 to q3)) than in survivors (1,184 (855 to 2,158) pg/ml, p = 0.001), while pct did not diff er (18.5 (3.3 to 45.7) vs. 10.8 (2.6 to 46.4) ng/ml, p = 0.31). presepsin decreased over time in survivors, but remained elevated in decedents (974 (674 to 1,927) vs. 2,551 (1,438 to 5,624) pg/ml at day 7, p = 0.02 for time-survival interaction); pct decreased similarly in the two groups (p = 0.19). patients with early elevated presepsin had worse sofa score, higher number of mofs, hemodynamic instability (lower mean arterial pressure at baseline and after 6 hours), and mortality rate at 90 days (75% vs. 42%, logrank p <0.001). the association between presepsin and outcome was more marked in patients with late enrollment (6 to 24 hours), and in septic shock. early presepsin had better prognostic accuracy than pct (auroc 0.69 vs. 0.56, p = 0.07), and improved discrimination over sofa score, especially in septic shock. conclusion early presepsin measurements may provide important prognostic information in patients with severe sepsis or septic shock, and may be of crucial importance for early risk stratifi cation. introduction infections are a major complication during the postoperative period after heart transplantation (ht). in our hospital, nosocomial pneumonia is the most frequent infection in this period. the objective of this study is to determine the epidemiological and microbiological characteristics of this disease in our centre. methods a descriptive retrospective study of all medical records of ht performed in a single institution from 1991 to 2009 followed until june 2010. clinical and microbiological variables were considered. centre for diseases control (cdc) criteria were used to defi ne nosocomial infections. invasive aspergillosis was considered if there were criteria for probable aspergillosis according to idsa criteria. results in 594 hts there were 97 infectious episodes in 75 patients (12.6%). eighty-fi ve patients (14.3%) died during hospitalization. infection is the second cause of mortality during the postoperative period (17.9% of dead patients). the most common locations of infections were pneumonia (n = 31, 31.9% of infection episodes), bloodstream (n = 24, 24.7%), urinary tract (n = 14, 14.4%), surgical site (n = 13, 13.4%) and intraabdominal infections (n = 13, 13.4%). patients with pneumonia were treated according to knowledge in a specifi c moment, thus diff erent antibiotics were used. the duration of antibiotic therapy was 20 ± 15.5 days. in nine episodes of pneumonia according to the cdc no germ was isolated in the cultures. six of the episodes were polymicrobial infections. the most frequent microbes isolated were e. coli (n = 7, 22.5% of pneumonia cases), a. fumigatus (n = 7, 22.5%), s. aureus (n = 3, 9.68%), p. aeruginosa (n = 3, 9.68%), p. mirabilis, k. pneumoniae, e. cloacae, e. faecalis, c. glabrata, and s. marcescens (one case each, 3.22%). pneumonia was suspected but not confi rmed in 75 patients. despite this, antibiotic treatment was maintained for a media of 17.35 ± 7.01 days: 56 wide-spectrum treatments and 18 targeted therapy after knowing the antibiogram. the length of icu stay was 38.4 ± 70.8 (3 to 264) days, of hospital stay was 66.2 ± 80.5 (3 to 304) days and of mechanical ventilation was 27.3 ± 50.2 (3 to 264) days. the mortality of patients with pneumonia was 32.3%. conclusion nosocomial pneumonia is the most frequent infection in our series. despite when infection was not confi rmed, antibiotic therapy was maintained in suspect cases. we found a high incidence of aspergillosis. limitations because of wide duration of this study should be considered. that numbers of cvc, intubation and surgery, the use of muscle relaxant and steroid were independent risk factors for developing vap. ventilator days and icu length of stay were longer in the vap group (25 vs. 6 and 25 vs. 7 days, respectively). lastly, the hospital mortality rate was signifi cantly higher in the vap group (33% vs. 12%, p = 0.008). conclusion the incidence of vap was 9.2% in the sicu of siriraj hospital, which was comparable with previous reports. bundles of care to prevent vap should include weaning from a ventilator. muscle relaxant and steroid should be administered according to strong indication. meticulous care of the airway should be implemented as protocol in order to prevent complications that can result in the development of vap. reference introduction this is a 1-year prospective study to determine the incidence, source and etiology of hospital-acquired bloodstream infection (habsi) in the indian context. the resistance pattern was also reviewed. methods a single-centre prospective study in a 35-bed icu. habsi was defi ned according to current cdc guidelines. hcap, catheterassociated uti (cauti) and skin-related infections causing bsi was also defi ned according to recent guidelines and analysed. results out of 332 positive samples, 90 samples (n = 45) were habsi. the microbiological analysis showed 60% were gram-negative, 6% were candida and 27% were gram-positive. the commonest isolate was klebsiella and mrsa was commonest in gram-positive. the source of habsi showed crbsi was the commonest cause at 69%, which correlates with international data. ventilator-associated pneumonia and cauti caused 9.5% bsi respectively. the resistance pattern among gram-negative bacteria showed multidrug-resistant (mdr) and extreme drug-resistant (xdr) isolates were highest. see tables 1 and 2 . introduction catheter-related bloodstream infection (crbsi) is a complication of central venous catheters (cvcs) with an attributable morbidity, mortality and cost [1] . we examined patient risk factors for crbsi in an adult parenteral nutrition (pn) population. the study was carried out in a 525-bed tertiary-referral teaching hospital over a 14-year study period (1997 to 2010). all inpatients referred for pn via cvcs were included. prospectively collected data were recorded in a specifi c pn record. the crbsi audit group met quarterly to review all sepsis episodes, assigning a diagnostic category (crbsi or non-crbsi). patient risk factors for development of crbsi were examined using a logistic regression model to take account of the dichotomous nature of the outcome. odds ratios from a model incorporating demographic and clinical data were tested for statistical signifi cance. introduction many patients develop infections following operations. decreased immune competence has been demonstrated in acute neurological conditions. a strong cytokine-mediated antiinfl ammatory response was observed in stroke patients at infection, although infection due to the decreased proinfl ammatory mediators can be expected as well. to investigate this question the following experiment was performed. methods twenty-two urinary bladder cancer patients with radical cystectomy and lymphadenectomy were studied. blood samples were taken on day 0 (before) and days 1, 3, 6, 9 and 14 after operation as well as on days 30, 60, 90 and 270 during follow-up. tnfα, soluble tnfα receptor i and il-6 levels in sera were determined by hs elisa and/or elisa. plasma acth and cortisol values were measured by ria kits. results from 22 patients, eight deep wound and urine infections were found in 14 days and six urine and wound infections in 30 days after surgery, all survived. all patients were bacterially contaminated, as wound samples taken at the end of operation demonstrated. on day 0 the circulating tnfα values were lower in infected patients. tnf started to increase from day 3 to day 9, never reaching values of the uneventful healing group. soluble tnf receptor i, il-6, acth, and cortisol concentrations did not demonstrate any diff erence on day 0 but from day 1 started to increase transiently, reaching higher levels in septic patients. conclusion a low proinfl ammatory response is a key facilitating factor for the development of infection. measuring serum tnfα levels before and after operations can thus predict the outcome. evaluation during 3 days in may 2012 including direct observation of hand hygiene compliance by control nurses and hand cultures of 50 healthcare workers (hcw). based on the who guidelines on hand hygiene in health care [1] , cleaning of hands with alcohol-based hand rubs (sterillium) was prescribed before touching a patient and before aseptic procedures, after body fl uid exposure risk and after touching a patient and touching his/her surroundings. promotion of the hand hygiene program consisted of lectures and web-based self-learning, posters located near points of care and verbal reminders by control nurses. new observations of hand hygiene by control nurses during 3 days and hand cultures of 50 healthcare providers were performed in september 2012. consumption of alcohol-based hand rub (product volume use per patient-days) was used as a surrogate marker of hand hygiene over time. the diff erence in hand hygiene compliance during the two periods was examined using a chi-squared test. diff erences in hand cultures were examined using a student's t test. time trends in the consumption of alcohol-based hand rub were examined using linear correlation. p <0.05 was considered statistically signifi cant. the study was approved by the institutional ethics review board. results during the survey, in may 158 opportunities to observe hand hygiene were presented and 286 in september. overall compliance improved from 34.2% (54/158) to 51% (146/286), χ 2 = 11.7 (p <0.001). in may, 50 hcw had a mean of 63.20 ± 39.37 colony-forming units (cfu) on their hands compared with 43.0 ± 40.19 cfu on the hands of 50 hcw in september (p = 0.024). we also observed an initial increased use of alcohol-based hand rubs from 21 ml per patient-day in may to a maximum 72 ml per patient-day in june, but a decline to 44 ml per patient-day in september, pearson correlation coeffi cient = 0.31 (p = 0.61). conclusion implementation of a new hand hygiene program at our icu resulted in improved hand hygiene compliance and less cfu on the hands of hcw. there was no signifi cant increased use of alcohol-based hand rubs over time. the results indicate that constant awareness is vital for success. reference introduction icu-acquired infection is directly related to hospital mortality. hand hygiene is an eff ective, low-cost intervention that can prevent the spread of bacterial pathogens, including multidrugresistant organisms. historical compliance with hand hygiene guidelines by physicians, nurses and other care providers is poor. methods present expectations by the infection control committee are to 'pump in, pump out' of every room, using 63% isopropyl alcohol. we performed 17,622 observations of hand hygiene in the surgical icu from march through october 2012, and intervened to change behavior by providing monthly feedback to specifi c provider groups and services. we made use of the unit coordinator to measure compliance of all individuals in the icu. results overall compliance by physicians was 82.1%, for nonphysicians was 84.8%. feedback to physicians, individually and by service, dramatically increased hand hygiene compliance, defi ned as both on entry and exit from the patient room, over the study period. see figure 1 . conclusion physician behavior is responsive to monthly feedback that is specifi c to the individual or surgical service. use of the unit coordinator was very eff ective at gathering a very large sample size in a short period of time. introduction the benefi ts of universal glove and gowning (bugg) study is a cluster-randomized trial to evaluate the use of wearing gloves and gowns for all patient contact in the icu. the primary outcome is vre and mrsa acquisitions; secondary outcomes include frequency of healthcare worker visits, infection rates, hand hygiene compliance and adverse events. methods we enrolled 20 icus in 15 states. icus collected nasal and perianal swabs on all patients at admission and discharge/transfer. after a 3-month baseline period, 10 units were randomized to the intervention arm and required to wear gloves and gowns for all patient contact. an intervention toolkit was created based on site feedback and compliance reports. swab collection compliance was fed back and discussed during site conference calls on a weekly basis. site coordinators monitored compliance with gloves and gowns, hand hygiene and frequency of hcw visits and reviewed patient charts for adverse events. results during the 12-month study period, 100,210 swabs were collected. after the baseline period, we were able to achieve and maintain swab compliance rates between 85 and 97%. monthly discharge compliance increased by 21% by the beginning of the intervention period ( figure 1 ). observers found 86% compliance with universal glove and gowning over 1,242 30-minute observation periods ( figure 1 ). ninety charts at each site were reviewed for adverse events. conclusion over a diverse group of us hospitals, we achieved high compliance with surveillance cultures and implementing universal gloving and gowning was achieved quickly with high compliance. introduction sepsis accounts for a very high mortality. the surviving sepsis campaign recommends a fi rst 6 hours resuscitative bundle to improve patient outcome. despite this, the bundle is poorly performed because of several organizational and cultural barriers. in recognition of this, we guess that an educational and organizational intervention out of the icus could impact on septic patient outcome. in order to test our hypothesis we carried out, in 12 hospitals, a pre-intervention survey of the human and organizational resources (hor) available in the management of septic patients. the aim is to seek any barrier potentially aff ecting correct guidelines implementation. methods thirty-nine medical wards (mw) and 12 emergency departments (ed) were enrolled. every unit was asked to fi ll in a pre-agreed hor checklist focused on the main requirements suggested by the guidelines. results analysing the human resources available, we see that the bedto-doctor ratio signifi cantly (p <0.01) increases from the day to the night shift: from 6 to 43 beds per doctor on the mw (median). otherwise, the ed staff remains roughly the same: from 3.5 to 2.5 doctors on duty (median). the analysis of the organizational tools (table 1 ) points out a low percentage of hospitals having: a diagnostic and therapeutic protocol for sepsis management (8.3%), some hospital empirical antibiotic therapy guidelines (0%) and an infective source eradication protocol (8.3%). moreover, just 25% of hospitals involve an infectious diseases expert in every case of severe sepsis or septic shock. conclusion we guess that the poor availability of hor showed by the hospitals could have a role in the guidelines implementation and in the patient's outcome. only a comparison between these results and data collected from a clinical checklist, focused on sepsis bundle compliance, and from a patient's outcome summary could confi rm our hypothesis. this is the aim for our next part of the study. reference introduction the incidence of patients carrying esbl-positive bacteria in our icu (12 in 780 admissions in 2011) was not considered problematic. however, routine cultures had identifi ed esbl-negative patients who had become colonized with esbl strains during their icu stay. self-disinfecting siphons, preventing bacterial growth by antibacterial coating and intermittent heating, and biofi lm formation by electromechanical vibration, were placed in all sinks in the icu. the aim of the present study was to evaluate the eff ect of this intervention. methods an intervention study in a 12-bed icu. the intervention involved placement of 19 self-disinfecting siphons (biorec). all patients with an expected icu stay of 2 days or more between january 2011 and december 2012 were studied. samples of throat, sputum and rectum were taken at admission and twice weekly, and cultured for esbls. between june 2011 and october 2011, sinks in patient rooms were cultured regularly for esbls. after the intervention in april 2012, multiple repeat cultures were taken. whenever the species and antibiogram of bacteria cultured from patients and sinks matched, they were typed by aflp. results before intervention multiple esbl-forming strains were found in sinks of all patient rooms. eighteen patients who were esbl-negative on icu admission became colonized with 11 diff erent esbl strains, that were present in sinks of their admission rooms ( figure 1 ). four contaminations were proven by aflp-tying. one patient died of esblpositive e. cloacae pneumonia. after intervention all sinks were negative for esbl strains. no further patients became esbl colonized during the icu stay. conclusion wastewater sinks were the likely source of esbl colonization for 18 icu patients. after placing self-disinfecting siphons introduction the present study investigated the eff ects of a single dose of intraperitoneal (i.p.) igg and iggam administration on various behavioral alterations in a cecal ligation perforation (clp)-induced sepsis model in rats. methods female wistar albino rats (200 to 250 g) were divided into fi ve groups (n = 8): a naive control group, a sham operated group receiving conventional antibiotic treatment, a clp group receiving clp procedure and conventional antibiotic treatment, and igg and iggam groups which were also applied 1 g/kg, i.p. igg and igam therapy 5 minutes after the clp procedure. ten, 30 and 60 days after the surgery, animals underwent three behavioral tasks: an open fi eld test to evaluate the locomotor activity, an elevated plus maze test to measure the level of anxiety, and a forced swim test to assess the possible depressive state. the results acquired from these tests were used to estimate the eff ect of immunoglobulin therapy on behavioral changes in clp-induced sepsis in rats. in the open fi eld test, the clp group showed a signifi cant decrease in total squares passed on days 10 and 30. similarly, total numbers of rearing and grooming were dramatically decreased in the clp group in comparison with control and sham groups (p <0.005). in the elevated plus maze test, the number of entries to open arms decreased in the clp group. in the forced swim test, there was a tendency for increase in immobility time in the clp group, although the data were statistically insignifi cant. all of these values which were indicating the importance of behavioral alterations were improved on day 60. immunoglobulin therapy prevented the occurrence of these behavioral changes. especially, animals in the iggam group conserved the values quite near to those of the control group in measured parameters. conclusion sepsis, even though it has been treated with conventional antibiotics, caused a negative eff ect on behavioral parameters. in this study, igg and iggam treated animals in the presence of clp did not show these behavioral changes. therefore our results suggest that a single dose of i.p. igg and iggam treatment, which was applied immediately after the sepsis procedure, prevents behavioral defects observed following sepsis. introduction thrombomodulin is an endothelial cell cofactor and glycoprotein for thrombin-catalyzed activation of protein c. a recombinant human soluble thrombomodulin (rhstm) has been recently developed, and this new agent has a unique amino-terminal structure exhibiting anti-infl ammatory activity including sequestraction and cleavage of high-mobility group box 1(hmgb-1). methods in this study, 13 patients with septic disseminated intravascular coagulation (dic) were treated with rhstm, which is recomodulin® inj. 12800 (asahi kasei pharma co., tokyo, japan). patients with septic dic were treated with 130 to 380 u/kg/day. results there were signifi cant results for improvement of apache ii score and dic diagnostic criteria score for critically ill patients after treatment using rhstm (p <0.01). improvement for platelet count and d-dimer level were also observed in this study (p <0.05). activation of antithrombin (at) also was signifi cantly increased after treatment (p <0.05). hospital mortality was 15.4% in this study. conclusion the rhstm might be one of most important endogenous regulators of coagulation, acting as the major inhibitor of thrombin as well as at iii. this new agent may play an important role in treatment for septic dic. introduction antithrombin iii (at iii) has been known to contribute to anti-infl ammatory response as well as its anticoagulation. our previous introduction sepsis and septic shock are complex infl ammatory syndromes. multiple cellular activation processes are involved, and many humoral cascades are triggered. presumably, endothelial cells play a pivotal rule in the pathogenesis of sepsis, not only because they may infl uence the infl ammatory cascade but also because, upon interaction with excessive amounts of infl ammatory mediators, the function of these cells may become impaired. it is likely that a general dysfunction of the endothelium is a key event in the pathogenesis of sepsis [1] . hmg-coa-reductase inhibitors have been shown to exhibit pronounced immunomodulatory eff ects independent of lipid lowering. most of these benefi cial eff ects of statins appear to involve restoring or improving endothelial function [2] . we hypothesize that statins can improve endothelial dysfunction in septic patients. methods a double-blinded, placebo-controlled, randomized trial was undertaken. we enrolled adult patients within 24 hours of severe sepsis or septic shock diagnosis and randomized them to placebo or atorvastatin 80 mg/day for a short term. endothelial dysfunction was assessed measuring plasmatic levels of il-6, et-1, vcam-1 by elisa and measuring fl ow-mediated vasodilatation of the brachial artery at basal, 24 and 72 hours after randomization. results we studied 47 patients, 24 in the placebo group (mean age 52 ± 20 years, 29.1% male; apache ii risk score 23.5 ± 7.3) and 23 in the statin group (mean age 49.5 ± 18 years, 53.4% male; apache ii risk score 23 ± 6.9). the baseline characteristics of the placebo group were similar to statin patients as well as the mean length of stay in the icu (8.6 ± 7.4 and 9.1 ± 8 days, respectively) and the time on vasopressors (49.3 ± 47.1 and 59 ± 91.1 hours, respectively). no signifi cant diff erence was observed on the temporal variation of biomarker levels (il-6, vcam-1, et-1) between treatment and control groups. the intrahospital mortality rate was 26% in the statin group and 45% in the placebo group (p = 0.17). introduction a novel sorbent hemoadsorption device for cytokine removal (cytosorbents, usa) was developed and successfully tested in animal models of sepsis. the experience in the clinical setting is still limited to case reports. in this fi rst clinical trial, we tested the hypothesis that treatment with sorbent hemoadsorption could safely and eff ectively reduce cytokines in septic patients with acute lung injury (ali). methods ventilated patients fulfi lling the criteria for severe sepsis and ali were enrolled in this multicenter randomized, controlled, openlabel study comparing standard of care with or without hemoperfusion treatment. primary endpoints were safety and il-6 reduction. treated patients underwent hemoperfusion at fl ow rates of ~200 to 300 ml/ minute for 6 hours per day for 7 consecutive days. the overall mean reduction in individual plasma cytokines for the control and treatment groups during the treatment period was calculated using a generalized linear model. results forty-three patients (18 treated, 25 control) completed the study and were further analyzed. incidence of organ dysfunction at enrollment (treatment vs. control) was: septic shock (94% vs. 100%, p = 0.42), acute respiratory distress syndrome (67% vs. 56%, p = 0.33), and renal failure (39% vs. 24%, p = 0.54). during 115 treatments no serious device-related adverse events occurred. on average, there were no changes in hematology and other blood parameters except for a modest reduction in platelet count (<10%) and albumin (<5%) with treatment. hemoperfusion decreased il-6 blood concentration signifi cantly (-49.1%, p = 0.01), with similar reductions of mcp-1 (-49.5%, p = 0.002), il-1ra (-36.5%, p = 0.001), and il-8 (-30.2%, p = 0.002). the 28-day mortality (28% vs. 24% control, p = 0.84) and 60day mortality (39% vs. 32% control, p = 0.75) did not diff er signifi cantly between the two studied groups. conclusion in this fi rst clinical study of a novel sorbent hemoadsorption device in patients with severe sepsis and ali, the device appeared to be safe and decreased the blood concentration of several cytokines. further research is needed to study the eff ect of the device on the clinical outcome of septic patients. response; and the changes of endotoxin and proinfl ammatory molecules. methods forty septic/septic shock patients with renal failure were enrolled in the study. all patients had preoperative endotoxin >0.6 level/units (eaa spectral d) and were submitted to high-volume hemodiafi ltration (50 ml/kg/hour, prismafl ex; gambro) with a new treated heparin-coated membrane (oxiris; gambro). at t0 (pretreatment) and t1 (24 hours) the main clinical and biochemical data were evaluated. all data are expressed as mean ± sd. one-way anova test with bonferroni correction was used to evaluate the data changes. p <0.05 was considered signifi cant. results table 1 presents the main results of this study. conclusion in septic/septic shock patients with renal failure, crrt with a new treated heparin-coated membrane (oxiris; gambro) is clinically feasible, and has a positive eff ect on renal function and hemodynamics. an adsorbing eff ect on proinfl ammatory mediators may have a role in these results. these data and the trend toward a decrease of endotoxin during the treatment warrant further investigation. reference introduction endotoxin, a component of the outer membrane of gramnegative bacteria, is considered an important factor in pathogenesis of septic shock [1] . the aim of our study was to determine whether endotoxin elimination treatment added to the standard treatment would improve organ function in patients with septic shock. methods adult patients with septic shock who required renal replacement therapy (rrt), with a confi rmed endotoxemia, and suspected gram-negative infection were consecutively added to the study within the fi rst 24 hours after diagnosis. all patients received full standard treatment for septic shock. endotoxin elimination was performed using the membrane oxiris (gambro, sweden), a medical device for continued rrt with the unique feature of endotoxin adsorbtion. an endotoxin activity assay was used to monitor endotoxin elimination therapy at baseline (t0), 3 hours (t1), 12 hours (t2), 24 hours (t3), 48 hours (t4), and 72 hours (t5). our key indicators were the improvement in hemodynamics and organ function, and decrease of endotoxin activity (ea) in blood. continuous variables are presented as mean values with standard deviations. results high ea level at baseline (0.74 ± 0.14 endotoxin activity units (eau)) signifi cantly decreased during rrt with oxiris membrane to 0.46 ± 0.02 (t1), 0.34 ± 0.01 (t2), 0.4 ± 0.02 (t3), 0.46 ± 0.04 (t4), 0.35 ± 0.07 (t5) eau (p <0.05). map increased from baseline 72 ± 14 to 81 ± 18, 76 ± 6, 77 ± 7, 83 ± 13, 87 ± 10 mmhg (p <0.05), and the mean norepinephrine use decreased from 0.23 ± 0.04 to 0.19 ± 0.02, 0.11 ± 0.01, 0.09 ± 0.01, 0.04 ± 0.01, 0.0 μg/kg/minute (p <0.05) at t0, t1, t2, t3, t4, t5, respectively. the sofa score had decreased from 14 ± 4 to 12 ± 2, 9 ± 3, 7 ± 3 points (p <0.05), and the procalcitonin level declined from 107 ± 123 to 45 ± 41, 29 ± 30, 17 ± 157 ± 1 ng/ml (p <0.05) at t0, t3, t4, t5. conclusion rrt with oxiris membrane resulted in the eff ective elimination of endotoxins from the blood. the therapy was associated with an increase in blood pressure, a reduction of vasopressor requirements, and an improvement of organ function. the application of the endotoxin activity assay was useful for bedside monitoring of endotoxemia in icu patients. introduction severe sepsis and septic shock remain the most serious problem of critical care medicine with a mortality rate of 30 to 55% [1] . several studies have demonstrated positive eff ects of selective adsorption of lps on blood pressure, pao 2 /fio 2 ratio, endotoxin removal and mortality [2, 3] . the purpose of the study was to evaluate the effi ciency of using the selective adsorption of lps, toraymyxin -pmx-f (toray, japan) and alteco® lps adsorber (alteco medical ab, sweden), in the complex treatment of patients with severe sepsis. methods forty-six patients with gram-negative sepsis in the postoperative period were enrolled into the study. toraymyxin -pmx-f was used in the pmx-f group (n = 14), while alteco lps adsorption was used in the alteco lps group (n = 32). the clinical characteristics are listed in table 1 . the sofa score, pao 2 /fio 2 , procalcitonin (pct), c-reactive protein (crp), endotoxin activity assay (eaa) was noted before, 24 and 48 hours after the selective adsorption of lps. results at 48 hours after pmx-f, signifi cantly decreased pct from 17.5 (5.0; 40.9) to 7.1 (4.8; 13.0) ng/ml, p = 0.028, decreased crp from 180 (133; 286) to 132 (68; 155) mg/l, p = 0.015 and sofa score from 7.0 (3,0; 8.0) to 6.0 (3,0; 7.0), p = 0.007. at 24 hours after alteco lps, signifi cantly decreased pct from 8.7 (3.0; 25.9) to 4.8 (2.1; 10.0) ng/ml. the 28-day mortality rate was 14.2% (n = 2) in the pmx-f group and 31.3% (n = 10) in the alteco lps group. introduction corticosteroid (cs) therapy in sepsis remains controversial and was fi rst introduced in sepsis management for its antiinfl ammatory property. cs has found a role in septic shock amelioration with inconsistent outcomes. the surviving sepsis campaign (ssc) includes cs as a level 2c recommendation in septic shock [1] . adapting and practicing ssc guidelines vary between critical care units. accordingly, a survey was conducted to elucidate the usage of cs for septic shock by uk critical care physicians (ccps). methods following approval by the uk intensive care society (ics), the survey was publicised on the ics website and its newsletter. results a total of 81 intensivists responded to this online survey. seventy-four (92.5%) ccps prescribed cs only if the septic shock is poorly responsive to fl uid resuscitation and vasopressor therapy. six (7.5%) initiated cs at the same time as vasopressor therapy. none initiated cs for patients with severe sepsis. no cs other than hydrocortisone is being used. the most commonly used intravenous regimen is 50 mg 6 hourly (65%) followed by 50 mg 8 hourly (11%). only 10% of ccps would prescribe it by infusion. less commonly used regimens were 100 mg 8 hourly (6%) and 100 mg 6 hourly (5%). only 5% would consider adding fl udrocortisone. prior to initiating cs, 5% of ccps would perform a short synacthen test, while 94% would not. the majority (89%) of ccps would stop cs after resolution of shock state or when vasopressor infusion is terminated whilst 11% after a fi xed duration. withdrawal of cs also diff ered, in that 25% tapered/weaned steroids, 31% stopped it abruptly and 44% of ccps would base their cs cessation pattern on the clinical context. only 46% of ccps believe that cs is benefi cial whereas 44% were unsure of the benefi ts in septic shock. only 29 (36%) responders indicated that their critical care unit had a written protocol for cs in septic shock. conclusion the perceptions, usage and cessation of cs in septic shock vary but do appear to have shifted in the last decade. a uk survey in 2003 identifi ed that only 60% of icus used cs for septic shock and over 22% perform a short synacthen test [2] . it appears that many intensivists are using cs for septic shock, despite confl icting outcome data. we all strive to practice evidence-based medicine but until we have a robust, reliable and methodical randomised control trial that attempts to resolve the cs debate, practice will remain diverse on this subject, as refl ected by our survey. references introduction from december 2009 to december 2010, 47 patients in scotland presented with confi rmed anthrax infection manifested by soft tissue disease related to heroin injection. these cases represent the fi rst known outbreak of a recently recognized form of anthrax, termed injectional anthrax, which appears to be associated with a high mortality rate (28% in confi rmed cases from the uk outbreak). while epidemiologic data from this outbreak have been published, no report has systematically described fi ndings in patients at presentation or compared these fi ndings in nonsurvivors and survivors. methods to better describe injectional anthrax, we developed a questionnaire and sent it to clinicians who had cared for confi rmed cases during the outbreak. completed questionnaires describing 27 patients, 11 nonsurvivors and 16 survivors, were returned. results in preliminary analysis of categorical data, a signifi cantly (fisher exact test) greater proportion of patients with compared with without the following fi ndings did not survive; history of alcohol use (p = 0.05); the presence of lethargy (p = 0.01), confusion (p = 0.03), nausea (p = 0.04), abdominal pain (p = 0.02), or the need for vasopressors (p = 0.002), oxygen, mechanical ventilation, or steroids (all p = 0.004) at presentation; and excessive bleeding at surgery (p = 0.01). initial analysis of continuous data demonstrated that, compared with survivors at presentation, nonsurvivors had signifi cantly (one-way anova) increased respiratory rate, percent neutrophils on complete blood count, hemoglobin, inr, c-reactive protein, and bilirubin and signifi cantly decreased temperature, systolic blood pressure, platelets, sodium, albumin, calcium (corrected for albumin), base excess and bicarbonate (all p ≤0.05). conclusion the implications of the apparent diff erences noted between nonsurvivors and survivors in this survey of cases from the fi rst known outbreak of injectional anthrax require further study. however, these diff erences might inform the design of research during future outbreaks or of methods to identify patients most in need of anthrax-specifi c therapies such as toxin-directed antibodies. introduction based on the results of our previous studies [1] we have identifi ed clinical risk factors for the emergence of gr(+) infections in our icu and we have developed a new algorithm for combating them. the choice of the particular antibiotic drug is guided by additional risk factors for severity of illness and data on the infectious focus. the response to therapy and its duration are also stated. the aim of the current study was to evaluate the effi cacy and safety of this preemptive approach. methods a randomized prospective controlled trial was carried out from september 2010 to september 2012. patients were submitted to block randomization and stratifi ed on the basis of their initial saps ii exp score. antibiotic therapy was started on the day of inclusion in the treatment group and only with proven gr(+) pathogen in the control group. initial data were gathered on demographics, diagnosis, proven risk factors for sepsis-related mortality, severity of infl ammatory response, ventilator-associated pneumonia and organ dysfunction. dynamics of sirs, cpis and sofa scores, subsequent infectious isolates, ventilator-free days, length of icu stay and outcome were followed for each patient. results a total of 170 patients were enrolled. no statistically signifi cant diff erences in their basal characteristics were found. the subsequent score values, length of icu stay and the number of ventilator-free days were also comparable between groups. the majority of gr(+) pathogens were isolated between 6 and 10 days of inclusion. no diff erences were found regarding the concomitant gr(-) fl ora and the related antibiotic therapy. the new organ dysfunction severity was similar in both groups (p = 0.37). the in-hospital mortality was 26.2% in the treatment group versus 18.6% in the control group (p = 0.56). signifi cant diff erences between the kaplan-meier estimates of survival were also not found (log-rank test p = 0.81). no major adverse reactions were observed. conclusion the implementation of this new policy failed to reduce the degree of organ dysfunction severity and was not associated with signifi cant survival benefi t. moreover, even though it did not reach statistical signifi cance, a second peak of gr(+) isolates was observed as a possible complication of the preemptive therapy. whether this approach could lead to vancomycin mic creep or there could still be a niche for it later in the course of treatment and/or in nontrauma patients remains to be further explored. reference introduction acinetobacter baumannii (a. baum) is a leading cause of septicemia of patients hospitalized in the icu with high mortality rates. the aim of our study is to investigate the risk factors associated with a. baum bacteremia and its mortality rates. introduction the french military hospital at the kaboul international airport (kaia) base provides surgical care for international force and afghan national army soldiers, and also local patients. the development of multiresistant bacteria (mrb) nosocomial infections has raised a major problem complicating the care of combat casualties [1] . the aim of this study is to assess the prevalence of mrb carriage on admission to the icu in this combat support hospital. methods we used a prospective observation study on patients admitted to the french military icu in kaia over 3 months (july to september 2012). all hospitalized patients were assessed for the presence of colonization with mrb: nasal and rectal swabs were performed to identify, respectively, methicillin-resistant staphylococcus aureus (mrsa) and extended-spectrum β-lactamases bacteria (esblb). the following data were recorded for each patient on admission: demographic characteristics, bacteriological results, length of stay, type of previous hospitalization. results sixty-three patients were admitted. the mean length of stay (mls) was 3 ± 3 days, and the mean age was 25 ± 14 (13 patients <15 years). patients were hospitalized for combat-related trauma (74%), noncombat-related trauma, medical pathologies (10%), and postoperative care (8%). they were afghans (92%) or westerners (8%). swabs were not realized for eight patients. forty-three percent revealed an esblb colonization: escherichia coli (22 patients), klebsiella pneumoniae (one patient), acinetobacter baumanii (one patient). no patients were colonized with mrsa. ten patients (16%) were directly admitted to the icu, 12 (19%) had been hospitalized before admission, 39 (62%) were transferred after resuscitative and stabilization care in a level 2 unit. for the two last categories, the mls (for previous hospitalization) was respectively 14 ± 28 days and 8 ± 6 hours. among patients transferred after care in a level 2 unit, mls was no diff erent between colonized and noncolonized patients: 8 ± 7 versus 9 ± 6 hours (p = 0.5, mann-whitney test). conclusion in this study, prevalence of colonization with esblb at admission is very high, suggesting a high prevalence of mdr colonization in the local population in afghanistan. it remains important to intensify the prevention policy against mrb cross-transmission in the deployed icu. critical care 2013, volume 17 suppl 2 http://ccforum.com/supplements/17/s2 introduction the aim of this study is to describe the clinical and epidemiological profi le of icu patients receiving tigecycline (tgc) and to evaluate the potential benefi ts of tgc higher doses. methods all patients admitted to our icu between 1 june 2009 and 31 may 2012 who received tgc were evaluated. cases were excluded when infections were not microbiologically confi rmed. results over the study period, 100 patients fulfi lled the inclusion criteria: 54 in the sd group (50 mg every 12 hours) and 46 in the hd group (100 mg every 12 hours). the sd group and the hd group were not signifi cantly diff erent in terms of age, severity of disease, duration of tgc therapy, rate of concomitant other active antibiotic use and of inadequate empirical antimicrobial therapy (iiat) (p = ns). mdr a. baumannii and k. pneumoniae were the main pathogens isolated. the percentage of germs other than a. baumannii and k. pneumoniae was higher in the sd tgc group (p <0.01). otherwise infections due to less susceptible germs (tgc mic value ≥1 μg/ml) were mainly treated with tgc higher doses (p <0.01). no signifi cant diff erences were found in terms of icu mortality (p = 0.8). the rate of abnormal laboratory measures during tgc treatment was similar between the two groups (p = ns). no patients required tgc discontinuation or dose reduction because of suspected adverse events. in the vap subpopulation (63 patients: 30 received sd and 33 hd), the clinical cure rate and microbiological eradication percentage were higher when tgc was used at higher doses (57.6% vs. 33.3%; p = 0.08 and 57.1% vs. 30.4%; p = 0.1). table 1 shows multivariate analysis of clinical cure predictors in the vap subgroup. conclusion in critically ill patients, hd tgc use seems to be safe and, combined with other active antibiotics, may increase the rate of mdr germ vap clinical success. iiat and the severity degree of patients' clinical condition still remain major determinants of vap treatment failure. reference introduction amikacin inhale (nktr-061, bay41-6551) is a drugdevice combination in clinical development for adjunctive treatment of intubated and mechanically ventilated patients with gram-negative pneumonia. the product uses a proprietary vibrating mesh nebulizer system (pdds clinical) with amikacin sulfate formulated for inhalation (3.2 ml of 125 mg/ml amikacin solution) for a 10-day twice-daily course of therapy. it is designed for use with two delivery systems: one system for intubated patients (on-vent; figure 1 ), and a second handheld (hh) system for patients who are extubated before completing the course of therapy ( figure 2 ). we investigated in vitro the amikacin lung dose delivered by pdds clinical. methods an estimated lung dose (eld) for on-vent setting was measured in vitro after collecting aerosolized amikacin from a fi lter at the end of an endotracheal tube during ventilation. the eld for the hh device was calculated from the fi ne particle fraction (fpf <5 μm) postmouthpiece, multiplied by the in vitro delivered dose post-mouthpiece. fpf <5 μm refl ects lung deposition observed during phase 2 clinical trials [1] . eighty-one nebulizers with volume median diameter (vmd) introduction recent studies demonstrate that a loading dose of 25 mg/kg (total body weight) of amikacin in septic patients is required to reach a suffi cient peak concentration. this study examines parameters infl uencing the relation between amikacin dose and peak concentration. methods in this retrospective study we looked at 47 patients (128 peak levels) between 2003 and 2012. multivariate linear regression analysis was done for several parameters: administered dose calculated with total body weight, ideal body weight, adjusted body weight, type of intensive care patient, bmi, daily fl uid balance, sofa score and apache score, and patient characteristics were analyzed. results a linear correlation between dose and amikacin peak level was confi rmed (figure 1) . a total 54.69% of all amikacin administrations did not result in a therapeutic peak level. the multivariate linear regression analysis showed the best linear correlation with adjusted body weight and sofa score. the comparison of variables between four patient groups, based on the deviation between measured peak level and predicted peak level (according the linear correlation), showed new variables that may infl uence peak level. conclusion this confi rms that low doses (<18 mg/kg) of amikacin in intensive care patients seldom result in a therapeutic peak level. the proposed loading dose of 25 mg/kg is good for reaching a therapeutic level, although 29.6% remains subtherapeutic. due to the linear correlation, more therapeutic levels may be reached with higher doses (25 to 30 mg/kg). new variables need further investigation to explain the high variability in achieved peak level. introduction antibiotic-associated diarrhoea (aad) occurs in as many as 30% of patients receiving antibiotics, often leading to increased morbidity, prolonged in-hospital stay and additional healthcare resource utilisation. age, antibiotics and prolonged postoperative ward and icu stay have been suggested to be independent risk factors. in such patient populations, probiotics may be used to prevent antibioticassociated diarrhoea, yet they are not routinely recommended as a component of perioperative care. the aim of this study was to model the long-term costs associated with aad and to assess the eff ectiveness of probiotics as a preventive strategy. we developed a simulation model to determine clinical costs and outcomes attributable to aad. to assess the cost-eff ectiveness of probiotics, as part of a perioperative regime, we constructed a decision critical care 2013, volume 17 suppl 2 http://ccforum.com/supplements/17/s2 s30 tree. the model observes long-term costs and outcomes of probiotics as compared with conventional therapy, from a societal perspective. input parameters, extracted from meta-analysis, clinical trials and national databases, include incidence numbers, costs and qualityadjusted health states for the remaining life (qalys). outcomes assessed were overall costs attributable to add and the cost-eff ectiveness of probiotics, described as costs/qaly. our results indicate an estimated incremental lifetime cost of £13,272.53 per add patient, largely driven by increased icu length of stay and readmission rates. the addition of probiotics to the standard perioperative regime is associated with a small survival benefi t of 1.2 months, yet a cost reduction of £917.3/add patient. the main cost was increased duration of icu stay and readmissions, which contribute to 85% of total expenses. conclusion aad is associated with a signifi cant increase in costs from a societal perspective. the provision of probiotics can achieve substantial cost savings and can be recommended as a cost-eff ective regime in the perioperative setting. preventing add off ers a potentially signifi cant reduction of in-hospital costs and resource expenditures. introduction novel treatment strategies for invasive candidiasis (ic) are constantly emerging. nevertheless, diffi culties in diagnosis pose a challenge on their reliability, effi cacy and safety. we have previously developed and approbated in our icu an algorithm for empirical antimycotic therapy, combining the most signifi cant risk factors for ic with three major clinical criteria for persistent nonbacterial sepsis [1] . on the other hand, preemptive therapy, based on identifi cation of mycotic antigens and/or anti-mycotic antibodies in serum, is regarded as more reliable, even though it is known for its low sensitivity. the aim of the current study was to compare and evaluate the possible outcome benefi t of our protocol implementation versus detection of galactomanan in patient's serum as a trigger for antimycotic treatment initiation. methods a randomized prospective controlled trial was carried out from september 2010 to september 2012. after the implication of the inclusion and exclusion criteria, patients were submitted to block randomization and stratifi ed on the basis of their initial saps ii exp score. antimycotic therapy was started on the day of inclusion in the control group and only with positive galactomanan serum test in the preemptive therapy group. initial data were gathered on demographics, proven risk factors for ic-related mortality, severity of infl ammatory response and organ dysfunction. dynamics of sirs and sofa values, candida colonization index, ventilator-free days, length of icu stay and outcome were followed for each patient. results a total of 106 patients were enrolled. no statistically signifi cant diff erences in their basal characteristics were found. the subsequent sirs and sofa scores showed fi rm dynamics in the control group, although the new organ dysfunction severity was insignifi cantly lower. the length of icu stay and the number of ventilator-free days were comparable. the in-hospital mortality was 47.1% in the preemptive therapy group versus 31.3% in the control group (p = 0.94). a total of seven adverse reactions were observed among treated patients, yet not associated with higher mortality risk. conclusion the choice of empirical versus preemptive therapy led to earlier and more stable reduction in the degree of organ dysfunction severity. it showed to be at least not inferior if not equal; in terms of survival benefi t and expediency of treatment. moreover, galactomanan detection fails to guide the choice of the individual antimycotic, based on the expected candida spp. reference introduction invasive candidemia is a major cause of increased mortality among icu patients. antifungal agents like liposomale amphotericin b and azoles could not accomplish the claim to be fi rst choice in the treatment of invasive fungal infection (ifi) because of side eff ects and eff ectiveness. especially, cardiothoracic surgery patients as a group of high-risk patients are in a focus for new strategies and agents. a new class of antimycotic agents, the echinocandins, with a low profi le of side eff ects, low interactive potential and high eff ectiveness in the treatment of candidemia, is a powerful option in the treatment of ifi. we report our single-center experience with a modifi ed clinical treatment approach based on clinical score of leon and using echinocandins as fi rst-line therapy for proven and suspected fungal infection. methods from may 2011 to october 2012, 2,844 patients were treated on our cardiothoracic icu. we evaluated 37 cardiothoracic postoperative patients with proven or suspected ifi or prophylaxis ( figure 1 ). the records were evaluated for cardiothoracic procedures, microbiological and yeast date, cardiothoracic surgery score (casus), icu and clinical data. mean age was 67.4 years with 64% male patients. most patients had combined cabg and valve procedure (n = 20), other groups were htx and ltx (n = 4), assist therapy (n = 4), tavi (n = 3) and other procedures. mean predicted mortality using the logarithmic casus score at the onset of ifi was 59%. c. albicans was isolated in 73%, c. glabrata in 21%. length of antifungal treatment using micafungin in 30 cases was 14 ± 5 days. eradication of yeast was successful in 79% but mortality of all patients remains high at 36.8% but was lower than predicted in the casus score. mortality was not yeast related. conclusion our described treatment approach shows encouraging results for the treatment of ifi especially in high-risk cardiothoracic patients. with fungi [1] . the relationship between colonization and invasive fungal infection (ifi) in severely ill icu patients with a vad support is not described. this study analyzes the incidence and outcome of fungal infection and colonization in vad patients in bridge to transplantation or in destination therapy. methods we conducted a retrospective review of all vad implantations in our surgical icu between 2007 and 2012. the incidence of fungal colonization, antifungal prophylaxis, bacterial sepsis and the mortality of ifi versus no ifi patients were compared. results in the study period, 34 patients with severe heart failure or cardiogenic shock were selected for a vad implantation (nine in destination therapy). the overall mortality rate was 50% during mechanical assistance. confi rmed (n = 8) and highly suspected (n = 2) ifi occurred during the icu stay in 29% of patients who were treated with echinocandins, voriconazole and/or liposomal amphotericin b. the isolated fungi were: six candida albicans, two parapsilosis, one glabrata and one invasive pulmonary aspergillosis. antifungal prophylaxis with fl uconazole was administered to 18% of patients at mean for 5 days mainly in the more recent implantations. in the no ifi population, 54% (n = 13) had a systemic or vad bacterial sepsis with a mortality rate about 54%. the mortality without any sepsis was reduced to 18%. fungal colonization was signifi cantly more present (90% vs. 50%) before ifi in vad patients. the mortality rate was dramatically higher with ifi (80% vs. 38%) in accordance with the literature [1] . see table 1 . conclusion in our center, we observed a high incidence of ifi in icu patients with vad that was associated with a mortality rate of 80%. screening of fungal colonization appears to be very important during the icu stay for vad patients. trials are needed for investigating the use, the drug choice and the timing of antifungal prophylaxis for such high-risk patients. reference introduction echinocandins are recommended fi rst-line treatment for candidaemia [1] . a cost-eff ectiveness model developed from a uk perspective examined costs and outcomes of antifungal treatment for candidaemia and other forms of invasive candidiasis based on european clinical guidelines [1] . methods costs and treatment outcomes with the echinocandin anidula fungin were compared with caspofungin, micafungin, fl uconazole, voriconazole and amphotericin b. the model included non-neutropenic patients aged ≥16 years with confi rmed candidaemia/ another form of invasive candidiasis receiving intravenous fi rst-line treatment [2] . patients were categorised as a clinical success or failure (patients with persistent/breakthrough infection); frequency data for each outcome were taken from a mixed-treatment comparison [3] . successfully treated patients switched to oral therapy. clinical failures switched to a diff erent antifungal class. it was assumed that second-line treatment duration was equivalent to that of fi rst-line treatment and only two lines of therapy were required to treat infection. other inputs were all-cause 6-week mortality, cost of treatment-related adverse events (aes) and other medical resource use costs. life-years were calculated using a published model [4] . antifungal agent-related aes were taken from the product label/literature. resource use was derived from the literature and discussion with clinical experts. drug acquisition/ administration costs were taken from standard uk costing sources. results first-line anidulafungin for treatment of candidaemia was cost-eff ective per life-year gained versus fl uconazole (incremental cost-eff ectiveness ratio £813). anidulafungin was cost saving versus caspofungin and micafungin in terms of life-years gained due to lower icu costs and a higher rate of survival combined with a higher probability of clinical success. conclusion anidulafungin was cost-eff ective compared with fl uconazole for treatment of candidaemia and was cost saving versus other echinocandins in the uk. european guidelines recommend echinocandins as fi rst-line treatments for candidaemia [1] ; this model indicates that anidulafungin marries clinical eff ectiveness and cost-eff ectiveness. introduction invasive fungal infections (ifi) aff ect 1% of icu patients and are increasing in incidence. ifis are associated with a poor prognosis, which is further complicated by diffi culties in identifi cation of fungal organisms by traditional culture methods and the emergence of candida species resistant to triazole therapy [1, 2] . this study aimed to assess the prevalence of ifis, the organisms responsible and outcomes of patients aff ected. the majority of patients (71%) were treated with echinocandins, whilst of the nine patients who were initially treated with fl ucanazole, six (67%) required therapy escalation to an echinocandin. the results of our study are consistent with other published data, in that whilst ifi prevalence is low, they are associated with increased morbidity in critically ill patients. this study has led to a change in hospital policy regarding antifungal use in the icu, with echinocandins being fi rst-line in the pre-emptive treatment of ifi. we keenly await the results of the fire study, which will provide important insights to identifi cation of patients at risk of ifis and optimal drug therapy. introduction the aim of this study was to compare self-reported beliefs with actual clinical practice of oxygen therapy in the icu. hyperoxia is frequently encountered in ventilated patients and prolonged exposure has repeatedly been shown to induce lung injury and (systemic) toxicity. methods an online questionnaire for icu clinicians was conducted to investigate beliefs and motives regarding oxygen therapy for critically ill patients. furthermore, arterial blood gas (abg) samples and corresponding ventilator settings were retrieved to retrospectively assess objective oxygenation between 1 april 2011 and 31 march 2012 in the icus of three teaching hospitals in the netherlands. results analyzable questionnaire responses were received from 200 icu physicians and nurses. the majority of respondents believed that oxygen-induced lung injury is a concern, although barotrauma and volutrauma are generally considered to impose a greater risk in mechanical ventilation. frequently allowed minimal saturation ranges in the questionnaire were 85 to 95% and 7 to 10 kpa ( figure 1 ). selfreported fio 2 adjustment in hypothetical patient cases with variable saturation levels was moderately impacted by the underlying clinical condition. to study actual clinical practice, a total of 107,888 abg samples with corresponding ventilator settings, covering 5,565 patient admissions, were retrieved. analysis showed a median (iqr) pao 2 of 11.7 kpa (9.9 to 14.3), median fio 2 was 0.4 (0.4 to 0.5), median peep was 5 (5 to 8). a total 63.5% of all pao 2 registries were higher than previously suggested oxygenation goals (7.3 to 10.7 kpa) [1] . in 56.8% of cases with pao 2 higher than the target range, neither fio 2 nor peep levels had been lowered when the next abg sample was taken. conclusion most clinicians acknowledge the detrimental eff ects of prolonged exposure to hyperoxia in the icu and report a low tolerance for high saturation levels. however, the self-reported intention for conservative oxygen therapy is not consistently expressed in our objective data of actual clinical practice and a large proportion of patients was exposed to high and potentially toxic oxygen levels. introduction during mechanical ventilation, oxygenation can be infl uenced by adjusting fio 2 and positive end-expiratory pressure (peep). there have been recommendations for how the fio 2 and peep should be set [1] . however, in a recent audit we found that the compliance of doctors of these recommendations is very low [2] . conclusion implementing an fpi ≤7-based algorithm signifi cantly reduced the fio 2 and increased the peep applied in mechanically ventilated within the fi rst 24 hours. whether this has any impact on earlier weaning due to reaching the weaning criteria of fio 2 sooner, and as a result shortening the duration of mechanical ventilation, has to be investigated in the future. references system) were applied with the humidifi er to optimize humidication. typeb was used in three patients and typev in four patients. the fl ow was started at 10 l/minute. this fl ow rate was titrated upwards to a maximum of 60 l/minute (10, 25, 30, 40, 50, 60 l/minute) and the agfr was measured. intratracheal pressure tracing was done over 1 minute. airway pressure measurement was repeated and the maximal expiratory pressure was measured in mmhg. the agfr in the respiratory circuit was almost same in typeb, but there was obvious decrease in the agfr in typev (7.1 ± 1.0, 17.7 ± 0.8, 21.9 ± 0.9, 29.9 ± 3.6, 36.9 ± 2.7, 45.0 ± 5.5 l/minute at assumed fl ow, 10, 25, 30, 40, 50, 60 l/minute, respectively). hfnc signifi cantly increased maximal expiratory pressure in both groups, 1.5 ± 2.1, 2.0 ± 1.0, 3.0 ± 2.8, 4.5 ± 3.5 mmhg for typev and 2.5 ± 0.7, 5.8 ± 2.4, 6.0 ± 2.8, 8.0 ± 2.8 mmhg (maximum 10 mmhg) for typeb, when agfr was set at 30, 40, 50, 60 l/minute. higher agfrs were found to result in larger increase in maximum expiratory pressure. the data indicate that hfnc are associated with an increase in intratracheal expiratory pressure. because it was diffi cult to determine end-expiratory pressure, we chose maximal expiratory pressure for a substitute. the reason why agfr in typev was lower than assumed fl ow may be the resistance generated by nc. the larger increase in expiratory pressure in our study than previously reported may be due to the eff ect of high respiratory resistance of japanese who have relatively small airway structure compared with western people. conclusion hfnc are eff ective in providing higher expiratory pressure. it is important to know the fl ow rate is lower than expected when the venturi type is used. results a weaning-induced pulmonary edema was diagnosed in 12 instances (paop signifi cantly increased from 15.6 ± 0.6 to 25.8 ± 0.9 in these cases). evlwi, bnp, plasma protein and hemoglobin concentrations signifi cantly increased in these instances (28.3 ± 5.7%, 20.2 ± 7.8%, 9.6 ± 0.8% and 9.3 ± 1.3%, respectively) while they did not signifi cantly changed in cases without weaning-induced pulmonary edema. the increase of evlwi ≥8.5% (+1.5 ml/kg), an increase in bnp ≥6.7% (+23 pg/ml), an increase in plasma protein concentration ≥5% and in hemoglobin concentration ≥5% exhibited good areas under the roc curves to predict weaning-induced pulmonary edema (0.97 ± 0.03, 0.80 ± 0.11, 1.0 ± 0.00 and 0.92 ± 0.05, respectively). these areas under the roc curves were not statistically diff erent. the baseline values of evlwi, bnp, plasma protein and hemoglobin concentrations did not predict weaning-induced pulmonary edema. conclusion the increases in evlwi, in plasma protein and hemoglobin concentration and in bnp are valuable alternatives to the pulmonary artery catheter for diagnosing weaning-induced pulmonary edema. the primary aim of this study is to assess the impact of pressure support ventilation (psv) on the rate of pneumothorax and mortality in critically ill patients with lung injury. the secondary aim is to evaluate pressure-volume (p-v) relationships. spontaneous modes of ventilation have been associated with lower rates of atelectasis, less muscle atrophy, better airfl ow distribution and importantly lower sedation requirements, which relates to lower mortality. accordingly, we hypothesized that the use of psv in patients with moderate/severe lung injury would have rates of pneumothorax and mortality within the standard of care. we further hypothesized that given its spontaneous nature, set pressures (peep and ps) but not tidal volume (vt) would be related to airway pressures. methods all adult patients admitted to two surgical/medical icus subjected to invasive mechanical ventilation (mv) were enrolled. patients were stratifi ed by lung injury score (lis) in two groups: <2.5 (lisl); ≥2.5 (lish). exclusion criteria included pneumothorax on admission, use of other ventilatory strategies, and inability to trigger ventilation. patients were ventilated with psv, and treated only with pro re nata haldol, morphine and clozapine. airway pressures and conclusion we demonstrate that psv in minimally sedated patients with severe lung injury is safe as it is associated with low incidence of barotrauma, atelectasis and mortality, and with ppl and duration of mv within standard of care. we also demonstrate in psv that p-v relationships may diff er and that in this setting higher vt may not be deleterious. introduction the aim of this study is to compare two ventilation strategies, the ardsnet protocol and open lung management, using computer control for 6 hours. the standard therapy for patients with ards does typically apply a mechanical ventilator to support breathing. the cost of therapy is high and it requires much attention from physicians to adjust the proper ventilation settings in a timely manner. a closed-loop ventilation concept has therefore been developed and tested with two induced ards pigs. methods the hardware system is composed of a ventilator (servo 300), a spectrophotometry (cevox), a capnography device (co2smo+), an electrical impedance tomography device (goe mf ii) and a patient monitor (sirecust). the software is developed with labview 7.1. with approval from the ethical committee, two 27 kg pigs were exposed to surfactant depletion with a warm saline washout to induce ards (pao 2 / fio 2 <200 mmhg). one pig model was ventilated with an automatic ardsnet protocol and another was automatically ventilated with open lung management. blood gas analysis (bga) was carried out every half an hour. results artifi cial ventilation using the auto ardsnet protocol successfully stabilized oxygenation, minimized plateau pressure (<30 cmh 2 o), and controlled the ph value for acidosis and alkalosis management. on the other hand, auto open lung management off ers a distinctive result of ventilation. a signifi cant improvement of oxygenation and lung compliance was observed within a few breaths after the recruitment maneuvers. both subjects were ventilated at the same tidal volume of 6 ml/kg and the comparative results of automatic ventilation settings and bga are provided in table 1 for every 2 hours. conclusion the auto open lung management concept gave much better gas exchange than the auto ardsnet protocol. these preliminary results showed a necessity to evaluate the two diff erent ventilation strategies. therefore, further experiments with pig models will be implemented in the near future to obtain results with statistical signifi cance and to ensure the safety of automation in a mechanical ventilation system. intellivent-asv has been developed to provide fully closed loop mechanical ventilation using a ventilation controller keeping etco 2 and spo 2 within expert-based ranges. ventilation of ards patients focuses on delivering adequate oxygenation and allowing elimination of co 2 while protecting the lung. the objectives were to compare intellivent-asv with conventional ventilation on safety and effi cacy, and to compare the number of manual adjustments between the two ventilatory modalities. methods a randomized, controlled study including all consecutive patients receiving mechanical ventilation for at least 48 hours. patients were randomly ventilated either with intellivent-asv or conventional ventilation, with a s1 (hamilton, bonaduz, switzerland). parameters were adjusted by the clinician in charge of the patient. ventilatory and oxygenation parameters were recorded cycle by cycle during 48 hours and blood gases were performed every 6 hours. results twenty-four patients with ards were included, 10 female, 14 male, median age 58 (46 to 63) years, apache ii score 22 (17 to 29), pao 2 /fio 2 at inclusion 136 (107 to 154). eleven were ventilated in the conventional group and 13 in the intellivent-asv group. the study was stopped for one patient from the intellivent-asv group because of a pneumothorax not caused by ventilation. the delivered vt was slightly higher during intellivent-asv (7.9 (7.5 to 8.5) vs. 7.2 (6.8 to 7.8) ml/kg, p = 0.013). the time spent by the various parameters in the suboptimal zone (safety) is the same for the two ventilation modes. the time spent in the optimal zone (effi cacy) is the same for the two ventilation modes, introduction ventilator-induced lung injury (vili) is a well-known side eff ect of mechanical ventilation. the pressures and volumes needed to induce vili in healthy animals are far greater than pressure and volumes applied in clinical practice [1] . a possible explanation may be the presence of local pressure multipliers (stress raisers). methods we retrospectively analyzed ct scans of 147 patients with ards and ct scans of 100 healthy subjects. a homogeneous lung would have the same gas/tissue ratio in all its regions. if a lung region expands less than the neighbour regions these will be more strained to vicariate the non/less expanding region. we measured the stress raisers by computing the ratio between the gas fraction of the region of interest and the neighbouring regions: if the infl ation would be the same (homogeneity), the ratio will be equal to one; if the infl ation of the surrounding regions would be greater than the region of interest (that is, more strained), the ratio between the two will be greater than one and was taken as a measure of stress raiser. we considered pathological stress raisers as the regions showing infl ation ratio greater than the 95th percentile of the control group (1.61) and defi ned as the extent of the stress raisers the fraction of lung volume above this threshold. the extent of stress raisers increased with the severity of ards (14 ± 5, 18 ± 8, 23 ± 1% of lung parenchyma in mild, moderate and severe ards, p <0.0001). the extent of stress raisers correlated with the dead space fraction (r 2 = 0.34, p <0.001), with the fraction of poorly aerated tissue (r 2 = 0.36, p <0.0001) and also has a negative correlation with the fraction of well infl ated tissue (r 2 = 0.47, p <0.0001). the response to peep, passing from 5 to 45 cmh 2 o is minimal (average decrease of stress raiser extent 6 ± 5%) and inter-individual variability is great (in 11 patients, stress raisers increased passing from peep 5 to peep 45). stress raisers turn out to be greater in nonsurvivor patients than in survivor patients (17 ± 7 vs. 20 ± 9% of lung volume, p = 0.03). the art strategy did not increase the risk of barotrauma (relative risk (rr) = 0.78, 95% ci = 0.19 to 3.30) in the fi rst 7 days after randomization or the need to initiate or increase vasopressors or mean arterial pressure <65 mmhg (rr = 1.14, 95% ci = 0.65 to 2.02, p = 0.67) 1 hour after randomization. however, the art strategy increased the risk for severe acidosis (ph <7.10) 1 hour after randomization (rr = 3.20, 95% ci = 1.12 to 9.20, p = 0.03). conclusion art is feasible. the incidence of adverse events was similar between groups except for severe acidosis 1 hour after randomization. hence we adjusted the study protocol, increasing the respiratory rate (from 10 to 15/minute) during msarm. introduction cardiac surgical procedures are associated with a high incidence of postoperative complications, increasing costs and mortality. the purpose of this study is to evaluate prospectively the impact of two protective mechanical ventilation strategies, both using low-tidal volume ventilation (6 ml/kg/ibw) after cardiac surgery. conclusion the reliability of pressure measurements and also of compliance estimation via the tested catheters is high. only in two catheters was the fi lling volume a critical point for a precise measurement of pressure or for estimation of compliance. immediately after unpacking, adhesion of the balloon material might prevent reliable pressure measurement, therefore before the fi rst measurement overfi lling of the balloon and retention of the excess gas seems strongly recommended. introduction low tidal volume (vt) ventilation in intensive care patients without lung injury attenuates the systemic infl ammatory response [1] . the contribution of the specifi c organ infl ammatory responses to the systemic picture remains to be elucidated. we investigated the eff ect of low vt ventilation compared with medium high vt on hepatic, splanchnic and cerebral cytokine responses in an experimental large animal postoperative sepsis model. methods twenty pigs, group protective ventilation (pv), were ventilated with low vt (6 ml/kg) and peep 10 cmh 2 o while 10 pigs, group control (c), were ventilated with a vt of 10 ml/kg and peep 5 cmh 2 o. catheters were introduced into an artery, the jugular bulb, the hepatic vein and the portal vein. laparotomy for 2 hours simulated a surgical procedure after which baseline ensued and a continuous endotoxin infusion was started at 0.25 μg/kg/hour for 5 hours. diff erences were analyzed with anova for repeated measures. results tnfα levels were higher in the hepatic vein than in the artery, the jugular bulb and the portal vein. il-6 levels were higher in the artery and the jugular bulb compared with the portal and hepatic veins. il-10 levels were higher in the portal vein compared with the jugular bulb and hepatic vein. the organ-specifi c il-10 concentrations were all higher than the arterial concentration. comparison between the ventilation groups showed that tnfα, il-6 and il-10 in the hepatic vein were higher in group c compared with group pv at the end of the experiment. peak concentrations of tnfα and il-6 in the portal vein were higher in group c compared with group pv. in this experiment tnfα was mainly generated in the liver while the results point to signifi cant nonhepatic il-6 and il-10 production. ventilation with low vt and medium-high peep attenuated hepatic and splanchnic cytokine production compared with mediumhigh vt and lower peep. reference introduction airway pressure release ventilation (aprv) allows spontaneous breathing throughout the ventilation cycle. it increases venous return and cardiac index, which will signifi cantly improve organ perfusion. this is important in septic shock patients to prevent extrathoracic organ system failure secondary to poor perfusion. benefi ts of aprv with cardiovascular changes are noticed in patients with acute lung injury and acute respiratory distress syndrome. it is not well established whether applying aprv will improve the survival outcome for septic shock patients. the primary outcome is whether the use of aprv in septic shock patients restores hemodynamic stability earlier than the cmv mode. the secondary hypothesis is whether the use of aprv in septic shock patients improves their survival in the icu. methods after institutional review board approval, we retrospectively analyzed the clinical data of 129 septic shock patients who received ventilator support between january and december 2011 at a tertiary care hospital. the cox proportional hazards model was used in adjusting potential confounding factors. the nonparametric wilcoxon rank sum test was used to assess signifi cant outcome diff erences between groups. time to event/survival data will be analyzed using kaplan-meier methods. these analyses were accomplished using sas, version 9.3. results among the 187 patients, 58 were excluded as per the exclusion criteria: incomplete data (n = 28), do not resuscitate (n = 16), icu readmission (n = 12) and head injury (n = 4). finally, 129 patients were included, from these 91 received cmv and 38 received aprv. at the beginning of the study, there were no diff erences between the groups in relation to hemodynamic parameters. reversal of shock achieved in less than 72 hours was statistically signifi cant between the groups (aprv, n = 16 (42%) and cmv, n = 8 (9%), p = 0.0101). the proportion of patients recovering from septic shock after initiation of ventilator therapy was higher in aprv than the cmv group (72% vs. 49%, respectively, p <0.0001). the mortality rate was signifi cantly higher in cmv (n = 46, 51%) as compared with aprv (n = 11, 29%) (p = 0.022). conclusion the use of aprv in septic shock patients restores hemodynamic stability earlier than the cmv mode. there was a signifi cant improvement in icu survival using aprv over cmv. early initiation of aprv in ventilated septic shock patients was associated with a decrease in icu mortality. obese patients are at risk of developing atelectasis and acute respiratory distress syndrome (ards) [1] . the prone position (pp) may reduce atelectasis, and improves oxygenation and outcome in severe hypoxemic patients in ards [2] , but little is known about its eff ect in obese ards patients. introduction protective mechanical ventilation (mv) in ards is based on reduced stretch of pulmonary tissue, sometimes resulting in severe hypoventilation that can be avoided when using high respiratory rate. high-frequency positive-pressure ventilation (hfppv) has not been fully explored, especially when associated with other strategies aiming to avoid hypercapnia. methods we induced ards in eight pigs by lung lavage with saline plus 3 hours of injurious mv with low peep and high driving pressure (dp). we then performed a recruitment maneuver (rm) followed by peep titration using the amount of alveolar collapse in electrical impedance tomography (eit). then stabilization during 1 hours with tidal volume (vt) at 6 ml/kg, respiratory rate (rr) 35 breaths/minute and peep selected with the peep-fio 2 table (arma study), which was kept constant during two steps of hfppv with a rr 60: one without an inspiratory pause (hfppv-60), and one with a pause of 30% of inspiratory time (hfppv-60 w/p30%). in another hfppv step, we used peep titrated with eit after rm (hfppv-60 w/rm). during each hfppv step, vt was set to reach a paco 2 of 60 ± 3 mmhg. distribution of regional ventilation was analyzed using eit. equilibrium was considered if paco 2 was stable (<5% of variation) for >30 minutes. results hfppv allowed reduction in paco 2 levels: 81 (77, 94) versus 60 (58, 61), 59 (58, 60), 60 (58, 61) mmhg, besides using lower vt: 5.2 (5.0, 5.9), 5.1 (4.5, 6.0), 4.7 (4.2, 5.7) and 4.8 (4.5, 5.6) ml/kg during stabilization, hfppv-60, hfppv-60 w/p30% and hfppv-60 w/rm, respectively. it had no signifi cant diff erent results comparing hfppv-60 with and without an inspiratory pause. hfppv-60 w/rm allowed a better alveolar homogenization and improvement in oxygenation, shunt, dead space and dp compared with the other steps. see table 1 . conclusion hfppv with a conventional mechanical ventilator is able to maintain stable paco 2 in clinically acceptable values, allowing reductions in vt. hfppv-60 w/rm and peep titration using eit allowed further physiologic benefi ts in a severe ards model. high-frequency percussive ventilation (hfpv) is a rescue technique for most severe acute lung injury/acute respiratory distress syndrome (ards) patients [1] , especially with smoke inhalation or respiratory burns [2] . this study aimed at characterizing hfpv as delivered by percussionnaire vdr4® and at evaluating how hypobarism interferes with hfpv, in order to assess its usability at altitude. methods using a mechanical test lung mimicking ards (compliance 17 ml/cmh 2 o) with two resistance levels (5 and 15 cmh 2 o/l/second) and ventilated with vdr4® in a hypobaric chamber, ascents/descents between 0 and 5,000 and then 0 and 8,000 ft were performed. adjustable vdr4® parameters were modifi ed one at a time at each altitude. besides these parameters (cross-measured with standalone hardware), oxygen consumption of the respirator and three calculated parameters were studied: low-frequency tidal volume (vt, integrated from instantaneous fl ows measured with a fleisch pneumotachograph), end-inspiratory (pmei) and end-expiratory (pmee) mean pressures. pmei and pmee in hfpv refl ect plateau pressure and positive end-expiratory pressure in conventional ventilation. the correction of altitude-induced off set with the modifi cation of working pressure was also tested. results data displayed by vdr4® overestimated pulmonary pressures by more than 10%, but were reliable for other parameters. during ascent, an off set appeared for all respiratory parameters: vt increased by 59% and pmei by 53% between 0 and 8,000 ft. during descent, the off set was reversely directed with a 39% decrease in vt and a 28% decrease in pmee between 8,000 and 0 ft. modifying working pressure adequately corrected pmei and pmee, but not vt. in all cases, manually correcting vdr4® parameters to their 0 ft level also corrected these off sets. multivariate analysis further established that, adjusting for other parameters, vt, pmei and pmee did practically not depend on altitude. oxygen consumption of the respirator was high, 25 l/minute at 0 ft, and stable with altitude. it was reduced with percussive rate and with fio 2 . conclusion hfpv can be safely used at altitude, provided that vdr4®displayed parameters are used to manually adjust settings in order to avoid exposing patients to volutrauma or barotrauma during ascent, and to major hypoventilation and alveolar collapse during descent. the high oxygen consumption is currently the main limit to its use for longrange aeromedical evacuations. the application of peep is commonly used in acute respiratory distress syndrome (ards) and has been shown to improve oxygenation. to identify patients that most benefi t from the application of peep, the discrimination of recruiters and nonrecruiters has been postulated by gattinoni and colleagues [1] . recently, dellamonica and colleagues [2] presented a method to predict alveolar recruitment. we hypothesised that the amount of recruitable volume allows the discrimination between ards patients and patients with healthy lungs (hl). methods we recalculated the recruited volume (rv) in 25 patients with ards [3] according to the method proposed by dellamonica and colleagues during an incremental peep manoeuvre (peep increased until the plateau pressure reached 45 cmh 2 o). rv was calculated as the change in end-expiratory lung volume minus total respiratory system compliance times the peep change (rv = δeelv -ctot×δpeep). for comparison, 12 patients with hl undergoing elective surgery in general anaesthesia were measured using the same protocol. results both ards and hl patients exhibited typical p-v curves and stepwise recruitment ( figure 1 ). by raising peep from 0 to 12 cmh 2 o, ards patients recruited 331 ± 195 ml (mean ± sd) and hl patients 435 ± 43 ml. there was a strong correlation (r 2 = 0.88) of the total rv with the end-inspiratory volume at a plateau pressure of 45 cmh 2 o in both groups; that is, recruitment was found to the same extent in both groups ( figure 2 ). conclusion the relative contribution of rv to lung volume gain is similar in ards and in patients with healthy lungs. our results question the relevance of recruitability as defi ned by dellamonica and colleagues as a typical phenomenon of ards, but support the baby lung concept, as the recruited volume was closely related to the size of the lung. introduction venovenous extracorporeal membrane oxygenation (vv-ecmo) for respiratory failure in the icu is used in a variety of clinical situations and has been demonstrated to signifi cantly improve survival without disability in adult respiratory distress syndrome [1] . ecmo has been presented as a risk factor for bloodstream infection although recently published data do not support this view or the use of antibiotic prophylaxis [2] . we aimed to examine vv-ecmo as a risk factor for nosocomial bloodstream infection. a larger study is needed to confi rm such fi ndings and to assess the need for specifi c intervention, namely routine antibiotic prophylaxis. introduction aptt is a common tool for anticoagulation monitor ing during extracorporeal membrane oxygenation (ecmo). thromboelasto graphy (teg) is another available option in this setting. methods a prospective observational study on 12 consecutive patients during venovenous ecmo. anticoagulation was provided critical care 2013, volume 17 suppl 2 http://ccforum.com/supplements/17/s2 s47 with unfractioned heparin titrated to an aptt ratio target of 1.5 to 2. kaolin-activated teg (k-teg) was contemporarily measured but did not guide heparin infusion. baseline k-teg reaction time (r) >20 minutes is accepted for anticoagulation but when it exceeds 90 minutes anticoagulation may be too great [1] . results mean ecmo duration was 9 ± 4 days. a total of 152 k-tegs were collected. comparison between aptt and k-teg r is reported in table 1 . four patients (33%) had hemorrhagic complications. neither aptt nor k-teg r were signifi cantly diff erent in patients with hemorrhagic events compared with patients without hemorrhagic events but the latter received a signifi cantly lower total heparin dose (p = 0.0097). conclusion anticoagulation was excessive in more than one-half of the samples according to teg monitoring, while negligible based on aptt. reference introduction the usefulness of extracorporeal membrane oxygenation (ecmo) is being rediscovered in the wake of the pandemic of h1n1 infl uenza. however, it has been reported that patients who received ecmo often developed virus-associated hemophagocytic syndrome (vahs), compared with those without ecmo support. although there is ample evidence that extensive cytokine activation is a key factor in vahs, ecmo itself could be a potential trigger to exacerbate the pathology by amplifying cytokine activation. in this study, we investigated whether mediators such as cytokines may be produced by ecmo. methods patients with severe respiratory failure who were placed on ecmo were enrolled between june and july 2012. this study was approved by the ethics committee. blood specimens were drawn from the blood circuit at the inlet of the centrifugal pump (before) and outlet of the hollow fi ber oxygenator (after) at a frequency of three to four times per day. blood il-1β, il-2, il-4, il-5, il-6, il-7, il-8, il-10, il-12(p70), il-13, il-17, g-csf, gm-csf, ifnγ, mcp-1, mip-1β, and tnfα were measured globally using a multiplex cytokine bead array system (bio-plex; bio-rad, tokyo, japan). hmgb1 was measured using an elisa kit (shino-test, tokyo, japan). results two patients with interstitial pneumonia were studied. the ecmo system consisted of a rotafl ow centrifugal pump (maquet japan, tokyo, japan), a biocube tnc coating 6000 (nipro, osaka, japan), and a percutaneous cardiopulmonary support system (capiox ebs; terumo, tokyo, japan). the blood fl ow rate was 2.0 ± 4.0 l/minute. a total of 34 blood sets were collected. in most cases, blood levels of il-1β, il-2, il-4, il-5, il-12(p70), il-13, il-17, gm-csf, ifnγ, and tnfα were below the detection limit and did not increase during ecmo. the other mediators were detected at the inlet (before), but no signifi cant increase was observed at the outlet (after) (hmgb1, p = 0.33; il-6, p = 0.12; il-7, p = introduction during severe exacerbation of chronic obstructive pulmonary disease (copd) tachypnea, as a consequence of respiratory acidosis, and airfl ow limitation, due to small airway obstruction, lead to lung hyperinfl ation, respiratory distress and gas exchange impairment. invasive mechanical ventilation could worsen lung hyperinfl ation and produce a vicious circle. we investigated whether increasing extracorporeal carbon dioxide removal (ecco 2 cl) could reduce the respiratory rate (rr), so prolonging time for lung emptying and allowing resolution of hyperinfl ation. methods six patients with copd exacerbation with respiratory acidosis (paco 2 83 ± 27 mmhg, ph 7.19 ± 0.1) and tachypnea (rr 39 ± 5) despite maximal non-invasive ventilation underwent venovenous extracorporeal membrane oxygenation (vv-ecmo). all patients were awake and spontaneously breathing an adequate air-oxygen mixture to correct hypoxemia (pao 2 72 ± 27 mmhg). while keeping the blood fl ow stable (2.9 ± 0.5 l/minute), we changed the gas fl ow of the artifi cial lung to modify the extracorporeal co 2 clearance as a percentage of total patient co 2 production (% ecco 2 cl/total vco 2 ) and we observed the variations of rr. we recorded rr at three levels of gas fl ow in each patient ( figure 1) . in all patients rr decreased with the increase of extracorporeal co 2 removal and a negative correlation was found between rr and ecco 2 cl/total vco 2 (r 2 = 0.42, p <0.01). in all patients we were able to obtain a reduction of rr below 15 (28 ± 4 vs. 8 ± 4, rr at low gas fl ow vs. rr at maximal gas fl ow, p <0.001). the selected maximal gas fl ow was variable between diff erent patients (6.7 ± 2 l/minute), corresponding to diff erent levels of ecco 2 cl/total vco 2 (83 ± 17%, range 53 to 100%) and rr response (8 ± 4, range 5 to 14). conclusion in patients with copd exacerbation, who failed noninvasive ventilation, vv-ecmo allows one to maintain spontaneous breathing. titration of extracorporeal co 2 removal leads to control rr. this approach could interrupt the vicious circle of dynamic hyperinfl ation and allow the defl ation of lung parenchyma. table 1 presents the main results. the co 2 removal by membrane oxygenator ranged from 56 to 37 ml/minute. all patients survived to the treatment and 7/10 were weaned from the ventilator at the end of ecco 2 removal. only one oxygenator was used for every patient without clotting of the circuit or any major bleeding problem. we have previously shown, in an ex vivo porcine model, that lung elastance calculated as the peep change divided by lung volume increase (δpeep/δeelv) is closely correlated to conventionally measured lung elastance using oesophageal pressure [1] . in this study we hypothesize that the successive change in lung volume during a peep-step manoeuvre could be predicted from δpeep and lung elastance as δpeep/el. the objective of the study was to validate this hypothesis in patients with acute respiratory failure (arf). methods thirteen patients with arf were studied during an incremental peep trial, 0-4-8-12-16 cmh 2 o. δeelv was determined as the change in expiratory tidal volume following each peep step. conventional calculation of lung elastance was obtained from tidal variation in airway pressure minus tidal variation in oesophageal pressure divided by tidal volume. position of the oesophageal catheter was verifi ed according to baydur [2] . the measured change in end-expiratory lung volume during the peep-step manoeuvre using spirometry was compared with the end-expiratory lung volume change calculated from el and stepwise changes in peep as δpeep/el. results there was a close correlation between the measured build-up of end-expiratory lung volume during a peep-step manoeuvre and δpeep/el where el was conventionally determined using oesophageal pressure measurements (see figure 1 ). conclusion esophageal pressure measurements are diffi cult to perform [3] and rarely used in routine clinical practice. our fi ndings indicate that a change in peep together with measurements of the resulting change in end-expiratory volume by spirometry in the ventilator could be used to determine lung elastance separately, the relation between lung and chest wall elastance as well as the transpulmonary pressure. references introduction long-term use of mechanical ventilators may lead to ventilator-induced diaphragmatic dysfunction (vidd) and increase the duration of weaning from mv [1] . it was hypothesized that stimulating the diaphragm during mv may prevent vidd and may lead to early weaning [2] . in this study, the feasibility of generating coordinated contraction of both diaphragms was investigated using a novel transvenous diaphragmatic pacing system. methods two juvenile pigs were anesthetized with propofol (150 to 250 μg/kg/minute) and ventilated (vent) with an assist control mode mv (nellcor puritan bennett 840). using fl uoroscopy, a novel multipolar neurostimulation catheter (inspirx rl picc53; respithera, bloomington, mn, usa) was threaded into the left internal jugular vein and advanced to the junction of right atrium and the superior vena cava using a modifi ed seldinger technique. the successful capture of the right and left phrenic nerves was confi rmed by fl uoroscopic visualization. peak airway pressures (pawp) and blood gases were determined after 10 minutes mv (mv), mv and stimulation applied together (mv+stim) and stimulation only (stim). no animal-ventilator dyssynchrony during stimulation (mv+stim) was noted while peak airway pressures were reduced. during stim there was no discernible paradoxical movement of the diaphragm. in addition, pco 2 and po 2 confi rmed that adequate ventilation and oxygenation can be provided by the system, while pawp could be reduced (table 1) . introduction retrospective studies suggest that cardiac troponin levels are often elevated in patients with acute exacerbation of chronic obstructive pulmonary disease (aecopd) indicating a poor survival. novel high-sensitivity cardiac troponin (hs-ctnt) assays have better analytical precision than standard troponin (ctnt) assays. we elaborated a prospective cohort study to investigate the prognostic value of this novel biomarker in patients with aecopd. methods fifty-six patients (mean age 64 years, 68% male) with the fi nal diagnosis of aecopd were enrolled. those who were diagnosed with acute coronary syndromes were excluded. we measured cardiac troponin t with a standard fourth-generation assay and a highsensitivity assay. clinical, electrocardiographic and echocardiographic data were collected at admission and the primary prognostic endpoint was death during 30 days of follow-up. introduction british thoracic society guidelines on communityacquired pneumonia (cap) advocate icu referral for patients with curb65 score of 4 and 5. a recently developed scoring system, smart-cop, designed to identify patients at need of intensive respiratory or vasopressor support (irvs), has been validated in a variety of settings. it predicts the need for icu admission (defi ned as need for irvs) with greater accuracy than curb65, but is not used routinely in our uk institution. methods we retrospectively analysed critical care admissions of patients with a diagnosis of cap in a uk district general hospital -icnarc-coded diagnoses of pneumonia (bacterial, viral, no organisms isolated) over a 7-month period (august 2011 to january 2012). we ascertained the curb65 and smart-cop scores on referral to the icu and matched them in relation to the need for irvs, length of inotropic and ventilatory support and icu length of stay. results our search revealed 28 potential matches. five patients were excluded (not cap) and the notes for seven patients were not available for analysis. we analysed the notes of 16 patients matching our criteria. in this small sample, there was a strong association between increasing smart-cop score and the need for irvs (correlation coeffi cient r = 0.96). there was also a strong correlation with longer inotropic support (r = 0.85) and longer ventilatory support (r = 0.96) with increasing smart-cop scores but a weaker correlation with length of icu stay (r = 0.49). moreover, none of the patients admitted to the icu had curb65 score higher than 3 at the time of icu referral. conclusion in our small sample, higher smart-cop score was associated with increased likelihood of irvs. this suggests that a further study with a larger sample size should be performed to investigate whether smart-cop is an improvement on curb65 in predicting the need for irvs in uk intensive care patients. introduction streptococcal pneumonia remains the most common cause of community-acquired pneumonia (cap), bacterial meningitis and bacteremia. severe pneumonia caused by streptococcal pneumonia frequently exists in the emergency room or icu. we performed this study to evaluate the eff ect of steroid therapy for severe streptococcal pneumonia patients with mechanical ventilation retrospectively. methods we enrolled 13 adults of streptococcal pneumonia patients who required mechanical ventilation. seven of 13 patients (s group) were administered with steroid (hydrocortisone 200 to 300 mg/day), and the remaining six patients received no steroid therapy (ns group). as the conventional therapies, mechanical ventilation was commenced when a patient's pao 2 /fio 2 showed less than 200 or they clinically complained of being short of breath. all patients received appropriate fl uid therapies, vasoactive agents and blood transfusion according to the protocol of early goal-directed therapy in the surviving sepsis campaign guidelines 2008, and also were treated with antibiotics, immunoglobulins (5 g/day for 3 days) and sivelestat sodium hydrate (4.8 mg/kg/day for 7 days). the apache scores in the s group and ns group were 27 ± 10 and 23 ± 4, sequential organ failure assessment scores were 8 ± 4 and 7 ± 3, respectively. these scores showed no signifi cant diff erence between the groups. procalcitonin (pct) in the s and ns groups was 20.7 ± 21.7 and 45.0 ± 47.7 ng/ml, respectively, and there was no signifi cant diff erence between the groups. pct declined signifi cantly in both groups. pao 2 /fio 2 of the ns group was signifi cantly higher than the s group on icu admission and 4 days after admission, but no signifi cant diff erence on 7 days after icu admission. il-6 of the ns group declined signifi cantly after icu admission, and the s group also tended to decline. conclusion steroid therapy for severe streptococcal pneumonia patients with mechanical ventilation may have a potential to maintain oxygenation of the lung, but no signifi cant eff ects on changes of infl ammatory markers (il-6, crp). introduction electrical impedance tomography (eit) is a non-invasive and nonradiating imaging technique, which can be used to visualize ventilation distribution of the lungs and could distinguish between the dependent (dorsal) and nondependent (ventral) parts. methods the aim of this study was to observe ventilation distribution between dependent and nondependent lung regions, for the individual patient, during three diff erent levels of support during pressure support (ps) and neurally adjusted ventilatory assist (nava) ventilation. ten mechanically ventilated patients in the icu were included. the ratio for dependent/nondependent distribution of ventilation is signifi cantly higher at lower support levels compared with higher support levels in both ps and nava. however, during nava there was signifi cantly less impedance loss between the diff erent levels of assist compared with ps. tidal volumes decreased when decreasing assist levels during ps whereas not during nava ventilation. the electrical activity of the diaphragm decreased in both ps and nava with higher levels of assist. three patients showed an increase in dependent tidal impedance variation (tiv) after lowering the assist level from 15 to 10 cmh 2 o. this increase in tiv did not occur during nava ventilation. conclusion there is more ventilation in the dependent part of the lung, compared with the nondependent part, at lower levels of assist. this could indicate that at higher support levels the contribution of the diaphragm is reduced. during nava ventilation, there is an autoregulation in which the patient is adjusting his tidal ventilation to maintain homogeneous ventilation distribution. in status asthmaticus. our purpose was to analyze bipap use and outcomes for children with status asthmaticus and obesity in our ped. methods patients placed on bipap in the ped for status asthmaticus from 1 january 2010 to 31 august 2012 were included in the analysis. subjects were divided into moderate and severe exacerbations and then further subdivided into the following growth curve-based weight subgroups: <90 percentile, 90 to 97 percentile and >97 percentile. subjects received standard asthma therapies in addition to bipap. data were obtained at the bedside by the respiratory therapist or collected retrospectively by study investigators. data were stored and analyzed using a redcap database. results three hundred and fi fty-nine subjects were analyzed. table 1 shows the time on bipap per visit. children whose weight was >97 percentile revealed trends towards longer treatment times on bipap compared with the other two groups. we explored the feasibility, reliability and physiological signifi cance of diaphragm thickening on ultrasound. methods five healthy subjects participated. we monitored inspiratory fl ow, volume, esophageal and gastric pressures, and diaphragm electrical activity (by esophageal and surface electromyography) while subjects performed a series of inspiratory maneuvers: tidal breathing, threshold-loaded breathing, a muller maneuver, and inspiration to various lung volumes above functional residual capacity. at the end of each inspiratory eff ort, subjects were instructed to close the glottis and relax the respiratory muscles (so as to maintain lung volume while eliminating diaphragm activation). sonographic images of diaphragm thickening during these maneuvers were obtained using m-mode with a 13 mhz linear array probe placed in the right ninth, 10th, or 11th intercostal space between the middle and anterior axillary lines. results diaphragm thickening in the zone of apposition was readily visualized by ultrasound in all fi ve subjects. mean end-expiratory diaphragm thickness was 2.1 mm (sd = 0.3 mm). during tidal breathing, the diaphragm thickened by a mean of 35% (sd = 31%). the bland-altman coeffi cient of reproducibility was 0.5 mm; approximately 50% of measurement variability arose from caliper positioning on the ultrasound machine; diaphragm thickness measurements changed as the probe was placed in diff erent intercostal interspaces. diaphragm inspiratory thickening increased signifi cantly with increasing inspiratory eff ort but also varied with lung volume independent of eff ort. at inspiratory volumes below 40% of inspiratory capacity, lung volume change contributed minimally to diaphragm thickening. conclusion visualizing diaphragm thickening in the zone of apposition by ultrasound provides a feasible non-invasive technique for monitoring diaphragm activation in healthy subjects. diaphragm thickening primarily refl ects muscular eff ort rather than altered muscle conformation induced by changes in lung volume, especially at lower inspiratory volumes. the theoretical advantages of monitoring the electrical activity of the diaphragm (eadi) and neural triggering of support breaths (nava-maquet) have not yet been shown to translate into signifi cant clinical benefi t [1] . here we assess the eff ect of eadi monitoring, in patients at risk of prolonged weaning, on outcomes. introduction emergency endotracheal intubation results in accidental oesophageal intubation in up to 17% of patients often with disastrous consequences. we have previously published a highly specifi c and sensitive novel method to detect endotracheal intubation based on diff erences in ventilation pressure waveforms in the oesophagus and in the trachea in patients with healthy lungs [1] . a detection algorithm, based on diff erences in compliance/elasticity between the lung and the oesophagus, generated a d-value indicating tracheal intubation if d >0.5 and oesophageal intubation if d <0.5. the aim of the current study was to validate the algorithm in patients with lung disease. methods after obtaining institutional approval, 20 intubated and ventilated icu patients were included. inclusion criteria were controlled mechanical ventilation and at least mild to moderate lung injury according to a murray lung injury score >0.1. a connecting piece was placed between the endotracheal tube and the ventilation bag. this piece comprised a thin air-fi lled catheter inserted through the tube lumen at 1 cm from the distal end, and a second catheter located at the proximal end of the tube. we performed three consecutive manual bag ventilations while recording the pressure curves through both catheters. for each ventilation, a d-value was calculated. results mean age (sd) of the patients was 60 (16) years, 60% were male. the mean (sd) murray score was 1.4 (0.6). pathologies included pulmonary oedema, pneumonia, atelectasis and traumatic lung injury. all 60 d-values are represented in figure 1 . the median (iqr, range) d-value was 38 (16 to 74, 0.8 to 1,272). our algorithm therefore confi rmed a high sensitivity to detect correct endotracheal intubation also in patients with lung disease. under the hypothesis that oesophageal compliance does not increase signifi cantly in patients with lung disease, the specifi city of our algorithm will not be aff ected. the aim was to compare two novel endotracheal tubes (ett), mallinckrodt taperguard (tg, tapered polyvinyl chloride (pvc) cuff ) and kimvent microcuff (mc, cylindrical polyurethrane cuff ), with conventional portex (pt, globular pvc cuff ) in leakages across cuff s (microaspiration) under simulated clinical situations. it has been shown that globular pvc cuff s protect poorly against leakages due to microchannels formed from infolding of redundant cuff material [1] . we hypothesized that tg and mc better prevent microaspiration, which is a major mechanism of ventilator-associated pneumonia (vap the most common cause of ventilator-associated pneumonia (vap) is aspiration of oral secretion through the endotracheal tube (et). subglottic suction drainage (ssd) has been recommended as a safety measure against aspiration due to its high eff ectiveness. currently, two types of cuff shape -spindle and tapered -are predominant in high-volume, low-pressure (hvlp) ets with ssd. however, the shape most suitable for preventing dripping onto the subglottis has not been determined. the purpose of this study was to determine whether an et with tapered-type cuff can reduce the incidence of vap. methods after approval from the appropriate ethics committee, we conducted a single-institutional prospective randomized clinical trial on the eff ectiveness of using an et with a diff erent cuff type. introduction national audit project 4 (nap4) highlighted the need to improve airway management in icus and key recommendations were the continuous use of end-tidal carbon dioxide (etco 2 ) monitoring, pre-intubation checklists and diffi cult airway trolleys [1] . this complete cycle audit aimed to quantify the current state of airway management on our icu and the eff ectiveness of implementing the nap4 recommendations. methods data collection was carried out prospectively for both phases and included documentation of intubation, use of etco 2 and the incidence of serious adverse events (saes). the contents of the intubation boxes were compared against the diffi cult airway society (das) guidelines [2] . the re-audit was carried out 6 months following the introduction of a pre-intubation checklist, a documentation sticker, a diffi cult airway trolley and standardization of the basic bedside airway boxes with a checklist of contents. a training program in airway management for all icu staff was also introduced. micro-ct scan (skyscan 1176; bruker, belgium) was performed using a resolution of 35 μm. axial sections of the 20 cm above the cuff were reconstructed, and the volume of secretions was assessed by a density criterion. microbiological cultures of the ett lavage fl uid were then obtained. patient's demographics and clinical data were recorded. in a diff erent set of bench experiments, we injected 1 ml water-based polymer into new etts of diff erent sizes. we measured resistance to airfl ow before and after using an ett cleaning device (airway medix closed suction system; biovo technologies, tel aviv, israel). we also obtained resistance values of intact etts as controls. the studied etts remained in place for a median of 7 days (iqr range 4 to 15). the amount of secretions assessed by ct scan was 0.293 ± 0.290 ml (range 0.032 to 0.777 ml). secretion volumes were not related to patient severity at admission (saps 2, p/f ratio) or days of intubation; an inverse correlation with patient's age was present (p = 0.032, r 2 = 0.46). bacterial growth was present in 9/11 (82%) ett fl uids cultures and candida spp. showed an elevated prevalence (6/11, 55%). in the bench tests, the cleaning device reduced resistance to airfl ow (diff erence before and after cleaning 5.5 (95% ci = 8.9 to 1.6) cmh 2 o/l/second, p = 0.006). after cleaning, resistance resulted higher than intact etts, although with a clinically negligible diff erence (diff erence 0.3 (95% ci = 0.2 to 0.6 cmh 2 o/l/second), p = 0.032). conclusion micro-ct scan is a feasible and promising technique to assess secretions volume in etts after extubation. the use of an ett cleaning device decreases resistance to airfl ow in bench tests; the eff ectiveness of such a device in the clinical setting could be properly assessed by post-extubation ct scan. [1, 2] . the objective was to develop and validate a simplifi ed score for identifying patients with di in the icu and to report related complications. methods data collected in a prospective multicenter-study from 1,000 consecutive intubations from 42 icus were used to develop a simplifi ed score of di, which was then validated externally in 400 consecutive intubation procedures from 18 other icus and internally by bootstrap on 1,000 iterations. in multivariate analysis, the main predictors of di (incidence = 11.3%) were related to the patient (mallampati score iii or iv, obstructive sleep apnea syndrome, reduced mobility of cervical spine, limited mouth opening), to pathology (severe hypoxia, coma) and to the operator (non-anesthesiologist). from the β-parameter, a sevenitem simplifi ed score (macocha score; introduction in mechanically ventilated neonates the fl ow-dependent resistance of the endotracheal tube (ett) causes a noticeable pressure diff erence between airway and tracheal pressure [1] . this may potentially lead to retardation of the passive driven expiration and dynamic lung infl ation consecutively but more importantly increases . the aim of this study was to evaluate the correlation between nt-probnp and cce and the potential usefulness of such variables during the weaning process from mv. methods twenty-two long-term (>48 hours) mechanically ventilated patients capable of performing a weaning trial of spontaneous breathing (sbt) were enrolled in the study. inclusion criteria were: age >18 years and equipment with a standard arterial catheter line. exclusion criteria were: neuromuscular disease, tracheotomy, renal failure, and traumatic brain injury. during the weaning process, nt-probnp plasma levels, cce, and standard hemodynamic and ventilatory data were collected 30 minutes before extubation (t1), 2 hours (t2) and 12 hours later (t3). after removal of tracheal tube, patients with a history of heart failure received continuous positive airway pressure (cpap group). patients with normal cardiac function were maintained with spontaneous breathing (sb group). results sixty-six paired nt-probnp and cce values were obtained. patients in the sb group and in the cpap group were 10 and 12, respectively. in both groups there was a trend towards an increase in nt-probnp values after extubation, an opposite trend was observed regarding cce values (p <0.05). nt-probnp levels showed an increase after extubation (t2, t3) compared with t1; conversely, cce showed an inverse trend. overall, a negative correlation was found between nt-probnp and cce values (r = -0.81, p <0.001). signifi cant inverse correlations were found between nt-probnp and cce at t1, t2, and t3 (r = -0.91, -0.75 and -0.73 respectively; p < 0.001). the overall correlation between nt-probnp and cce was -0.74 in the sb group and -0.86 in the cpap group. standard hemodynamic and ventilatory data did not show signifi cant changes during the study. conclusion nt-probnp correlated well with cce. the latter seems to be an additional attractive index of cardiovascular state that, in association with nt-probnp changes, may provide information about cardiac function on a beat-by-beat basis during weaning process from mv. comparison of outcomes between early and late tracheostomy for critically ill patients k suzuki 1 , s kusunoki 1 , t yamanoue 1 , k tanigawa introduction tracheostomy is one of the more commonly performed procedures in critically ill patients requiring long-term mechanical ventilation. however, the optimal timing or method of performing tracheostomies in this population remains to be established. in the present study, we compared outcomes of early and late tracheostomy in critically adult patients with diff erent clinical conditions. methods all patients needing tracheostomy in the critical care medical center of hiroshima prefectural hospital from january 2009 to december 2011 were surveyed. patients with tracheostomy who were not indicated for mechanical ventilation were excluded from the subjects. early tracheostomy (et) was defi ned as <10 days after tracheal intubation and late tracheostomy (lt) was defi ned as ≥10 days after intubation. we compared patient characteristics, type of tracheostomy procedure, length of weaning from ventilator and outcomes between the groups. data are shown as the mean ± sd, with unpaired t test and mann-whitney u test used for statistical analyses. statistical signifi cance was accepted at p <0.05. results one hundred patients were surveyed. the et and lt groups included 49 and 51 patients, respectively. tracheostomy was performed using a percutaneous procedure in 48 patients (et: 25, lt: 23) and a surgical procedure in 52 patients (et: 24, lt: 28). sixty-two patients (et: 34, lt: 28) survived to discharge and 16 patients died in the icu (et: 7, lt: 9). fifty-six patients (et: 31, lt: 25) were weaned from ventilator support and tracheostomy cannula was removed in 20 patients (et: 11, lt: 9). there were no signifi cant diff erences in type of tracheostomy procedure, period from tracheostomy until icu and hospital discharge, rate of patients who could be weaned from ventilator and removed tracheostomy cannula, and icu and hospital mortality between the groups. the length of mechanical ventilation and the time to removal of tracheostomy cannula were signifi cantly shorter in the et group (5 ± 7 vs. 26 ± 41 and 29 ± 24 vs. 94 ± 83 days, respectively). conclusion in this retrospective study, early tracheostomy reduced the length of weaning after tracheostomy and the time to removal of tracheostomy cannula, while there were no diff erences in the length of icu stay and patient outcome. in critically ill adult patients who require mechanical ventilation, a tracheostomy performed at an earlier stage may shorten the duration of artifi cial ventilation. a further randomized clinical trial is essential to determine the eff ectiveness and safety of early tracheostomy. reference s60 variability in the course of blood vessels in the pre-tracheal area. a 5% risk of clinically relevant bleeding was recently reported for patients undergoing pdt [1] . we conducted a systematic review of reports evaluating clinical outcomes following use of ultrasound scanning (us) for pdt. methods two investigators performed a search of the literature using the following databases: central, embase, medline and scopus. the following eligibility criteria were used: population including adults >16 years managed in the icu; use of ultrasound to guide decisionmaking pre-pdt or guide pdt performance; report of clinically relevant outcome measures. nonrandomised controlled trials were classifi ed according to cochrane non-randomised study methods group criteria [2] and evaluated for risk of bias. results an initial search identifi ed 2,043 reports, of which 10 studies met eligibility criteria: eight case series, one randomised controlled trial (rct) and one prospective cohort study, incorporating 488 patients. two studies specifi cally reported data on patients with obesity (n = 29 patients) and one study reported data for a group of patients with spinal cord fi xation (n = 6). us was used to guide decision to perform pdt or surgical tracheostomy in fi ve studies, with decision to perform surgical tracheostomy ranging from 0 to 27% of cases. us was used to guide insertion point in seven studies, and used real-time in four studies. times to perform us-guided pdt were reported in four studies (ranging from 8 to 12 minutes). no studies compared time taken with or without us. data on complications of procedure were reported in nine studies. minor bleeding was reported for eight cases (1.6% overall). prolonged bleeding was reported in two cases (0.4%). there were no episodes of catastrophic bleeding among 488 cases. high risk of bias was identifi ed in fi ve studies in terms of patient selection. an intervention protocol was not defi ned in three reports. no attempt was made at blinding any aspect of the 10 studies. conclusion use of us guidance could theoretically help minimise risk of haemorrhagic complications during pdt and perhaps reduce time taken to perform pdt. however, there is currently inadequate evidence from controlled cohort studies or rcts to suggest that routine use for pdt in selected or unselected groups improves clinically relevant outcome measure. introduction failed airway situations are potentially catastrophic events and require a correct approach with appropriate tools. recently, ventrain has been presented as a manual device for emergency ventilation through a small-bore cannula, which can provide expiratory assistance by applying the venturi eff ect. methods we used the simularti human patient simulator to evaluate ventrain. initially, we studied the eff ectiveness and security in ventilating and oxygenating the patient. in a second phase, the ventrain performance was compared with what is considered to be the present gold standard (quicktrach ii, portex mini-trach ii seldinger kit, melker emergency cricothyrotomy catheter set). seven anesthesiologists performed an emergency transcricoid ventilation with each device in the same setting. results ventrain provided an average tidal volume of 334 ml and an average minute volume of 2.4 l in the considered situation, with a modifi cation of pao 2 from 32 to 702 mmhg and of paco 2 from 54.5 to 38.8 mmhg. in the second phase, the time needed to obtain an eff ective oxygenation with ventrain was found to be shorter than other devices (median diff erence; vs. minitrach -60 seconds; vs. melker -35 seconds; vs. quicktrach -25 seconds) ( figure 1 ); the ability to remove co 2 resulted bigger (average diff erence: vs. minitrach -11.9; vs. melker -0.3; vs. quicktrach -5.9) ( figure 2 ) and moreover the users judged it more favorably. conclusion in this manikin study, ventrain seemed to be able to appropriately oxygenate and ventilate a patient in a cicv situation. when compared with the best available choices, it has shown not to be inferior. introduction eff ective delivery of aerosolized bronchodilators for patients with asthma is crucial for adequate therapy in critical care and emergent settings. often administered with pressure-metered dose inhalers (pmdis), bronchodilator delivery depends on the correct patient technique during administration [1] and the ability to measure treatment response, which are diffi cult to monitor at the point of care and particularly so in resource-poor settings where standard inhospital monitoring is unavailable [2] . methods a point-of-care device for airfl ow measurement during bronchodilator delivery was designed and tested for use in resourcelimited settings. the handheld device was constructed from a clinical aerosol delivery tube with a bidirectional sensor for pressure diff erential detection about the aerosol element ( figure 1 ). the custom low-cost introduction protocol-based care of the tracheostomised patient is important, as adverse events confer a high rate of mortality. little is known regarding the existence of formal evidence-based guidelines on tracheostomy care. the aim of this study was to perform a systematic review for evidence-based guidelines on adult tracheostomy care. methods a systematic search of pubmed, medline, guideline clearinghouses, centres of evidence-based practice, and professional societies' guidelines relating to care of adult patients with a tracheostomy was performed by two reviewers. in addition, a google search of publicly available tracheostomy care guidelines was performed. search terms: (tracheostom* or tracheotom*) and (protocol* or guideline* or standard* or management or consensus or algorithm*). filters: english language, human, from 1 january 1990 to date, adult patients. guideline appraisal criteria: the quality of guidelines retrieved was assessed using the appraisal of guidelines research and evaluation ii (agree ii) instrument [1] . the search results are summarised in table 1 . a total of 80 guidelines were identifi ed. five were found to satisfy the agree ii criteria and only three related to the entire spectrum of tracheostomy management. the majority was informal and was not published or evidence based. conclusion five evidence-based guidelines on adult tracheostomy management were identifi ed. this may represent a paucity of evidence on the subject, suggesting that further clinical trials on the topic are needed to contribute to the evidence base. this also highlights the need for international consensus on the topic, to reduce duplication of eff orts, standardise practice, and improve outcomes. [1] concluded that the majority of airway-related signifi cant complications in icus resulted from displaced or blocked tracheostomies and recommended together with the intensive care society and the national tracheostomy safety project that each icu in the uk should have an emergency airway management plan and guidelines [2] . the aim of this survey was to establish whether such guidelines exist and are familiar to those working within the icus of the east of england (eoe), their ease of availability in an emergency and the degree of emergency tracheostomy training within the region. methods data collection was via a telephone survey of 11 icus in the eoe training region during july 2012 with one senior icu nurse and one icu trainee questioned per hospital. questions related to the existence and accessibility of guidelines for tracheostomy emergencies, and to the respondent's degree of emergency tracheostomy training and their perceived availability of formal training. results all 11 icus questioned perform and manage tracheostomies. of 22 respondents, 10 knew of guidelines covering all of the emergencies described above and their location. four respondents thought that these guidelines were accessible in an emergency setting, one-half of which were on computer systems requiring a login and search function. with regards to emergency management, 19 respondents felt competent in a tracheostomy emergency; almost exclusively through experience and in-house teaching. no respondents were aware of any formal emergency tracheostomy management courses. conclusion despite national guidance within the uk this survey highlights that implementation and awareness of emergency tracheostomy guidelines in icus in the eoe region is poor, and when present they are not readily accessible in an emergency. emergency training has largely been informal and the availability of formal training courses has not been recognised. in order to improve patient safety there is a need to ensure that emergency tracheostomy management including guidelines, equipment and formalised tracheostomy emergency training are adopted and embraced universally. references introduction a fatal incident related to a blocked tracheostomy tube prompted a review in our trust. to provide safe tracheostomy care, changes in staffi ng, education and operational policies were recommended. training of potential fi rst responders to tracheostomy or laryngectomy emergencies remains outstanding. we aim to quantify the training defi cit. tracheostomies are common in critical care but these patients require ongoing management of an artifi cial airway on discharge to the ward and even the community. in 2010 our critical care unit cared for 108 tracheostomy patients, of which 30 were transferred to the wards. the 4th national audit project highlighted complications including hypoxic brain injury and death [1] and the national patient safety agency recognised a number of avoidable aspects [2] . existing guidelines for management of these patients including emergencies are not widely known. methods an anonymous online survey was sent to all trainees who may respond to a tracheostomy emergency in our organisation. trainees in anaesthesia/critical care, general medicine, general surgery, ent, thoracics and a&e were approached. all completed forms were included. we achieved a response rate of 39% (65/168). respondents comprised: 33% anaesthesia/critical care, 47% medicine and 14% surgery. over one-half (36/65) had managed tracheostomy/laryngectomy emergencies, with 42% (15/36) of these incidents occurring on the wards and one in an outpatient clinic. only 20% (13/65) had received any formal training on management of a blocked/misplaced tracheostomy tube and only 18% (12/65) were aware of any guidelines. one-third of responders lacked confi dence in management of these emergencies and 88% felt they would benefi t from formal training including simulation. conclusion the population of patients with exteriorised tracheas is increasing and represents a high-risk group. management of airway emergencies in these patients is not part of standard life-support courses. according to our trainees, these scenarios are relatively common and a signifi cant proportion of fi rst responders are poorly equipped to deal with them. our trust will be including specifi c training on the emergency management of neck breathers as part of in-house resuscitation training. we would contend that national resuscitation courses should consider doing the same. introduction usually percutaneous tracheostomy is accomplished via the tracheal tube. some severe complications during percutaneous dilatational tracheostomy (pdt) may be related to poor visualization of tracheal structures. the alternative implies extubation and reinsertion of a laryngeal mask (lma). an accidental extubation as well as an injuring of the vocal cords (because of the infl ated cuff during dislocation) appears impossible in this method. subjectively, the bronchoscopic view obtained via a lma seems to be better than that obtained with an endotracheal tube (et) [1, 2] . methods in this prospective observational study, the bedside pdt was performed using the ciaglia blue dolphin method in 150 critically ill patients. the patient's tracheal tube was exchanged for a lma fastrach™ before undertaking pdt. the insertion of the lma, the quality of ventilation, the blood gas values, the view of the tracheal puncture site, and the view of the balloon dilatation were rated as follows: very good (1), good (2), barely acceptable (3), poor (4), and very poor (5) . results pdts with lma were successful in 99.3% of the patients (n = 149). the ratings were 1 or 2 in 96% of cases with regards to ventilation and to blood gas analysis, in 96.6% for identifi cation of relevant structures and tracheal puncture site, and in 93.3% for the view inside the trachea during pdt. a rating of 5 was assigned to one patient requiring tracheal reintubation for inadequate ventilation. there were no damages to the bronchoscope or reports of gastric aspiration. conclusion the blue dolphin pdt using a lma showed defi nite advantages regarding inspection of dilation process. this method improves visualization of the trachea and larynx during a video-assisted procedure and prevents the diffi culties associated with the use of an et such as cuff puncture, tube transection by the needle, accidental extubation, and bronchoscope lesions. the lma results as an eff ective and successful ventilatory device during pdt. this may be especially relevant in cases of diffi cult patient anatomy where improved structural visualization optimizes operating conditions. the intensivist performing pdt should be scrupulous when deciding which method to use. in our icu the blue dolphin pdt with lma has become the procedure of choice. introduction acute cor pulmonale (acp) is associated with increased mortality in patients ventilated for acute respiratory distress syndrome (ards). interventional lung assist (ila) allows a lung-protective ventilatory strategy, whilst allowing co 2 removal, but requires adequate right ventricular (rv) function. rv restriction (including presystolic pulmonary a wave) [1] is not routinely assessed in ards. methods a prospective analysis of retrospectively collected data in patients with echo during ila was performed. data included epidemiologic and ventilatory factors, lv/rv function, evidence of rv restriction and pulmonary hemodynamics. data are shown as mean ± sd/median (interquartile range). results thirty-two patients (45 ± 17 years), 22 male (68%), sofa score 11.15 ± 2.38 were included. pulmonary hypertension (pht) was 53%, and hospital mortality 43%. mortality was not associated with age, days on ila, length of icu stay, inotropic support, nitric oxide or level of ventilatory support, but was associated with pressor requirement (p = 0.005), a worse pao 2 :fio 2 ratio (9.4 (7.8 to 12.6) vs. 15.2 (10.7 to 23.9), p = 0.009) and higher pulmonary artery pressures (56.5 mmhg (50 to 60) vs. 44.5 (40.5 to 51.2), p = 0.02). no echo features of acp were found, with no signifi cant diff erence between rv systolic function, pulmonary acceleration time and pulmonary velocity time integral between survivors and nonsurvivors. the incidence of rv restriction was high (43%), and independent of pht, rv systolic function and level of respiratory support, but correlated with co 2 levels (restrictive 7.1 kpa (7.4 to 8.0) vs. 6.1 (5.8 to 6.8), p = 0.03). see figure 1 . conclusion typical echo features of acp were not seen in this study, possibly because of the protective ventilatory strategies allowed by use of ila. the incidence of rv restriction may refl ect more subtle abnormalities of rv function. further studies are required to elucidate rv pathophysiology in critically ill adult patients with ards. reference introduction global left ventricular electromechanical dyssynchrony (glvd) is uncoordinated lv contraction that reduces the extent of intrinsic energy transfer from the myocardium to the circulation leading to a reduction in peak lv pressure rise, prolonged total isovolumic time (t-ivt) and fall in stroke volume [1] . this potentially important parameter is not routinely assessed in critically ill cardiothoracic patients. methods a prospective analysis of retrospectively collected data in cardiothoracic icu patients who underwent echocardiography was performed. in addition to epidemiological factors, echo data included comprehensive assessment of lv/rv systolic and diastolic function including doppler analysis of isovolumic contraction/ relaxation, ejection time (et) and fi lling time (ft). t-ivt was calculated as (60 -(total et + total ft)) and the tei index as (ict + irt) / et. t-ivt >14 second/minute and tei index >0.48 were used to defi ne glvd [2] . data are shown as mean ± sd/median (interquartile range). results a total of 103 patients (63.5 ± 18.4 years), 65 male (63%), apache ii score (14.6 ± 7.4) were included. the prevalence of glvd was high (24/103, 22%) and associated with signifi cantly increased mortality, 7.5% vs. 25% (p = 0.02). there was no diff erence in requirement for cardiorespiratory support between the two populations, but there were signifi cant diff erences (no glvd vs. glvd) in requirement for , p = 0.43), mitral regurgitation (40.5% vs. 62.5%, p = 0.06), or any other measures of lv systolic or diastolic function between the two groups. there was good correlation between the two methods used to assess dyssynchrony (lv t-ivt:lv tei index correlation coeffi cient = 0.80, p <0.001). conclusion glvd that limits cardiac output is common in the cardiothoracic icu, and signifi cantly related to mortality. when diagnosed, the underlying cause should be sought and treatment instigated to minimize the t-ivt (pacing optimization/revascularization/ inotrope titration/volaemia optimization). references introduction correction of coagulopathy before central venous catheter (cvc) insertion is a common practice; however, when ultrasound guidance is used this is controversial as mechanical complications are rare. studies in oncology patients suggest that cvc placement without prior correction of coagulopathy is safe but no studies are available for critically ill patients and guidelines do not give recommendations [1, 2] . we do not routinely correct coagulopathy, even if severe, when ultrasound guidance is used and the purpose of this retrospective study was to evaluate the safety of this practice. methods data for all ultrasound-guided interventions, including complications, are prospectively collected in our department for audit purposes; in this study we involved only cvc insertions in the icu between february 2011 and november 2012. electronic medical and laboratory records and paper-based nursing charts were retrospectively studied for all interventions, specifi cally looking for blood results, coagulation abnormalities and intervention-related complications. in the study period, ultrasound guidance was employed for a total of 291 central line insertions in 220 icu patients. coagulopathy was detected in 127 cases at the time of cvc placement (43.6%). on the day of cvc insertion, coagulation abnormalities were corrected in 20 cases (15.7%); 33 out of 50 patients with severe coagulopathy (66.0%) and 74 out of 77 patients with coagulopathy of moderate severity (96.1%) had no correction at all. correction was started only after cvc insertion for reasons unrelated to cvc placement in a further eight and two patients with severe and less severe coagulopathy (16.0% and 2.6%), respectively. no bleeding complications were observed. conclusion in patients undergoing cvc insertion in our icu, coagulopathy is common. we observed uncomplicated cvc placement in all 41 patients with severe uncorrected coagulopathy and in a further 76 patients with coagulopathy of moderate severity. when combined with other studies, our data suggest that ultrasound-guided cvc placement without routine correction of coagulation abnormalities may be safe in the icu. introduction early bleeding from the exit site after cvc or picc placement is a very common event that causes diffi culties in the patient's care and logistical problems. in our experience, the rate of signifi cant local bleeding after placement of piccs without reverse tapering may be as high as 40% at 1 hour and 15% at 24 hours, while the rate of bleeding after placement of a large-bore dialysis catheter is above 50% at 1 hour. methods the aim of this pilot study was to verify the effi cacy of a cyanoacrylate glue in reducing the risk of early bleeding at the exit site after cvc or picc placement. we studied a group of adult patients consecutively undergoing placement of polyurethane cvcs or piccs without reverse tapering in a non-intensive ward of our hospital. all lines were inserted according to the same protocol, which included 2% chlorhexidine antisepsis, maximal sterile barriers, ultrasound guidance, ekg guidance and securement with sutureless device. two minutes after placement of the glue, the exit site was covered with a temporary gauze dressing, which was replaced by transparent membrane at 24 hours. all patients were assessed at 1 hour and at 24 hours. results in 65 consecutive patients (45 piccs, 11 dialysis catheters and nine cvcs), there was no signifi cant local bleeding at 1 hour or at 24 hours after catheter placement. no local adverse reaction occurred. no damage to the polyurethane of the catheters was detected. conclusion glue is an inexpensive and highly eff ective tool for avoiding the risk of early bleeding of the exit site after catheter placement. we also suggest that in the next future the glue might prove to have benefi cial collateral eff ects on the risk of extraluminal contamination (by reducing the entrance of bacteria in the space between the catheter and the skin), as well as on the risk of dislocation (by increasing the stability of the catheter inside the skin breach). introduction about 10 years ago the use of chest radiographs as the golden standard to ensure correct positioning of central venous catheters (cvc) was questioned. the frequent use of cvcs was also challenged. we decided to retrospectively evaluate our routines in a large surgical unit in a swedish university hospital. methods all x-rays were centrally registered. chest x-ray performed in our unit is almost entirely used to confi rm cvc positioning. the certofi x cvc set for the seldinger technique in combination with certodyn -universaladapter (b braun, germany) is now used as the routine equipment and the right jugular vein is our standard approach. in 2002 the total number of x-rays performed in patients at our unit was 2,306, which corresponds to the approximate number of inserted cvcs at that time, since a confi rmatory x-ray was routine. x-rays were rarely performed on other indications in our unit. x-ray costs were at that time approximately €300,000 (~€130/each). the year after, 1,726 chest x-rays were performed, refl ecting both the use of intracardiac confi rmation of correct cvc position and also a reduced use of cvcs. this trend has continued over time. in 2011 approximately 600 cvcs were inserted at our unit. x-rays were performed in about 20% of these cases. the cost for a chest x-ray is today ~€200, meaning that x-ray costs were approximately €24,000. we have not experienced any medical problems when intracardiac ecg was used for positioning confi rmation. on the contrary, aspiration of venous blood without apparent p-waves in a patient with sinus rhythm may suggest improper placement of the cvc; for example, the right brachial vein. conclusion if we had continued to use cvcs at the same frequency as we did 10 years ago, and used x-ray confi rmation in practically all cases, we would have paid approximately €460,000 annually. reduced use of cvcs, in combination with intracardiac confi rmation of cvc positioning, has not only allowed us to reduce costs associated with cvc insertion by more than €400,000, corresponding to a reduction rate of more than 90%, but also decreased the patient's exposure to x-ray irradiation. introduction in cases of arrhythmia, the beat-to-beat variation of arterial pressure (ap) may impair the accuracy of automated cuff measurements. indeed, this oscillometric device relies on the detection of arterial wall oscillations. our aim was to determine, in icu patients, whether brachial cuff measurements are really less reliable during arrhythmia than during regular rhythm. methods patients with arrhythmia and carrying an intra-arterial catheter were prospectively and consecutively included in this multicenter study. after each arrhythmic inclusion, a regular rhythm patient was included. a second inclusion was possible in case of change in the cardiac rhythm. three pairs of invasive and brachial cuff (philips® mp70 monitor) measurements of mean arterial pressure (map) were respectively averaged. some patients underwent a second set of measurements, after a cardiovascular intervention (passive leg raising, volume expansion, initiation of/increase in catecholamine infusion) allowing the assessment of map changes. introduction signifi cant changes in haemodynamics occur after brain stem death (bsd) and there is evidence that yield of transplantable organs may be decreased in donors who remain preload responsive prior to donation [1] , suggesting that optimisation of the cardiac output (co) may be benefi cial in potential organ donors. we describe current uk practice with regard to co monitoring in this group. methods we reviewed a database of 287 brain-stem-dead potential organ donors collected by specialist nurses in organ donation (sn-od) over a 6-month period (30 april 2011 to 31 october 2011) across multiple uk centres. the database contained data on donor management in the period from initial sn-od review to immediately prior to transfer to the operating theatre. we analysed data on co monitoring and vasopressor/inotrope use. where information was missing/not recorded in the dataset, the treatment referred to was interpreted as not given/not done. fifty-three patients (18.5%) had evidence of co monitoring. lidco was the most popular method ( figure 1 ). a total of 264 (94%) patients received treatment with vasopressors and/or inotropes. co data were utilised in a variety of ways ( figure 2 ). conclusion the majority of potential donors require vasopressors and/or inotropes post bsd, but it seems only a minority currently have their co monitored. there is variation in how co data are utilised to direct haemodynamic management. we welcome the development of standardised bundle-driven donor management. reference the indocyanine green plasma disappearance rate (icg-pdr) is a dynamic liver function test that can be non-invasively measured by pulse densitometry. icg-pdr is associated with mortality and other markers of outcome. due to predominant use of icg-pdr in the icu setting, the normal range is based on scarce data available outside the icu and given with 18 to 25%/minute. methods to prospectively re-evaluate the normal range and to analyze the potential impact of biometric data on icg-pdr, we measured icg-pdr (i.v. injection of 0.25 mg/kg icg; limon, pulsion, munich, introduction mixed venous oxygen saturation (svo 2 ) represents a well-recognized parameter of oxygen delivery (do 2 )-consumption (vo 2 ) mismatch and its use has been advocated in critically ill patients in order to guide hemodynamic resuscitation [1] and oxygen delivery optimization. nevertheless, the pulmonary artery catheter (pac) is not readily available and its use is not devoid of risks. furthermore, its use has been decreasing in recent years in surgical and cardiac surgical patients as the benefi t of guiding therapy with this device is unclear [2] [3] [4] . central venous oxygen saturation (scvo 2 ) has been suggested as an alternative to svo 2 monitoring due to its feasibility in several settings. unfortunately concerns arise from its capability to correlate with svo 2 , the relationship being infl uenced by several factors, such as hemodynamic impairment and pathological process. hemodynamic instability and shock often complicate cardiac surgery, and the svo 2 -scvo 2 relationship has not been specifi cally investigated in this setting. the aim of this study is to compare svo 2 and scvo 2 values in patients with cardiogenic shock after cardiac surgery. methods a prospective observational study was designed and conducted. inclusion criteria were: patients who had underwent elective or urgent/emergent cardiac surgery, with cardiac index (ci) <2.5 l/minute/m 2 estimated by means of a pac, left ventricle ejection fraction (lvef) <40%, lactate >2 mmol/l, age >18 years. a central venous catheter (cvc) and a pac were inserted for each patient before surgery in the same right internal jugular vein in accordance with standard procedure. proper position of the pac was confi rmed with pressure tracings and chest x-ray. mixed and central venous blood samples were collected from the distal ports of the pac and cvc respectively 30 minutes after icu admission, and every 6 hours for a total of three samples in a 24-hour period for each patient. all blood samples were analyzed by a co-oximeter (radiometer abl800 fl ex; radiometer, copenhagen, denmark). statistical analysis was performed by stats direct (ver.2.5.8, cheshire, uk) and graphpad (vers. prism 4.0; san diego, ca, usa). all data were tested for normal distribution with the kolmogorov-smirnov test. statistical analysis was performed by linear regression analysis. the agreement between absolute values of scvo 2 and svo 2 were assessed by the mean bias and 95% limits of agreement (loa) ((mean bias ± 1.96)×standard deviation) according to the method described by bland and altman [5] . results a total of 20 patients were enrolled. in 18 out of 20 cases all three blood samples were collected. in two patients only two blood samples were drawn as they exited the inclusion criteria. linear regression analysis between the two variables resulted in an r 2 of 0.708. bland-altman analysis ( figure 1 ) for the pooled measurements of svo 2 and scvo 2 showed a mean bias and loa of 6.82% (sd of bias 5.3) and -3.71 to +17.3% respectively. conclusion scvo 2 has been advocated as an attractive and simple indicator of do 2 -vo 2 mismatch [6] . its role as a surrogate of the wellestablished svo 2 has been investigated in several settings, and it has been purposed in the hemodynamic resuscitation of critically ill septic patients [1] . nevertheless, the svo 2 -scvo 2 relationship can be infl uenced by several factors due to scvo 2 dependency from global blood fl ow redistribution that can occur during hemodynamic impairments. it has been shown previously that in healthy people scvo 2 values tend to underestimate svo 2 values, due to the higher oxygen content from inferior vena cava [7] . during circulatory shock, not homogeneous oxygen extraction and regional blood fl ow methods we assessed the benefi t these tee data provided in the assessment of fi ve domains: hypovolemia, right ventricular dysfunction, left ventricular dysfunction, sepsis, and valvular abnormality. bedside practitioners listed their diagnoses before and after seeing primary tee images perform by trained physicians. we used a 0 to 5 likert scale to assess diff erential diagnosis before and after the tee, comparing changes using a paired t test. results all requests for tee were to access hemodynamic instability. a total of 18 patients were screened and nine were eligible, in which 16 total tee studies were performed. there were no complications with tee and all patients tolerated the long-term placement of the probe well. of the fi ve diagnostic domains studied, right ventricular failure was the most commonly underdiagnosed contributor to the hemodynamic instability among patients prior to tee (p = 0.054) (figures 1 and 2 ). introduction echocardiography is increasingly utilized by inten sive care physicians in everyday practice. standardization of echocardiographic studies and reporting, quality assurance and medicolegal requirements necessitate establishment of a dedicated system within the critical care setting. we describe the process of setting up a critical care echocardiography (cce) laboratory based on our experience from three separate icus. methods a retrospective review and analysis of the process involved in establishment of echocardiography laboratories within icus. results creating a cce service involves a number of stages and takes several years to achieve. major components include staffi ng, equipment, quality control, study archiving and networking capability. for staffi ng the objective is to identify and recruit staff with adequate training and expertise in cce, providing 24/7 specialist cover in addition to supporting and training junior medical and nursing staff . there is further a need to acquire funding for high-quality ultrasound machines and related hardware as well as long-term dicom-based archiving and reporting systems. this should be based on projections of annual volumes of echo studies and corresponding digital storage. networking connectivity is highly desirable, including obligatory back-up solutions and site allocations. a business case incorporating all the above should precede any development as identifi able funding sources and administrative approval are essential. the implementation stage requires the presence of a project leader who can organize the trialing of scanners, archiving, reporting and research systems, ensure compatibility with existing hospital and cardiology networks, and who can assist in individualizing archiving and reporting software refl ecting institutional and icu specifi cs. coordination with the it department is very important. clear contractual vendor obligations for service, maintenance and future upgrades of hardware and software need to be specifi ed. training and credentialing of staff is best achieved within a systematic framework that includes ongoing competency review, education and qa programs. partnership with cardiology may benefi t both groups. major pitfalls are associated with poor initial training, lack of expertise and leadership, and bad vendor contracts. conclusion establishment of a cce laboratory requires careful planning, and allocation of adequate human and fi nancial resources. many potential problems can be identifi ed and prevented in advance. strong expert leadership plays an important role. introduction contrast-enhanced ultrasonography (ceus) is a dynamic digital ultrasound-based imaging technique, which allows quantifi cation of the microvascularisation up to the capillary vessels. as a novel method for assessment of tissue perfusion it is ideally designed for use in the icu. ceus is cost-eff ective and safe and can be repeatedly performed at the bedside without radiation and nephrotoxicity. critical care 2013, volume 17 suppl 2 http://ccforum.com/supplements/17/s2 methods the frequency of ceus use in the multidisciplinary surgical icu was retrospectively evaluated for the period from 1 september 2011 to 1 september 2012. furthermore, contributions of this novel method to the management of critically ill icu patients as well as its accuracy were assessed. results in total, 33 ceus studies were performed in critically ill icu patients. the most frequent indications included: assessment of the liver perfusion, assessment of the pancreas and kidney perfusion after pancreas and kidney transplantation, assessment of the renal perfusion in acute kidney injury (aki), assessment of active bleeding and assessment of the bowel perfusion. in all studies, the correct diagnosis was achieved and the transport of critically ill patients to the radiology department for further diagnostic procedures as well as application of iodinated contrast agents was avoided. in 16 cases signifi cant new fi ndings were detected. twelve of them were missed by conventional standard doppler ultrasound prior to ceus. in assessment of seven cases with aki, impaired or delayed perfusion and microcirculation of the kidney was observed in six patients. in three patients urgent surgical intervention was performed because of ceus results. in three cases active bleeding was excluded at the bedside due to absence of contrast agent extravasation into hematoma (thigh and perihepatic) or into abdominal cavity, without need for complementary ct imaging or angiography. in one case the regular perfusion of intestinal anastomosis was confi rmed with no need for surgical exploration. none of patients undergoing ceus manifested any adverse reactions or developed any complications associated with the imaging technique. conclusion contrast-enhanced ultrasonography clearly improves visualization of the perfusion in various tissues. it is very likely to be superior to standard doppler ultrasound, and is safe and well tolerated in critically ill patients. promising indications for the use of ceus in the icu may be the assessment of kidney microcirculation and assessment of liver perfusion in liver transplant and liver trauma patients. introduction even though invasive hemodynamic devices are usually used for assessment of septic shock victims, they cannot evaluate the heart function. lv dysfunction as well as right heart syndrome are not uncommon in sepsis and critical patients. intensive care ultrasound discloses these data and leads to appropriate treatment. methods the study was a prospective cross-sectional study. the measurement was performed within 24 hours of icu admission. we excluded patients with history of copd and pulmonary hypertension from any diseases. only good-quality images acquired from subjects were included for analysis. the primary objective was to disclose how the hemodynamic changed in septic patients by icu-us. introduction thermodilution (td) is considered a gold standard for measurement of cardiac index (ci) in critically ill patients. the aim of this study is to compare intermittent bolus td ci with intermittent automatic calibration ci (autoci) and two continuous cis obtained by pulse contour analysis with picco 2 (picci) and pulsiofl ex (pucci). methods interim results of an ongoing prospective multicentre study in 53 patients. age 58.7 ± 15.4, saps ii score 51.4 ± 14.7 and sofa score 10 ± 3.2. all patients underwent picco monitoring via a femoral line whilst a radial line was kept in place during four 8-hour time periods (in the fi rst two periods, the pulsiofl ex was connected to a radial line; in the last two it was connected to a femoral line). in the fi rst and third periods, the pulsiofl ex was calibrated with tdci, for the second and fourth periods pulsiofl ex was calibrated with autoci. simultaneous picci and pucci measurements were obtained every 2 hours while simultaneous tdci and autoci were obtained every 8 hours. we also looked at the eff ects of 40 interventions. in total, 940 cci and 382 tdci values were obtained: 940 paired picci and pucci; 358 paired autoci-tdci measurements. tdci values ranged from 1.5 to 6.9 l/minute/m 2 (mean 3.6 ± 1.1), autoci from 1.8 to 7.2 (3.6 ± 0.9), picci from 1.0 to 7.1 (3.5 ± 1.1) and pucci from 1.3 to 7.6 (3.6 ± 1). pearson's correlation coeffi cient comparing mean pucci and picci values per patient had an r 2 of 0.79. comparison between autoci and tdci had an r 2 of 0.51. changes in autoci correlated well with changes in tdci (r 2 = 0.44, concordance coeffi cient = 95.7), as did changes in pucci versus changes in picci (r 2 = 0.99, cc = 93.4%). changes in picci and pucci induced by an intervention correlated well with each other (r 2 = 0.86, cc = 100%). the percentage error (pe) obtained by bland and altman analysis and r 2 for the diff erent comparisons are presented in table 1 . the preliminary results indicate that in unstable critically ill patients, ci can be reliably monitored with pulsiofl ex technology via a femoral line. pulsiofl ex was also able to keep track of changes in ci. interim results of an ongoing study on the use of non-invasive hemodynamic monitoring with nexfi n in critically ill patients introduction perioperative goal-directed therapy (pgdt) can substantially improve the outcome of high-risk surgical patients [1] . but the approach needs an initial investment and increases the staff workload. economic factors might participate in the weak adherence to the pgdt concept. some model studies support pgdt cost-eff ectiveness, but real economic data based on a recent clinical trial are lacking. we performed an economic analysis of hemodynamic optimization using the stroke volume variation trial [2] in order to elucidate this issue. methods the hospital care invoices of all 120 patients included in the trial were retrospectively extracted. due to the nature of the data we have adopted the healthcare payer's perspective. we performed a comparison of induced costs between the vigileo (n = 60) and control (n = 60) groups and constructed a cost tree using the study group and complications occurrence as distributive parameters. the incremental cost-eff ectiveness ratio per complication avoided was calculated and, fi nally, diff erent reimbursing categories were assessed as potential cost drivers. results a decreased rate (18 vs. 35 patients) and number of complications (34 vs. 78) were observed in the original trials vigileo group. the mean cost of intervened patient was lower (€2,877 ± 2,336 vs. €3,371 ± 3,238; p = 0.38). according to the cost-tree analysis, patients with complications (n = 53; 44%) consumed signifi cantly more resources (€235,623; 63%). a gain of €634 per avoided complications confi rms that the lower complications rate was the most important cost driver. both the clinical care for patients costs (€505 vs. 912; p = 0.04) and ward stay costs (€244 vs. 402; p = 0.03) were decreased by the intervention. on the contrary, the intervention increased anaesthesia costs (€880 vs. 688; p = 0.001). conclusion intraoperative fl uid optimization with the use of stroke volume variation and the vigileo/flotrac system showed not only a substantial improvement of morbidity, but was also associated with an economic benefi t. this observed benefi t highly exceed the increased monitoring costs in our trial. introduction hemodynamic monitoring is important in high-risk surgical patients in order to detect and correct circulatory instability, thereby improving outcome [1] . the extravascular lung water index (evlwi) refl ects pulmonary edema [2] . the new ev1000/volumeview (edwards lifesciences) can accurately measure evlwi corrected for the actual volume of lung parenchyma (evlwic). the aim of our study is to prove a stronger correlation between evlwic and pao 2 /fio 2 compared with evlwi in patients undergoing pulmonary resection. methods a prospective observational study. seven patients with lung cancer undergoing pulmonary resection were monitored using the ev1000 plathform. evlwi was assessed by thermodilution at the following time points: after intubation (t1); during single-lung ventilation (t2); after lung resection (t3); after icu admission (t4); 12 hours (t5) and 18 hours after icu admission (t6). evlwic values were also collected at t3 and t4. pao 2 /fio 2 was measured at the same time points. results no signifi cant correlation was found between evlwi and pao 2 / fio 2 (r = -0.3124, p >0.05), while a signifi cant correlation was seen between evlwic and pao 2 /fio 2 (r = -0.528, p =0.009; figure 1 ). conclusion despite the small sample size, this study shows that in patients undergoing pulmonary resection the evlwic is more strongly correlated to pao 2 /fio 2 than evlwi. therefore, the ev1000 may be a valuable tool for more reliable hemodynamic monitoring in this subgroup of patients. references or extracardiac arteriopathy) were allocated to gdt or conventional hemodynamic therapy. we excluded patients with endocarditis, previous use of dobutamine, need for iabp, high dose of vasopressors and emergency surgery. the gdt protocol involved hemodynamic resuscitation aimed at a target of a cardiac index >3 l/minute/m 2 through a three-step approach: fl uid therapy of 250 ml lactated ringer's solution, dobutamine infusion up to a dose of 20 μg/kg/minute, and red blood cell transfusion to reach a hematocrit level above 28%. results twenty patients from the gdt group were compared with 20 control patients. both groups were comparable concerning baseline characteristics and severity scores, except for a higher prevalence of hypertension and heart failure in the gdt group. intraoperative data showed no diff erence regarding length of extracorporeal circulation, fl uid balance, transfusion or inotropic requirement. patients from the gdt group were given more fl uids within the fi rst 8 hours as compared with the conventional group (1,250 ml vs. 500 ml, p <0.001). gdt patients showed a median icu stay of 3 days (95% ci: 3 to 4) compared with 5 days in control patients (95% ci: 4 to 7). moreover, hospital stay was less prolonged in gdt patients (10 days vs. 14 days, p = 0.043 methods sixteen patients were divided into two groups: one group was treated with a restrictive approach (≤8 ml/kg/hour), and the other with a liberal approach (> 8 ml/kg/hour). patients were randomly allocated using sealed envelopes. during the thoracic part of the surgical procedure, all patients received one-lung ventilation (olv). in the group treated with a restrictive volume approach, patients received fl uids at the rate of 7.0 ± 1.0 ml/kg/hour. pao 2 /fio 2 was 288 ± 14 after intubation and 270 ± 22 before extubation. in the group treated with a liberal volume approach, fl uids were replaced at 11.0 ± 2.0 ml/kg/hour. pao 2 /fio 2 was 259 ± 24 after intubation and 223 ± 43 before extubation. surgery combined with olv was found to signifi cantly aff ect the pao 2 /fio 2 value (anova, f 1,14 = 15.85a, p = 0.001, partial η 2 = 0.531). the average pao 2 /fio 2 level was signifi cantly higher in the restrictive-replacement group than in the liberal-replacement group (anova, f 1,14 = 9.66, p = 0.008, partial η 2 = 0.408). there was no interaction between the groups (anova, f 1,14 = 1.7a, p = 0.215, partial η 2 =0.108). mean length of stay in the icu was similar between the restrictive-replacement group (5.2 ± 2.3 days) and the liberalreplacement group (6.3 ± 1.6 days) (anova, f 1,14 = 0.814a, p = 0.382, partial η 2 = 0.055). conclusion results from this small sample indicate that esophageal carcinoma surgery by itself had a detrimental eff ect on the pao 2 /fio 2 value, which restriction of perioperative volume did not signifi cantly aff ect. volume restriction also did not aff ect length of stay in the icu. we hypothesized that goal-directed therapy (gdt) is not associated with an increased risk of cardiac complications in high-risk, noncardiac surgical patients. patients with limited cardiopulmonary reserve are at risk of mortality and morbidity after major surgery [1] . augmentation of the oxygen delivery index (do 2 i) with a combination of intravenous fl uids and inotropes (gdt) has been shown to reduce the postoperative mortality and morbidity in high-risk patients [2] . however, concerns regarding cardiac complications associated with fl uid challenges and inotropes used to augment cardiac output may deter clinicians from instituting early gdt in the very patients who are more likely to benefi t. methods systematic search of medline, embase and central databases for randomized controlled trials of gdt in high-risk surgical patients. studies including cardiac surgery, trauma, and pediatric surgery were excluded to minimize heterogeneity. we reviewed the rates of all cardiac complications, arrhythmias, acute myocardial ischemia, and acute pulmonary edema. meta-analyses were performed and forest plots drawn using revman software. data are presented as odd ratios (ors) (95% cis), and p values. and compared with those calculated with the echocardiographic standard formulation (stroke volume = cross-sectional area×velocity time integral; coecho = sv×heart rate). in every patient co was measured twice: at baseline (t1) and after volume loading (500 ml lactate ringer solution) (t2). agreements between covig, comc, and coecho were evaluated by means of simple linear regression (r 2 ) and bland-altman analysis. results twenty patients were enrolled in the study. values of r 2 , bias and limit of agreement at t1 and t2 are summarized in table 1 . co values ranged from 3.9 and 8.6 l/minute (echo), from 3.4 to 9.9 (vigileo) and from 4 to 8.3 (mostcare); the pearson's and bland-altman methods showed poor agreement between coecho and covig, demonstrating a tendency to overestimation (see figure 1 ). the percentage of error (pe) was 51.7% at t1 and 49.3% at t2. on the contrary, mostcare measures showed good agreement with echocardiography (see table 1 ) with a pe of 22.4% at t1 and of 17% at t2. conclusion vigileo did not prove to be a substitute to the reference system; pre-loaded data, necessary for vascular impedance estimation, may be one of the main limitations that made vigileo measurements less accurate than the mostcare ones. on the contrary, mostcare, an uncalibrated totally independent system, was shown to properly estimate the vascular impedance in these hemodynamically stable patients. further comparisons in unstable conditions are needed to confi rm our observations. references previous studies have found an association between severity of acute infl ammatory states and increased arterial stiff ness but it is not known whether non-invasive pulse waveform analysis could predict development of multiple organ failure in septic patients. the purpose of this study was to evaluate the photoplethysmographic brachial artery pulse wave transit time and augmentation index and their changes in response to induced forearm ischemia in septic icu patients and correlate these indices to the development of subsequent end organ damage. methods a prospective observational study in patients with sepsis within 24 hours of admission. severity of sepsis was assessed with apache ii score (median 18.5) and sofa score (median 7.5). threeminute signal recording was done concurrently from the brachial artery at the elbow and the radial artery at the wrist with an originally designed photoplethysmograph at rest and after 5 minutes of induced forearm ischemia. recordings were analyzed to obtain the pulse wave transit time and augmentation index at rest and 60 seconds after induced ischemia. the sofa score was recalculated at 48 hours post recording. results we studied 14 consecutive general icu patients. there was a negative linear relationship between the pulse wave transit time (median 22.6 ms) at rest and increase in sofa score in 48 hours (p = 0.02, r = 0.96). the postischemic pulse wave transit time increased in all patients (median 25.7 ms) but no association was found between the proportion of increase and subsequent change in sofa. correlation between rest (median 7.6) and postischemic (median 7.2) augmentation index and 48-hour sofa scores was not statistically signifi cant (r = 0.57, p = 0.46). conclusion this study indicates that in early sepsis pulse waveform characteristics could predict the risk of developing end organ failure. the pulse wave transit time is more robust than the augmentation index and could be easier to use in patients with poor perfusion. vascular reactivity indices do not seem to have predictive value in this context. reference in clinical practice, blood volumes (bv) are typically measured by thermodilution. recently, contrast-enhanced ultrasound (ceus) has been proposed as an alternative minimally invasive approach for bv assessment [1] . this method measures bv using a single peripheral injection of a small bolus of ultrasound contrast agent (uca) detected by an ultrasound scanner. by measuring the acoustic backscatter, two indicator dilution curves (idcs) can be derived from two diff erent sites in the circulatory system. idc analysis permits deriving the mean transit time (mtt) the bolus takes to travel between the injection site and two measurement sites. assessment of the bv between these sites is obtained by multiplying the diff erence in mtt (δmtt) by the blood fl ow. in this study, we compare diff erent volumes in an in vitro set-up by ceus with true set-up volumes and thermodilution acquired volumes. methods the in vitro set-up consisted of a centrifugal pump, a network of tubes with variable volumes, an electromagnetic fl owmeter to measure and adjust the generated fl ow, heating devices to maintain constant temperature (37°c), two thermistors for thermodilution measurement, an ultrasound transducer and a pressure stabilizer. a small bolus of uca diluted in cold saline (1 mg sonovue® in 20 ml saline at 4°c) was injected into the system. the cold uca passage through a fi rst and a second region of interest (roi) was measured simultaneously with the ultrasound transducer and the thermistors. the measurements were performed at diff erent fl ows and volumes. bvs were estimated using the two diff erent approaches, namely ceus and thermodilution. the idcs were processed and fi tted separately with a dedicated model to estimate the δmtt of the cold uca bolus between the two rois and the two thermistors. all the measurements were repeated three times. results a linear relation between bvs estimated by the two techniques was observed with a correlation coeffi cient of 0.94. the bias of ceus with respect to the true volumes was -40.1 ml; the bias of thermodilution was 84.3 ml. the most prominent diff erences between the two techniques were observed in case of high volume and low fl ow, possibly due to diff erent transport kinetics between ucas and heat. the use of cardiac output monitoring has been shown to be benefi cial in the setting of perioperative medicine and critical illness [1, 2] . more recently, its application in the setting of major trauma has been described [3] . here, we describe our preliminary experience of embedding bioreactance fl ow monitoring within the major trauma primary survey of severely injured patients and the subsequent eff ect on patient management. methods institutional ethical approval was obtained. intubated major trauma patients were sequentially enrolled. exclusions included major thoracic burns and children. bioreactance fl ow monitoring (nicom; cheetah) was applied at the same time as ecg leads and the calibration step performed during handover from the prehospital team. time to availability of oxygen delivery data was recorded and trauma team members surveyed regarding for perceived benefi ts and concerns from this monitoring. the infl uence of fl ow monitoring on fl uid resuscitation, time to ct and defi nitive disposal (to or/icu) was measured and compared with a control population matched for injury severity score, age and sex. results cardiac index was available at mean 10.6 minutes (median 9 minutes; sd 3.9), fl uid responsiveness at mean 35.9 minutes (median 35; sd 11.3) and oxygen delivery calculation at mean 25.3 minutes (median 25; sd 7.7). passive leg raise was not performed in 63% of patients due to concerns about pelvic or brain injury. volume of fl uid infused (mean 738 vs. 925 ml; p = 0.124), time to ct (mean 57.4 vs. 68.8 minutes; p = 0.08), and time to defi nitive disposal (mean 124.9 vs. 146.1 minute; p = 0.069) were all reduced in the fl ow monitored group, although not signifi cantly diff erent when compared with a matched control group (mann-whitney u rank sum). eighty-four percent of trauma team members surveyed felt the fl ow monitoring data to be useful, and only 11% felt it may impair clinical management. conclusion cardiac index, fl uid responsiveness and oxygen delivery data can be obtained inform a primary survey. rather than introducing delays, the use of fl ow monitoring was associated with a trend towards decreased time to imaging; less fl uid use pre-damage control point and reduced time to defi nitive disposal. further research is required to confi rm benefi ts and mechanism. references introduction pulse pressure variation (ppv) is a dynamic indicator of fl uid responsiveness, which is known to have a low sensibility and specifi city in patients ventilated in pressure support (ps) [1] . we aim to investigate patient-ventilator asynchrony as a potential source of hemodynamic interference in ps. methods we performed a prospective study including ps ventilated patients who met inclusion criteria for fl uid depletion [1] . patients who showed an asynchrony index (ai) exceeding 10% were included in the asynchrony group (ag). the remaining patients were included in the synchrony group (sg) [2] . beat-to-beat hemodynamic variables were recorded through pram (mostcare; vytech health srl, padova, italy). ppv cutoff of 13% was used to identify fl uid responders/nonresponders. a fl uid challenge of 500 ml normal saline was given in 5 minutes. an increase of 15% of cardiac index after 10 minutes indicated fl uid responsiveness. results so far, eights patients showed an ai >10% while 16 did not. overall sensitivity was 28.6% versus 50% in sg; overall specifi city was 76.5% versus 91.7% in ag. overall cohen's k was 33.3% versus 61.2% in ag (see figure 1 ). however, because none of the responders in the ag group was detected by ppv, statistical analysis was not feasible within this subgroup. the mini-fl uid challenge is a widely used strategy to manage fl uid loading in the icu and or. although it might be a rational strategy, data on the mini-fl uid challenge and its reliability are very limited. we investigated the value of changes in pulse contour cardiac output as a result of a mini-fl uid challenge of 50 and 100 ml to predict fl uid loading responsiveness. methods we measured the eff ects after the administration of 50, 100 and 500 ml bolus colloid infusions on co (modelfl ow (com) and lidco (coli)), cvp and map in 21 patients on mechanical ventilation after elective cardiothoracic surgery. from the data we analysed the smallest volume that was predictive for the eff ects of 500 ml on cardiac output. results coli and com increased after 50, 100 and 500 ml fl uid loading. best results are observed for changes in com after 100 ml fl uid loading (area under the roc 0.86, 95% ci between 0.65 and 1.00). a change in modelfl ow co of at least 4.3% has a sensitivity of 67% and a specifi city of 100% after 100 ml fl uid loading. sensitivity is 60% and specifi city 83% for a similar cutoff in co measured with the lidco device after 100 ml fl uid loading. in our patient population, map and coli did not predict responsiveness with more accuracy than mathematical chance. see figure 1 . conclusion changes in pulse contour co can be used in a mini-fl uid challenge to assess fl uid responsiveness in our postcardiac surgery patients. introduction fluid responsiveness is defi ned based on an arbitrary increase of cardiac output (co) or stroke volume (sv) of 10 to 15%. we hypothesise that the variation of heart effi ciency (eh) and the slope (s) defi ned by the relative increase of co over the relative increase of mean fi lling pressure (pmsa) can be used as alternative defi nitions of fl uid responsiveness. introduction fluid overload is associated with poor outcome in the critically ill. thus, an accurate predictor of a positive haemodynamic response (increase in stroke volume) to fl uid challenge is vital. methods we studied the predictive value (positive response defi ned as change in stroke volume >15% after 10 ml/kg fl uid bolus) of a range of haemodynamic variables: static (cvp, active circulating volume, central blood volume, total end diastolic volume), dynamic (systolic pressure variation, stroke volume variation) and contactility (dp/dt), in a group of 100 ventilated children (median weight 10 kg). variables were measured using transpulmonary ultrasound dilution and pram (an arterial pulse contour method). we performed 168 paired measurements (pre-fl uid and postfl uid challenge), with a sv response rate of 45%. overall predictive values were poor, but slightly better for static versus dynamic variables (table 1) . when sv response was analysed as a continuous variable, the two predictive multivariable variables were change in tedvi and baseline dp/dt (r 2 = 0.30, both p <0.001). conclusion the predictive ability for typical static and dynamic haemodynamic variables, when taken in isolation, is poor. however, improved prediction is seen when baseline contractility is taken into account. pressure (map)-guided fl uid therapy on microcirculatory perfusion in patients undergoing abdominal surgery. methods patients undergoing elective abdominal surgery were randomized into a ppv/ci-guided group (n = 11) or a map-guided (n = 12) group. ppv, ci and map were measured using the non-invasive fi nger arterial blood pressure measurement device ccnexfi n (edwards lifesciences bmeye, amsterdam, the netherlands). tidal volumes were ≥8 ml/kg with peep ≥8 mmhg. in both groups, map of 70 mmhg was maintained. in the ppv/ci group, an intraoperative algorithm was used keeping the ppv under 12% and ci above 2.5 l/minute/ m 2 using fl uid therapy and dobutamine and noradrenaline infusion, respectively. sublingual microvascular perfusion was measured after anesthesia induction, and every subsequent hour using sidestream dark-fi eld imaging (microscan; microvision medical, amsterdam, the netherlands). the perfused small vessel density (pvd) values were offl ine quantifi ed. the fi rst hour during surgery, the ppv/ci-guided group tended to receive more fl uids than the map-guided group (1,014 ± 501ml vs. 629 ± 463 ml; p = 0.07). at this time point, the pvd was slightly lower in the ppv/ci-guided group (16.7 ± 3.1 mm/mm 2 ) when compared with the map-guided group (17.9 ± 3.9 mm/mm 2 ; p = 0.41). in both groups the pvd remained stable during the fi rst 2 hours of surgery. however, 2 hours after the start of surgery, the pvd in the ppv/ci group restored and tended to be higher than in the map-guided group (21.1 ± 1.9 vs. 18.1 ± 3.4 mm/mm 2 ; p = 0.09). after 1 hour of surgery, the administered fl uid volume correlated inversely with pvd (r = -0.59, p = 0.011). conclusion goal-directed fl uid management resulted in a higher administered fl uid volume in the beginning of surgery, and this was associated with a slightly reduced microcirculatory perfusion when compared with map-guided fl uid management. microcirculatory perfusion tended to improve as surgery progressed in the goal-directed fl uid therapy group. our fi ndings suggest that goal-directed and mapguided fl uid management are associated with distinct patterns in fl uid resuscitation, which may be of consequence for microvascular perfusion. introduction previous studies demonstrate that loss of glycocalyx integrity is associated with impaired microvascular function. we investigated whether glycocalyx dimensions are reduced in patients undergoing cardiac surgery with or without cardiopulmonary bypass (cpb), and are paralleled by loss of microcirculatory perfusion using in vivo microcirculation measurements. methods patients undergoing on-pump surgery with nonpulsatile (n = 11) or pulsatile (n = 13) cpb or off -pump surgery (n = 13) underwent sublingual sidestream dark-fi eld imaging at baseline, during coronary grafting and upon icu admission to assess perfused microvascular vessel density. glycocalyx integrity was evaluated using the glycocheck measurement software, and expressed as the perfused boundary region (pbr). an increase in pbr represents deeper penetration of erythrocytes into the glycocalyx, and is indicative for compromised glycocalyx thickness. introduction cold exposure can be adapted for exercise or therapeutic purposes, but its impact on microcirculation in healthy humans has not been well defi ned. we hypothesize that whole body cold stress may impair microcirculation. methods seven volunteers were recruited for the water immersion procedure. during the cooling protocol the volunteers every 20 minutes of immersion were asked to step out from the bath and rest for 10 minutes in a room environment and then return to the water bath for the next 20 minutes of immersion. this head-out immersion procedure in bath water at 14°c continued until the rectal temperature was dropped to 35.5°c or the time of 180 minutes was terminated. maximum cold water immersion time was 120 minutes. before, at the end of whole body cooling and 1 hour after cooling was ended, systemic hemodynamics and direct in vivo observation of the sublingual microcirculation were obtained with sidestream dark-fi eld imaging. assessment of microcirculatory parameters of convective oxygen transport (microvascular fl ow index (mfi), proportion of perfused vessels (ppv)), and diff usion distance (perfused vessel density (pvd) and total vessel density (tvd)) was done using a semiquantitative method. results during cooling and 1 hour after cooling was ended, a signifi cant increase in cardiac output (p = 0.028 and p = 0.043) was observed, but there were no changes in heart rate or mean arterial pressure in comparison with baseline variables. there were no signifi cant changes in ppv, mfi, pvd and tvd of small vessels in comparison with baseline variables during all observational time. conclusion defined cold exposure had no effect on the microcirculation. introduction vasodilation and increased skin blood fl ow (also sweating) are infl uential in heat dissipation during heat exposure and exercise. it is unclear how heat stress infl uences microcirculation. side dark-fi eld imaging visualizes the blood fl ow at the capillary level and helps to assess perfusion heterogeneity. clinical and experimental data show that the sublingual region is clinically relevant for detecting microcirculatory alterations and more represents central microcirculation than cutaneous perfusion. we hypothesize that whole body heat stress may increase capillary density. methods eight healthy men with no history of cold and/or heat injury were recruited to this study. passive body heating was performed by continuous immersion up to the waist in the water bath at 44°c and continued until rectal temperature reached 39.5°c. before, at the end of whole body heating and 1 hour after heating was ended, systemic hemodynamics and direct in vivo observation of the sublingual microcirculation were obtained with sidestream dark-fi eld imaging. assessment of microcirculatory parameters of convective oxygen transport (microvascular fl ow index (mfi), proportion of perfused vessels (ppv)), and diff usion distance (perfused vessel density (pvd) and total vessel density (tvd)) was done using a semiquantitative method. vessels were separated into large (mostly venules) and small (mostly capillaries) using a diameter cutoff value of 20 μm. results whole body heating resulted in signifi cantly increased heart rate (p = 0.012) and cardiac output (p = 0.046) in comparison with baseline variables. one hour after heating was ended, the heart rate introduction serial measurements of lactate over time may be a better prognosticator than a single lactate concentration [1] . early lactateguided therapy also reduces icu length of stay and icu and hospital mortality [2] . this study aims to assess the prognostic value of the lactate clearance (lc) in the fi rst 24 hours in surgical patients. methods in a prospective cohort during 1 year, we followed consecutively enrolled patients admitted immediately postoperative to the surgical icu of hospital santa luzia, brasília, brazil. patients were assigned to two groups: lc >10% and lc ≤10%. the primary outcome measure was mortality at 7 and 28 days. the secondary outcome included hospital and icu length of stay (los). results a total of 417 patients were followed. in total, 50.4% were male and 83% underwent elective surgery. the mean age was 59 ± 16, apache ii score 8 ± 5, saps 2 26 ± 11. the mortality at 7 days was 0.95% (n = 4) and the mortality at 28 days was 2.15% (n = 9), respectively. hospital mortality was 4.79% (n = 20). sixty-one percent (n = 255) of the patients had lc >10% versus 39% (n = 162) with lc ≤10%. those who had lc ≤10% were older (62 ± 16 vs. 57 ± 17, p = 0.00) and had greater apache ii score (9 ± 6 vs. 7 ± 4, p = 0.00) and saps 2 (28 ± 12 vs. 25 ± 10, p = 0.02). there was no diff erence in icu los (5 ± 12 vs. 4 ± 9 days, p = 0.54) and hospital los (10 ± 15 vs. 9 ± 11 days, p = 0.48). initial lactate levels were lower in the group with lc ≤10% (1.1 ± 0.9 vs. 1.9 ± 1.6, p = 0.00); however, mean lactate was higher in 24 hours (2.0 ± 1.8 vs. 1.0 ± 0.7, p = 0.00). all of the patients who died in the fi rst 7 days had lc ≤10% (2.46%, n = 4, p = 0.02); this group also had a higher mortality at 28 days (4.32%, n = 7 vs. 0.78%, n = 2; p = 0.03). the relative risk for mortality lc ≤10% in 7 and 28 days was 1.02 (95% ci: 1.00 to 1.05) and 5.07 (95% ci: 1.17 to 27.09), respectively. signifi cant diff erence was observed in the kaplan-meier survival curves for 7 and 28 days (p = 0.01 and 0.02, respectively). the sensibility of lc ≤10% was 100% (95% ci: 51 to 100%) for 7-day mortality and 78% (95% ci: 45 to 94%) for 28-day mortality. the specifi city was 62% (95% ci: 57 to 66%) for 7-day mortality and 62% (95% ci: 57 to 66%) for 28-day mortality. conclusion despite initial lactate levels, lactate clearance ≤10% proved to be a good predictor of mortality in 7 and 28 days in surgical patients admitted in the postoperative period to the icu. references introduction the use of peripheral perfusion objective parameters to anticipate successful resuscitation in septic shock has been recently investigated [1] . the mottling score, a perfusion parameter used for decades, has been proposed to correlate with septic shock survival [2] , and was tested in this study as a clinical tool in predicting mortality. methods a prospective observational study was conducted, with patients consecutively admitted to a tertiary hospital icu in brasília, brazil. from july 2011 to may 2012, all patients diagnosed with septic shock were enrolled. demographic data, diagnoses, shock origin and severity scores were recorded. after initial resuscitation, the score was registered in the fi rst 3 days by the same observer, considering the score on the lower limb without an arterial catheter, or the worst between the lower limbs, and the worst in the 3 days. exclusion criteria were terminal illness with no intervention decision and incomplete methods pigs (20 to 30 kg) were randomized into one of the groups: sham (n = 2), hs (n = 9), lr (3× volume bled; n = 9) or terli (2 mg bolus; n = 9). hs induced to target map of 40 mmhg was maintained for 30 minutes. brain tissue oxygen pressure (pbto 2 ), intracranial pressure (icp), cerebral perfusion pressure (cpp), haemodynamics and blood gas analyses were assessed prior to hs (baseline) up to 120 minutes after treatment. tissue markers of brain oedema (aquaporin-4 (aqp4) and na-k-cl cotransporter-1 (nkcc1)), apoptosis (pre-apoptotic protein (bax)) and oxidative stress (thiobarbituric acid reactive substances (tbars)) were also measured. results sham animals had no signifi cant changes in the variables assessed. hs resulted in a signifi cant decrease in cpp (mean varied from 36 to 39 mmhg), pbto 2 (from 23.6 to 26.6 mmhg), icp (from 1 to 2 mmhg) and haemodynamics (map from 38 to 40 mmhg; ci from 1.8 to 2.1 l/minute/m 2 ), and a signifi cant increase in blood lactate (from 6.7 to 8.9 mmol/l) and cerebral aqp4 (mean ± se; 167 ± 54% of sham), nkcc1 (237 ± 47% of sham), bax (167 ± 44% of sham) and tbars. fluid resuscitation was followed by an increase in icp (from 7 to 9 mmhg) and a decrease in cpp (from 41 to 52 mmhg), with an increased expression of cerebral aqp4 (210 ± 56% of sham), nkcc1 (163 ± 32% of sham) and bax (137 ± 24% of sham introduction shock induces mitochondrial damage, which can lead to tissue injury and infl ammation. resuscitative adjuncts to limit mitochondrial injury may be eff ective to reduce tissue injury and protect against the sequelae of hemorrhagic shock (hs). others and we have demonstrated the protective eff ects of inhaled carbon monoxide (co) or nebulized sodium nitrite (nano 2 ) in models of hs. our aim was to test the hypothesis that co and nano 2 protect against hemorrhagic shock-induced tissue injury/infl ammation by limiting mitochondrial damage and preventing bioenergetic failure. methods twenty anesthetized female yorkshire pigs were subjected to severe hemorrhage until unable to compensate or 90 minutes, and were then resuscitated with volume/pressors. muscle and platelet samples were obtained at baseline (bl) and 2 hours after resuscitation (endobs). animals were randomized to: standard of care (hsr, n = 5); hsr+co (co; 250 ppm×30 minutes, n = 6); or hsr+nano 2 (nano 2 ; 11 mg in pbs×30 minutes, n = 6), and sham (n = 3). co or nano 2 were initiated ~30 minutes before resuscitation. primary endpoints were changes in muscle and platelet mitochondrial respiration between bl and endobs, quantifi ed by muscle respiratory control ratio (rcr, traditional respirometry), and by the change in proton-leak respiration (plr) and mitochondrial reserve capacity in platelets. secondary endpoint was mortality at endobs. results skeletal muscle rcr decreased in the hsr group (p = 0.04) but not in sham. decrease in rcr was primarily due to decreased adpdependent respiration, without change in state 4 respiration. hsr also resulted in platelet mitochondrial dysfunction as demonstrated by increased plr and decreased reserve capacity. this correlated with increased platelet activation (%cd62p+ by fl ow cytometry) in hsr. co or nano 2 treatment prevented these deleterious changes in both muscle and platelet mitochondrial respiration, as well as limited hsr-induced platelet activation. co treatment also improved reserve capacity compared with baseline. mortality was higher in hsr than in co or nano 2 (80 vs. 33 and 33%, respectively). conclusion in severe hs, mitochondrial injury in platelets and muscle was limited by co or nano 2 . although not powered for a secondary endpoint, mortality was double in hsr versus adjunctive therapies. this suggests that co and nano 2 may protect mitochondrial function by maintaining atp-coupled respiration and reserve capacity, and that this may confer a survival advantage. however, further investigations are required. introduction norepinephrine has been widely used in septic shock. however, its eff ect remains controversial. we conduct a systematic review and meta-analysis to compare the eff ect between norepinephrine and other vasopressors. methods the pubmed, embase, and cochrane library databases from database inception until october 2012 were searched. we selected randomized controlled trials in adults with septic shock and compared norepinephrine with other vasopressors. the quality of each study included was assessed with jadad score. after assessing for heterogeneity of treatment eff ect across trials using the i 2 statistic, we used a fi xed eff ect model (p ≥0.1) or random-eff ects model (p <0.1) and expressed results as the risk ratio (rr) for dichotomous outcomes or the standardized mean diff erence (smd) for continuous data with 95% ci. results eighteen trials (n = 2,715) met inclusion criteria, which compared norepinephrine with fi ve diff erent vasopressors (dopamine, vasopressin, epinephrine, terlipressin and phenylephrine). the mean jadad score was 3.11. overall, there was no diff erence in mortality in the comparisons between norepinephrine and vasopressin, epinephrine, terlipressin and phenylephrine (p >0.05, respectively). however, norepinephrine had a trend in decreasing mortality compared with dopamine (rr, 0.84; 95% ci, 0.68 to 1.02; p = 0.08). there were a decreased heart rate (hr) (smd, -2.10; 95% ci, -3.95 to -0.25; p = 0.03), cardiac index (smd, -0.73; 95% ci, -1.14 to -0.03; p = 0.004) and an increased systemic vascular resistance index (svri) (smd, 1.03; 95% ci, 0.61 to 1.45; p <0.0001) with the treatment of norepinephrine compared with dopamine. conclusion there is not suffi cient evidence to prove that norepinephrine is superior to vasopressin, epinephrine, terlipressin and phenylephrine in terms of mortality. however, norepinephrine is associated with a decreased hr, cardiac index and an increased svri, and appears to have a greater eff ect on decreasing mortality compared with dopamine. introduction vasoplegic syndrome is a common complication after cardiac surgery, with negative impact on patient outcomes and hospital costs. pathogenesis of vasodilatory phenomenon after cardiac surgery remains a matter of controversy. loss of vascular tone can be partly explained by the depletion of neurohypophyseal arginine vasopressin stores. vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its eff ect on vasoplegic shock is unknown. we hypothesized that the use of vasopressin would be more eff ective on treatment of shock after cardiac surgery than norepinephrine, decreasing the composite endpoint of mortality and severe morbidity. methods in this prospective and randomized, double-blind trial, we assigned patients who had vasoplegic shock to receive either vasopressin (0.01 to 0.06 u/minute) or norepinephrine (0.01 to 1 μg/ kg/minute) in addition to open-label vasopressors. all vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. the primary endpoint was major morbidity according to sts (30-day mortality, mechanical ventilation >48 hours, mediastinitis, surgical re-exploration, stroke, acute renal failure). secondary outcomes were time on mechanical ventilation, icu and hospital stay, new infection, the time to attainment of hemodynamic stability, occurrence of adverse events and safety. results a total of 300 patients underwent randomization, were infused with the study drug (148 patients received vasopressin, and 152 norepinephrine), and were included in the analysis. patients who received vasopressin had a lower rate of morbidity (23.5% vs. 34%, p = 0.001) as compared with the norepinephrine group. the 30-day mortality rate was 6.1% in the norepinephrine group and 4.6% in the vasopressin group (p = 0.570). there were no signifi cant diff erences in the overall rates of serious adverse events (7.4% and 6.6%, respectively; p = 0.772). results patients in the two groups were statistically comparable with respect to sex (p = 0.31) and age (p = 0.53). the causes of the syndrome of tako-tsubo were: subarachnoid hemorrhage (six patients) after coronary artery bypass graft (four patients), and polytrauma (two patients). all patients had low cardiac output. in the levosimendan group the ejection fraction at entrance was 25 ± 6%, after 12 hours 36 ± 10%, and 47 ± 5% after 24 hours. in the control group the ejection fraction at entrance was 24 ± 7%, after 12 hours 28 ± 6% and after 24 hours 33 ± 4%. comparing the two groups we reached statistical signifi cance, p = 0.026. conclusion comparing the two groups, we noticed that both started from a low cardiac output. however, in the group who used the drug therapy based on levosimendan we saw a return of systolic function of the left ventricle to near-normal levels within 24 hours, while in the control group there remains a dysfunction in systolic function. we have shown the drug therapy based on levosimendan contributes to improving the systolic function of the left ventricle compared with treatment with dobutamine despite the initial cardiac stunning. reference introduction in the critically ill, the incidence of raised cardiac troponin t (ctnt) levels is high. although the mechanisms of myocardial injury are not well understood, raised ctnt levels are associated with increased mortality. the aim of our study was to determine the incidence, prevalence and outcome of silent myocardial injury as determined by raised ctnt levels and concomitant ecg changes in critically ill patients admitted for noncardiac reasons. methods ecgs were taken and ctnt was measured daily during the fi rst week and on alternate days during the second week until discharge from the icu or death. after completion of the study, all ctnt levels and ecgs were analysed independently and patients were classifi ed into four groups: defi nite mi (ctnt ≥15 ng/l and defi nite ecg changes of mi), possible mi (ctnt ≥15 ng/l and ischaemic changes on ecg), troponin rise alone (ctnt ≥15 ng/l with no ischaemic ecg changes), or normal. all medical notes were reviewed independently by two icu clinicians. results a total of 144 patients were included in the analysis (42% female; mean age 61.9 (sd 16.9); mean apache ii score 19.4). in total, 121 patients (84%) had at least one ctnt level ≥15 ng/l during their stay in the icu. twenty patients (14%) fulfi lled criteria for a defi nite mi, of whom 65% were septic and 50% were on noradrenaline at the time (icu and hospital mortality: 25% and 30%, respectively). thirty-nine patients (27%) had a possible mi, of whom 69% were septic and on noradrenaline (icu and hospital mortality: 31% and 41%, respectively). sixty-two patients (43%) had a raised troponin without ecg, of whom 69% were septic and 50.7% were on noradrenaline (icu and hospital mortality: 23% and 31%, respectively). twenty-three patients had normal ctnt results and serial ecgs, of whom 61% had sepsis. icu and hospital mortality was 4%. only 25% of defi nite mis and 18% of possible mis were recognised by the clinical teams at the time. conclusion eighty-four per cent of critically ill patients had a raised ctnt level at some stage during their stay in the icu. more than 40% of patients fulfi lled criteria for a possible or defi nite mi, of whom only 20% were recognised clinically. icu and hospital outcome were signifi cantly worse in patients with a ctnt rise. the proportion of patients with sepsis was similar between the patients with a defi nite, possible or no mi. the grace risk score for predicting death within 6 months of hospital discharge was validated and can be used in patients with acs. it would be perfect in the future to include the grace risk score in the medical records of this type of patients. also it would be very interesting to validate this in a multicentric study. figure 1 ). patients in group 2 had more prolonged length of stay in the icu and in hospital than patients in group 1. after recovery from septic shock we notice a huge accumulated fl uid balance. a more positive fl uid balance was associated with a more prolonged length of stay in the icu and in the hospital. ugib patient needs an intervention or not. however, the intervention which the gbs mentions includes not only endoscopy but also blood transfusion. therefore, we cannot determine whether a ugib patient needs urgent endoscopy or just blood transfusion by gbs alone. we hypothesized that high lactate clearance (clac) would decrease the likelihood of sustained ugib. methods this is a retrospective study. ugib patients, who visited the emergency department (ed) of the national center for global health and medicine from april 2011 to march 2012 and received urgent endoscopy in the ed, were enrolled. we collected for each patient the gbs, the blood lactate value on arrival in the ed, the blood lactate value after bolus administration of 20 to 40 ml/kg ringer's acetate (initial fl uid therapy) and the report of urgent endoscopy. we classifi ed the severity of ugib according to gbs. a score ≤12 was classifi ed as moderate, and a score ≥13 was classifi ed as severe. clac was defi ned as the percentage decrease in blood lactate from the time of arrival in the ed to the time when an initial fl uid therapy was fi nished. clac <50% was defi ned as low, and clac ≥50% was defi ned as high. whether a patient had sustained bleeding or not was determined based on the report of urgent endoscopy. the relationship between clac and sustained bleeding was examined by fisher's exact test, and p <0.05 was considered statistically signifi cant. results seventy-nine patients were enrolled. fifty-one patients were with moderate ugib, and 28 patients were with severe ugib. as indicated in tables 1 and 2 , there was a signifi cant relationship between clac and sustained bleeding in moderate ugib (p = 0.02). on the other hand, there was no signifi cant relationship between clac and sustained bleeding in severe ugib (p = 0.58). introduction the aim of our study was to assess the muscular glucose by microdialysis and its association with mortality in septic shock patients. we conducted a preliminary prospective study. we included septic shock patients hemodynamically optimized according to international recommendations. a microdialysis catheter was inserted in the femoral quadriceps. interstitial fl uid samples were collected every 6 hours for 5 days. the determination of muscular glucose was performed by the cma 600 analyzer (cma/microdialysis ab, sweden). we also performed a dosage of concomitant blood glucose. the study population was divided into two groups according to hospital mortality. statistic analysis: mann-whitney test and chi-squared test: comparisons between groups. quantitative variables were expressed as mean ± standard deviation or median (interquartile range) as appropriate. results we included 12 patients with septic shock. the mortality rate was 50%. demographics were comparable between groups except for age (66 ± 9 vs. 41 ± 12, dead patients vs. survivors, respectively; p = 0.002). pneumonia was the major cause of septic shock (10 patients). we analysed 167 blood samples and 166 muscular glucose samples. we found a positive association between muscular glucose, blood glucose and mortality. tissue glucose was signifi cantly higher among dead patients compared with survivors at the 54th hour. comparing all data, muscular glucose (p = 0.02) and blood glucose (p = 0.007) were signifi cantly higher in dead patients (table 1) . conclusion our data suggest that muscular glucose assessed by microdialysis and blood glucose are associated with mortality in septic shock patients. therefore, muscular glucose may refl ect the metabolic alterations and microcirculatory dysfunction induced by septic shock. methods the audit had the trust audit committee's approval. the existing protocol was used as the benchmark. patients were studied prospectively to assess compliance with the local bowel protocol, incidence of constipation and relationship to weaning from respiratory support and feeding. all hdu and all mechanically ventilated icu patients who stayed on the ward for more than 3 days were included, except for patients after bowel surgery and patients with encephalopathy. results among the 24 hdu and 21 icu patients audited in the royal liverpool university hospital, 67% and 57% respectively were constipated. laxatives were prescribed when patients had not opened their bowels for 3 days in 25% hdu and 75% icu cases. taking into consideration that the median age, apache ii score and length of stay for constipated and nonconstipated patients were similar, the relationship to feeding and respiratory support were assessed. introduction it was noted on our unit that dislodgement of nasogastric tubes occurred commonly. this can lead to an increased risk of aspiration, interruptions in nutritional support, skin breakdown and radiographic exposure [1] . it is recommended that the position of nasogastric tubes should be confi rmed by aspiration and ph testing, with radiographic confi rmation used only when this is not possible [2] . methods we performed a retrospective review of chest x-ray (cxr) requests for the 3-month period june to august 2012 using the trust radiology information system. the proportion of cxr requests for confi rmation of position and patient demographics were measured with an estimation of the fi nancial cost performed. results there were 541 patients admitted to the critical care area in the study period. in total, 207 out of 2,340 (8.8%) cxrs performed were for confi rmation of position. repeated x-rays were required in some patients (see table 1 ); these patients were older and tended to have a longer length of stay. a mobile cxr costs £25 in our trust, if one cxr is accepted per patient with a nasogastric tube; there was an excess of 160 images with a cost of £4,000 in the 3-month period. conclusion an excess of cxrs were performed for confi rmation of nasogastric tube in our patient population. the recommended methods for position confi rmation were reinforced amongst medical staff . the high number of repeated imaging for some patients indicates that dislodgement of tubes was also a problem. we propose that nasogastric tubes should be bridled after fi rst dislodgement or at tracheostomy insertion to minimise dislodgement in the future. methods mechanically ventilated, not enterally fed icu patients (n = 9) were recruited from an interdisciplinary icu. healthy, overnight-fasted volunteers (n = 6) served as reference. a primed constant i.v. infusion of 2 h-labeled phenylalanine (phe) and tyrosine was used to quantify whole-body protein metabolism. patients remained on parenteral nutrition (pn) as clinically indicated; controls received pn starting 2.5 hours before starting enteral feeding. intrinsically 13 c-phe-labeled casein was infused for 6 hours by nasogastric tube at 0.75 g protein/ hour, together with maltodextrin at 2.73 g/hour. protein breakdown, synthesis, net balance, and phe splanchnic extraction were calculated before and at the end of the enteral feeding period, using equations for steady-state whole-body protein kinetics. comparisons were made by wilcoxon matched pairs and mann-whitney u tests; values are reported as mean ± sd. results protein net balance was lower in patients than in the reference group at baseline (-1.8 ± 1.7 vs. 0.6 ± 0.6 mg/kg bw/hour, p = 0.003), and after enteral feeding (-1.1 ± 1.5 vs. 0.6 ± 0.6 mg/kg bw/hour, p = 0.049). recovery of labelled phe from enteral feeding into the systemic circulation was higher in the reference group as compared with patients (20.3 + 11.2% vs. 7.0 + 4.8%, p = 0.005). enteral feeding did not aff ect protein metabolism in the reference group. in patients, protein breakdown became slightly lower during enteral feeding (10.6 ± 3.3 vs. 11.2 ± 3.3 mg/kg bw/hour, p = 0.086) and protein net balance became slightly higher (-1.1 ± 1.5 vs. -1.8 ± 1.7 mg/kg bw/ hour, p = 0.086). conclusion intrinsically isotope-labelled casein can be used to quantify dietary contribution to protein metabolism in critically ill patients. hypocaloric enteral feeding marginally improved protein balance in these patients. the low recovery of enterally administered labelled amino acid underlines the need to quantify uptake from the gastrointestinal tract when protein turnover measurements are performed in critically ill patients on enteral nutrition. methods this small-scale study of 25 ngt placements during a 5-week period collated data supplied by questionnaire by healthcare workers responsible for ngt placements. results analysis of adverse incident reports identifi ed no never events of misplaced ngts within the previous 10 years. this audit revealed that the commonest type of ngt was a radio-opaque tube with stylet (corfl o) (92% of placements), with occasional use of the electromagnetic placement system (cortrak) (8% of placements). sizes 10 (40%) and 12 (56%) were most common. tube placement was confi rmed by: x-ray (72%); ph of aspirates (35%); electromagnetic tube placement (one patient). the time taken from decision to place ngt to use varied (range 15 to 510 minutes). little distinction was seen in the time taken to use and ngt confi rmed by aspirate alone (205 minutes) or by x-ray (220 minutes), although the shortest interval was seen in electromagnetic ngt placement (15 minutes). the cost of ngts confi rmed by aspirate alone was low (approximately £10.00), higher with x-ray confi rmation/electromagnetic placement (approximately £45.00). conclusion despite the small dataset the results demonstrate a concerning delay in the application of enteral feeding and/or drug administration. whilst reassuring in the steps taken to avoid never events, this study demonstrates that there may be delays in time-critical administration of enteral medicine or optimal nutritional practices. this study reveals a signifi cant problem with aspirating gastric contents for ph testing, necessitating a large number of x-ray position confi rmations. even if the frequency and volume of gastric aspiration were greater, there is a belief that ph testing may not be suffi ciently accurate (since many factors alter patients' gastric ph). it is possible that new technologies such as electromagnetic ngt placement may allow faster/equally safe practices. further study including cost/benefi t analysis will be needed to confi rm this. reference . eighteen readings were from newly placed ng tubes and 150 readings from old ng tubes. fiftythree per cent of routine ph readings were falsely high; that is, ph 6 or above despite the ng tube being in the stomach (figure 1 ). twentyeight per cent of newly placed ng tubes had falsely high ph readings ( figure 2 ). conclusion in this population of icu patients, routine/daily checks of ng ph aspirate appear to be limited. this is almost certainly due to the use of continuous ng feed together with ppis. the usefulness of ph testing in newly placed ng tubes, however, appears more reliable. introduction sepsis is the most common cause of death in icus [1] . destruction of intestinal barrier function and increased translocation of bacteria to systemic blood fl ow can lead to sepsis [2] . probiotics may have benefi cial eff ects in improvement of critically ill patients by modulating intestinal barrier and reduction of infl ammation [3] . the aim of this trial was to determine the eff ect of probiotic on infl ammatory biomarkers and mortality rate of sepsis in critically ill patients in the icu. methods this double-blind, randomized controlled trial was conducted on 40 critically ill patients admitted to the icu. they were randomly assigned to receive placebo or probiotic for 7 days. the apache score, sequential organ failure assessment (sofa) and systemic concentrations of il-6, procalcitonin (pct) and protein c were measured before initiation of the study and on days 4 and 7. also, 28day mortality was evaluated for each patient. results il-6 and pct levels decreased and protein c levels increased signifi cantly in probiotic group over the treatment period (p <0.001). there was a signifi cant diff erence in il-6, pct and protein c levels of the 7th day between two groups (p = 0.001, 0.006 and <0.001, respectively). compared with controls, probiotic was eff ective in improving apache and sofa scores in 7 days (p <0.001). there was signifi cant diff erence between the probiotic and control group in the 28-day mortality rate (20% vs. 55% respectively, p = 0.048). conclusion probiotics reduce infl ammation and mortality rate in critically ill patients and might be considered as an adjunctive therapy to sepsis. introduction the aim of this study is to establish whether diff erent types of sepsis have an impact on selenium levels. selenium is an essential trace element involved in antioxidant and immunological reactions. selenium levels have been shown to be low in patients with systemic infl ammatory response syndrome and sepsis. selenium replacement has been recommended in patients with sepsis [1, 2] . greater than 5 days of supplementation may also help to prevent the development of new infections on icus [3] . methods this is a prospective survey where selenium levels were collected from patients admitted with septic shock to a tertiary icu, for 6 months from october 2010 to march 2011. results selenium levels were measured in 31 patients with septic shock. abdominal and chest sepsis were the main sources of infection. those with an abdominal source of sepsis had the lowest levels, as shown in table 1 . all septic shock patients who had selenium levels taken within the fi rst 10 days of admission had subnormal levels (<0.8 mg/dt), and after 10 days had levels within the normal range, as shown in figure 1 . introduction glutamine regulates many biological functions in preserving the cell, acts as a key respiratory fuel and nitrogen donor for rapidly dividing cells, and modulates the expression of many genes associated with metabolism, cell defences and repair, and cytokine production. in severe thoracic trauma, glutamine supplementation is essential because the body consumes more than it produces and glutamine eff ects become dependent on its route of delivery. methods fifty-two patients 19 to 78 years old with surgery for severe thoracic trauma were assessed in two groups: group a received 0.3 to 0.5 g/kg/day i.v. glutamine + 20 g enteral glutamine for 7 days, supplementation to enteral nutrition; group b receive only i.v. glutamine supplementation to enteral nutrition 0.3 to 0.5 g/kg/day for 7 days. weaning time, the duration of p.o. ileus, incidence and time to resolution of vap, glycemic level and the percentage decrease of crp at 96 hours were assessed in both groups. results weaning time and the duration of p.o. ileus were signifi cantly lower in group a; although the incidence of vap is similar in both groups, the time of vap resolution is lower, the glycemic control is better in group a. the percentage of crp decrease is higher in group a. see figure 1 . conclusion glutamine becomes an essential amino acid in severe thoracic trauma and when the patients are fed other than tpn (enteral, oral); although hard evidence is lacking, both administration routes may be effi cient as soon as possible. results total cholesterol (tc) and low-density lipoprotein-cholesterol (ldl-c) levels were less changed signifi cantly in the low ratio group (3 ± 18 vs. 16 ± 23 mg/dl, p = 0.027 for tc, 4 ± 12 vs. 12 ± 18 mg/dl, p = 0.026 for ldl-c) compared with the high ratio group in postoperative patients. other laboratory parameters and adverse events did not show statistically signifi cant diff erences between the groups. see table 1 . introduction the optimal feeding of critically ill patients treated in the icu is controversial. present guidelines for protein feeding are based on weak evidence obtained with suboptimal methods. whole body protein kinetics is an attractive technique to assess optimal protein intake by measuring the eff ect of protein feeding strategies on protein synthesis rates, protein degradation rates and protein balance. here protein kinetics were measured in critically ill neurosurgical patients during hypocaloric and normocaloric parenteral nutrition. methods neurosurgical patients on mechanical ventilation (n = 16) were studied. energy expenditure was measured with indirect calorimetry. after that, the patients were randomized to receiving 24 hours of 50% of measured energy expenditure followed by 24 hours of 100% or 100% before 50%. whole body protein kinetics were measured during the last half hour of the feeding periods using stable isotope-labeled phenylalanine as a tracer. during a continuous infusion of labeled phenylalanine and tyrosine, plasma samples were obtained and later analyzed for the content of the labeled amino acids using mass spectrometry. protein kinetics were calculated using standard steady-state kinetics. in addition, amino acid concentrations were analyzed by hplc. student's t test was used for statistical analyses. the patients received 0.5 ± 0.1 and 1.1 ± 0.2 g amino acids/ kg/day (p <0.001) on the days with 50 and 100% of measured energy expenditure respectively. energy expenditures were 23.4 ± 2.7 and 24.5 ± 2.3 kcal/kg/day (p = 0.05) on the 50 and 100% days respectively. plasma amino acids concentrations were 2.8 ± 0.5 and 2.9 ± 0.4 mm (p = 0.085) on the 2 days respectively. whole body protein synthesis was 12% lower when 50% of energy expenditure was given, 11.7 ± 3.0 versus 13.3 ± 2.2 mg/kg/hour (p = 0.025), whilst protein degradation was unaltered 13.6 ± 3.5 versus 14.0 ± 2.6 mg/kg/hour (p = 0.56). also protein oxidation was unaltered 3.0 ± 2.1 versus 2.9 ± 1.4 mg/kg/hour (p = 0.85). this resulted in a 60% higher whole body protein balance with the normocaloric nutrition, -1.9 ± 2.1 versus -0.7 ± 1.3 mg/kg/ hour (p = 0.014). conclusion the protein kinetics measurements and the protocol used were useful to assess the effi cacy of nutritional support in critically ill patients. in the critically ill neurosurgical patients treated in the icu, hypocaloric feeding was associated with a more negative protein balance, while the amino acid oxidation was not diff erent. controlled trial (epanic: clinicaltrials.gov: nct00512122) [2] showed that withholding parenteral nutrition during the fi rst week of icu stay whereby tolerating substantial caloric defi cit (late pn) accelerated recovery and shortened weaning time as compared with early parenteral substitution for defi cient enteral feeding (early pn). we examined the impact of late pn, as compared with early pn, on incidence and recovery of icuaw. methods a preplanned subanalysis of adult patients included in the epanic trial. the study was performed between october 2008 and november 2010 and included those patients who required intensive care for ≥8 days as well as a computer-generated, admission categorymatched, random sample of short-stay icu patients, the latter to correct for possible bias evoked by earlier icu discharge in one of the two study groups. assessors blinded for treatment allocation evaluated muscle strength clinically three times weekly from awakening onward and performed nerve conduction studies and electromyography (ncs and emg) weekly. the primary outcome was the incidence of icuaw, diagnosed clinically by the medical research council (mrc) sum score (<48/60) [3] at fi rst evaluation. secondary outcomes included icuaw at worst and last mrc evaluation, recovery from icuaw and incidence of abnormal fi ndings on ncs and emg. all analyses were performed on the total dataset and on a for-baseline characteristics propensity score-matched sample to correct for possible imbalances between the groups. [1] . plasma total bilirubin was quantifi ed in all patients daily while in the icu. liver enzymes alt, ast, ggt and alp were quantifi ed twice weekly in all patients while in the icu. in a random predefi ned subset of patients, circulating bile salts were also quantifi ed with ms-hplc at baseline and on day 3, day 5 and the last day in the icu (n = 280). gallbladder sludge was evaluated by ultrasound on icu day 5 by blinded assessors (n = 776). results from day 1 after randomization until the end of the 7-day intervention window, plasma bilirubin was higher in the late pn than in the early pn group (all p <0.001). in the late pn group, as soon as pn was started on day 8, plasma bilirubin also fell and the two groups became comparable. maximum levels of ggt, alp and alt during the icu stay were higher in the early pn group (all p <0.01). compared with baseline, the circulating glycine and taurine conjugated primary bile salts were elevated on day 3, day 5 and last day of the icu stay (p <0.01 for all). however, there was no diff erence between the two groups. more patients in the early pn than in the late pn group had gallbladder sludge on day 5 (45% vs. 37%; p = 0.04). conclusion tolerating substantial caloric defi cit by withholding pn until day 8 of critical illness increased circulating levels of bilirubin but reduced the occurrence of gallbladder sludge and lowered ggt, alp and alt levels. these results suggest that hyperbilirubinemia during critical illness dies not necessarily refl ect cholestasis and instead may be an adaptive response. additional analyses on a propensity scorematched patient population are ongoing. reference the duration of renal replacement therapy (rrt) [1] . the impact of the intervention on early markers of catabolism has not been investigated. methods we studied the impact of early versus late pn on daily markers of catabolism in the icu in the total study population and in propensity score-matched subgroups of long-stay patients. in addition, we calculated the net incorporation rate of the extra amino acids supplied by early pn. results plasma urea, the urea/creatinine ratio and nitrogen excretion increased over time in the icu. early pn further increased these markers of catabolism, from the fi rst day of amino acid infusion onward, and only marginally improved the nitrogen balance. also in the group that received pn only after the fi rst week in the icu, ureagenesis was increased by infusing amino acids. over the fi rst 2 weeks, approximately two-thirds of the extra amino acids supplied by early pn were net wasted in urea. the above fi ndings were confi rmed in propensity scorematched subgroups of long-stay patients. the higher urea levels with early pn, rather than the kidney function as such, may have driven the observed longer duration of rrt, as supported by multiple regression analysis. conclusion the extra amino acids supplied by early pn appeared ineffi cient to reverse the negative nitrogen balance, not because of insuffi cient amino acid delivery, but rather because of insuffi cient incorporation with, instead, increased degradation into urea. the substantial catabolism of the extra amino acids, leading to pronounced urea generation, may have prolonged the duration of rrt in the early pn group. introduction muscle weakness of critical illness is associated with prolonged dependency on ventilatory support and delayed rehabilitation. muscle wasting related to poor nutrition has long been considered a major determinant, whereas the importance of myofi ber integrity only recently emerged [1] [2] [3] [4] . we hypothesized that nutrient restriction early during illness aggravates atrophy while preserving myofi ber integrity by activating the crucial cellular quality control pathway autophagy. the latter could be important to preserve muscle function. methods critically ill patients (n = 122) were randomized to early (early-pn) or late (late-pn) initiation of parenteral nutrition to complete failing enteral nutrition, while maintaining normoglycemia (80 to 110 mg/ dl) with insulin, in the epanic study [5] . vastus lateralis biopsies were harvested after 1 week and compared with matched controls (n = 20). results as compared with controls, muscle from critically ill patients showed reduced myofi ber density, a shift to smaller (especially type i) myofi bers, lower myosin and actin mrna, upregulated mrna of the ubiquitin ligases muscle-ring-fi nger-1 and atrogin-1, a small increase in the autophagosome formation marker lc3-ii/lc3-i, and increases in the autophagic substrates ubiquitin and p62 (all p ≤0.006). late-pn, resulting in a larger caloric defi cit than early-pn, had no substantial impact on atrophy markers. in contrast, late-pn increased lc3-ii/lc3-i (p = 0.02), which coincided with less accumulation of ubiquitinated proteins/aggregates (p = 0.05). fewer patients on late-pn developed muscle weakness as compared with early-pn (42% vs. 68%, p = 0.05). in multivariable analysis, a lower lc3-ii/lc3-i ratio (p = 0.05) and higher myofi ber density (p = 0.04) were independently associated with muscle weakness. conclusion early-pn did not counteract muscle atrophy whereas it suppressed autophagy and aggravated weakness. statistically, muscle weakness was not explained by atrophy or wasting but rather by impaired autophagy and preservation of muscle density. thus, tolerating nutrient restriction early during critical illness may preserve myofi ber integrity by activating autophagy. introduction closure of an acute hospitals emergency department (ed) has important ramifi cations for those centres expected to take up the resultant workload. the continued reconfi guration of emergency care is likely to produce an increasing number of these scenarios. little evidence is available to support planning of such initiatives and thus the implications are diffi cult to anticipate. this study aims to demonstrate one hospital's experience of the rationalisation of emergency care and its eff ect on workload. methods this retrospective study was conducted in a large teaching hospital. activity data were analysed for a 12-month period following the closure of a neighbouring ed. the results were subsequently compared against the year prior to closure. attendance, triage data, admission rates and waiting times were compared across the two periods, as were workload data for all grades of physician. the chisquared test was used to examine diff erences between groups. results in the period studied, the gross attendance fi gure increased by 20,480 (33.72%), whilst the admission rate rose from 22 to 27%. following closure of the neighbouring ed, the proportion of highacuity patients attending our institution increased dramatically, with the proportion of category one and two patients (manchester triage scale) increasing by 8.33% (p = 0.076) and 18.80% (p <0.001), respectively. likewise, ambulance arrivals increased out of proportion to the total increase in attendances (p = 0.016). admissions from the ed to the icu increased by 63.04%. consultants workloads now include 50% more category 1 and 2 patients (p = 0.001). conclusion reconfi guration of emergency care can have dramatic implications for existing services; these may not always be anticipated. rationalisation of ed's may result in a concentration of high-acuity patients accompanied by a downturn in the numbers of patients whose presentations are amenable to care delivered in other settings. this abrupt change in case mix requires a re-examination of existing workforces and their seniority. overcrowding estimation in the emergency department: is the simplest score the best? introduction emergency department (ed) overcrowding is a major international problem with a negative impact on both patient care and providers. among validated methods of measurement, emergency physicians have to choose between simple and complex scores [1, 2] . the aim of the present study was to compare the complex national emergency department overcrowding scale (nedocs) with the simple occupancy rate (or) determination. we further evaluated the correlation between these scores and a qualitative assessment of crowding. methods the study was conducted in two academic hospitals and one county hospital in liège, chênée and verviers; each with an ed census of over 40,000 patient visits per year. samplings occurred over a 2-week period in january 2011, with fi ve sampling times each day. results ed staff considered overcrowding as a major concern in the three eds. median or ranged from 68 to 100, while the nedocs ranged from 64.5 to 76.3. we found a signifi cant correlation between introduction it is evident that accident and emergency departments are overloaded with patients, which results in delays in healthcare provision [1] . a large proportion of patients consist of patients with minor illness that can be seen by a healthcare provider in a primary care setting. the aim of the study was to determine the characteristics of patients using gp walk-in services, patients' satisfaction and the eff ect on emergency department (ed) services. methods the survey was conducted in sheffi eld and rotherham walk-in centres over 3 weeks during september and october 2011. a self-reported, validated questionnaire was used to conduct survey on the patients presenting at these centres. we estimated that a sample size of around 400 patients from each centre was required to achieve statistically robust results. a post-visit, short questionnaire was also sent to those who agreed for the second questionnaire and provided contact details. ed data were also obtained from april 2008 to march 2010, 1 year before and 1 year after the opening of the gp walk-in centre. data were entered and analysed in pasw statistics 18. ethical approval of the study was obtained from the nhs ethical review committee. results a total of 1,030 patients participated in the survey (rotherham 501; sheffi eld 529). the mean age of the participants was 32.1 years at sheffi eld and 30.88 years at rotherham. a higher proportion of users were female, around 59% at both centres. most of the patients rated high for convenience of the centre opening hours and location (above 85%, apart from the location of sheffi eld centre, which was rated high by around 72% of the research participants). overall 93% patients were satisfi ed with the service at rotherham centre and around 86% at the sheffi eld centre. based on the estimation of the monthly counts of patients attending ed and the gp walk-in centre, around 14% monthly reduction in minor attendances at ed was expected. however, ed routine data did not show any signifi cant reduction in minor attendances as a result of the opening of the gp walk-in centre. conclusion these walk-in centres have been shown to increase accessibility to healthcare service through longer opening hours and walk-in facility. although the eff ect on the reduction of patients' load at the ed is not visible as these centres cover a fraction of the population, the centre has a potential to divert patients from the ed. reference overcrowding in emergency departments (eds) is a widely known problem. it causes problems and delays in the ed and has a negative impact on patient safety [1] . the aim of this study was to analyse whether a reform of emergency care can reduce patient fl ow into the ed. methods a substantial reform of emergency care took place in the province of kanta-häme in southern finland. three separate out-ofhours services in primary healthcare (phc) and one ed in the hospital were combined into one large ed in april 2007. basic principles of the new ed were: the ed is only for those patients who are seriously ill or injured, and need immediate care; phc (healthcare centres) take care of acute ordinary illnesses and nonserious injuries during offi ce hours. to achieve these principles a regional fi ve-scale triage system was planned and implemented. the information plan was established. citizens were systematically informed about the principles of the new ed by mail, articles in the newspapers and interviews in the radio and television. the ed's internet pages were planned and established. the number of patient visits (hämeenlinna region) was analyzed 2 years before and after establishing the new ed. results during the 2-year period before the establishment of the new ed the mean number of gp patient visits was 1,845 ± 43/month. during the 2-year period after the reform the number was diminished to 1,364 ± 21/month. this change was not associated with the increase of the patient visits taken care of by specialists and hospital residents. see figure 1 . conclusion an extensive reform of the emergency services can notably reduce patient fl ow into the ed. reference abdominal pain in adolescent females has undergone recent changes with regards to its management under various specialities. the authors report a single-centre audit looking at the correct investigation and management of 12-year-old to 16-year-old girls with abdominal pain in the emergency department setting. methods a single-centre audit and retrospective analysis of patients took place using case notes and computerised records. documentation was analysed using statistical analysis and minimum standards were set and reviewed. results after exclusion criteria 62 females between the ages of 12 and 16 presented to the paediatric emergency department in leicester with abdominal pain as the predominant admission symptom during a 12-month period. documentation of the gynaecological history was poor (menstrual history 47%, sexual history 14%, contraception 8%), as was the performance of basic investigations (urine dipsticks 65%, pregnancy test 42%). documentation was analysed with regard to discharge diagnosis. ultrasound investigation was performed on seven of the patients but only once admitted to various specialities. no ultrasound was undertaken upon admission. conclusion improvement in documentation of minimum standards for these patients is needed. a multidisciplinary care pathway could improve outcome. consideration should be given to whether early ultrasound investigation is appropriate and there is a further need for investigation as to whether this would improve longer term outcomes. introduction bipap utilization for the treatment of severe refractory status asthmaticus patients has become an accepted therapy but is not well described for moderate exacerbations. we sought to analyze outcomes from our bipap quality database for children presenting in status asthmaticus at varying levels of severity. methods ped status asthmaticus patients requiring bipap from 1 january 2010 to 31 august 2012 had a bedside interview and documentation of information at the time therapies were given. incomplete data were collected retrospectively. all data were stored and analyzed using a redcap database. subjects were stratifi ed into severity groups based on asthma score at the time of bipap placement. results there were 206 subjects in the moderate severity group and 197 in the severe group. table 1 shows the groups were well matched and compares other pertinent data. children with severe presentations were placed on bipap sooner (p <0.001) and remained on bipap longer (p <0.001). the moderate group had a longer wait until bipap placement. tables 2 and 3 demonstrate higher initial bipap (ipap/epap) settings with increasing age and severity. figure 1 trends initiation and termination asthma scores stratifi ed by severity at bipap we present a case series of toxicity due to a novel substance in the uk: eric-3. novel drugs of abuse are becoming more common throughout the world, and they represent particular diffi culties in their acute management. a recent report from the european monitoring centre for drugs and drug addiction and europol has reported 49 new psychoactive substances reported via its early warning system. methods this was a retrospective case-note review over a 6-month period. patients were included if their presentation was due to recent ingestion of eric-3. physiological data, symptoms, outcome and destination of the patient from the emergency department were collected. postmortem toxicological analysis was obtained for one of the two patients who died. results forty-one attendances were identifi ed from 18 patients. two patients died and fi ve were admitted to the icu. heart rate and temperature on arrival tended to be above normal (mean heart rate was 112 bpm, with an sd of 18; mean temperature was 37.45°c with an sd of 0.95). in total, 63.4% of attendances included agitation and 34.1% choreiform movements. α-methyltryptamine and 3-/4-fl uoroephedrine were found in the blood of one of the patients who died. conclusion in this outbreak in the uk, eric-3 gave symptoms similar to other stimulants known as legal highs, including death. it may have been a novel substance, 3-/4-fl uoroephedrine. this underlines the need for prospective data collection and early national and international information sharing. introduction thallium is an odorless, tasteless, heavy metal that has been often used for intentional poisonings. in severe patients, thallium poisoning produces neuromuscular symptoms such as extreme pain and muscle weakness. methods five case reports. results all patients worked at a pharmaceutical factory. they joined a tea party held at their workplace at the end of april 2011. the fi ve patients drank tea from a teapot someone had put thallium in. a few days later, they complained of femoral numbness and pain caused by pressure. about a week later, three of fi ve patients had profound hair loss. three weeks after the party, they came to our er. we thought that their symptoms might be caused by some chemicals. we searched the keywords: 'lower extremity pain' , 'hair loss' and 'poison' in the internet. as a result, thallium, mercury, lead, and so forth, were suspicious metals. in those metals, thallium was most likely because it was used in their factory. we immediately examined the blood concentration of several metals and ordered iron(iii)hexacyanoferrate(ii) that is known as the antidote for thallium poisoning. only thallium was positive in the blood metal concentration test. three patients consented to oral administration of an antidote. two patients rejected administration because their symptoms were mild and getting better. all symptoms of all patients gradually disappeared by august. we also followed up the course of blood concentration of thallium. the concentration in three patients who took the antidote was reduced more rapidly than the two patients who did not take it. conclusion all patients recovered without any sequelae. three patients' hair started to grow 3 months from ingestion of thallium, and after half a year their hair was restored to their former state. we had diffi culty ordering iron(iii)hexacyanoferrate(ii) because this is also known as an antidote for cesium. on 11 march 2011 a megathrust earthquake and tsunami hit japan and the giant tsunami gave rise to an accident at a nuclear power generation plant. because the rumor of radioactive substances including cesium might be spread was the talk in the city near the nuclear power plant, the authorities put the antidote under heavy supervision. we could also collect the data for the course of thallium concentration. thallium concentration of the patients who had an antidote was reduced more rapidly but these patients had a loose stool, thought to be a side eff ect of this antidote. reference 17.5 ± sd 3.0 9.5 ± sd 1.8 drugs aff ects the central nervous and cardiovascular systems, resulting in severe arrhythmia and death. heart rate variability (hrv) analysis is a non-invasive assessment method that allows evaluation of the cardiac autonomic (sympathetic and parasympathetic) activity. the aim of this study was to evaluate hrv in children requiring icu stay due to tca poisoning. methods twenty children with isolated tca poisoning aged between 3 and 16 years who were hospitalized in the pediatric icu, between march 2009 and july 2010, and 20 healthy children as a control group were enrolled. clinical and electrocardiographic (ecg) fi ndings were noted in the tca poisoning group. in both groups, 24-hour time domain hrv analysis (sdnn, sdann, sdnni, rmsdd, nn50, and pnn50) was performed. we also recorded frequency domain analysis results at the fi rst 5 minutes and the last 5 minutes of the 24-hour record (vlf, nlf, nhf, lf/hf ratio). the average level of tca in the study group was 1,116 ± 635 and tca levels were positively correlated with the duration of qrs interval (p <0.01). in time-domain nonspectral evaluation, sdnn (p <0.001), sdnn (p <0.05), rmsdd (p <0.01), and pnn50 (p <0.01) were found signifi cantly lower in the tca intoxication group compared with the control group, while nn50 (p <0.01) was signifi cantly higher in value. the spectral analysis (frequency domain) of data recorded at fi rst 5 minutes after intensive care admission showed that the values of the nlf (p <0.05) and lf/hf ratio (p = 0.001) were signifi cantly higher in the tca intoxication group than the controls, while nhf (p = 0.001) values were signifi cantly lower. the frequency domain spectral analysis of data recorded at the last 5 minutes showed a lower nhf (p = 0.001) in the tca intoxication group than the controls, and the lf/hf ratio was signifi cantly higher (p <0.05) in the intoxication group. sdnn (p <0.001), rmsdd (p <0.01), sdnni (p <0.01), and pnn50 (p <0.01) levels were higher in patients with positive ecg fi ndings than those without positive ecg fi ndings. the lf/hf ratio was higher in seven children with seizures (p <0.001). conclusion existing fi ndings give us an idea about hrv's value to determine arrhythmia and predict convulsion risk in tca poisonings. hrv can be used as a non-invasive method in determining the treatment and prognosis of tca poisoning. results hmmd receives an average of 30 cases of stroke monthly, and thrombolysis did not occur before the implementation of the tm project, because of the lack of neurologists available to conduce the cases. after implementation of the tm program, six cases of ischemic stroke were thrombolyzed with alteplase; only one case (16%) progressed to death from septic shock, and one case (16%) presented symptomatic intracranial hemorrhage. conclusion thrombolysis in ischemic stroke reduces 30% the risk of disability and 18% the mortality rate. this procedure has been only feasible to be done in the community setting because of the implementation of the tm project, which permits the presence of a real time consultation with a specialized neurological team from a tertiary center. analyses, and then returned home. in total, 25.50% of patients were hospitalized in a medical or surgical department, and 12.42% in the short-term hospitalised unit of the emergency department (stay duration <24 hours). some 5.10% of patients worsened and were oriented in the icu. a total 3.77% of patients in a cardiac icu. in total, 73.84% of patients had stay duration less than 6 hours in the ed, 24.45% <24 hours. forty percent of patients supported by fi remen and 54% supported by private ambulance left the hospital after a single medical consultation. conclusion nearly 70% of patients calling the french emergency medical dispatching centre are sent to hospital. those transportations are supported for two-thirds of cases by a private ambulance or fi remen ambulance. one out of two patients only receive a simple medical consultation in the ed, and go back home. this may concur to the defi ciency of using general medicine in town. they prefer using emergency services for free. only one patient out of four was hospitalized more than 24 hours. introduction early onset eff ective care in the emergency department (ed) has been reported to have a great infl uence on the intensive care patients' morbidity and mortality [1] . little is known about the infl uence of the reorganisation of the ed on patient intake to the icus. the aim of this study was to analyse monthly intake of patients from the ed to the cardiac care unit (ccu) and icu before and after the reform of emergency services. methods in kanta-häme central hospital, a new ed started on 1 april 2007. four older emergency rooms were combined into one bigger emergency department and an observation ward was introduced with continuous follow-up of vital signs. this study is a retrospective analysis of the patient intake to the ccu and icu 1 year before and after the reorganisation. using as data the finnish intensive care quality consortium (intensium, finland) database and the cardiac database of the hospital, patient transfer from ed to the icu and ccu was collected and analysed. monthly pre/post comparisons were carried out statistically by a nonparametric wilcoxon signed-rank test. the total decrease in monthly patient infl ow from ed to the icu and ccu was 30.1% (p = 0.003); that is, from the mean of 47.7 ± 8.2 to 33.3 ± 8.3 patients (figure 1) <0.001) . the result is longer overall hospitalization of patients having wi (p < 0.001) and a higher number of surgeries (p <0.02). after the er, 54% of patients with wi were hospitalized in the icu (86% of them after surgery) but only 26% of patients involved in a ca (71% after surgery). as many patients with wi as involved in a ca (40%) were admitted to the ward (89% of patients with wi after surgery but only 63% of patients with injuries due to a ca). thirty-three per cent of patients involved in a ca returned home and one was transferred, whereas only three patients with wi returned home after being in the er, three patients were transferred and one died in the operating room. observed paediatric mortality in our medical treatment facility was 2.9% (10 children out of 341): three children died of wi, three due to a ca and one of septic shock due to a medical cause. conclusion war injuries are more prone to cause polytrauma than ca. according to the pts, iss, niss, triss and ascot, children experiencing wi have higher severity scores and predicted mortality rate than others, stay longer in the hospital and have more surgeries. our research indicated that disaster medicine should be established systematically or it is necessary to compile a compendium of disaster medicine from a broad perspective or from a bird's-eye and long-term view. the japanese version was tentatively completed with 22 volumes as of the fi nancial year 2005, of which nearly three-quarters are written in japanese. although this worked partly during the aboveshown catastrophe in japan 2011, several problems are left to be solved; that is, the insuffi cient operation system of the japan dmat or disaster medical assistant team that seemed to have caused a large number of preventable deaths. conclusion the large number of casualties during a major disaster is a global problem, even in the developed countries. when the role of the intensivist is reviewed, many roles were verifi ed to be important; that is, as a leader of a medical team or triage offi cer as well as a professional in the fi eld of specifi c intensive care. however, there are many problems to be solved in the fi elds of disaster medicine. in order to solve the diversifi cation or the various medical problems, it is necessary to compile or systematize a disaster medicine of the world version. the concept of the compendium and our process of trial are shown in relation to intensive care. there are distinct diff erences in the pathophysiology between medical cardiac arrests and tca. traumatic pathologies associated with an improved chance of successful resuscitation include hypoxia, tension pneumothorax and cardiac tamponade [1] . the authors believe a separate algorithm is required for the management of out-of-hospital tca attended to by a highly trained physician and paramedic team. methods a suggested algorithm for tca was developed based on the greater sydney area helicopter emergency medical service's standard operating procedures and current available evidence. results an algorithm for the general management of tca can be seen in figure 1 . in tca, priority should be given to catastrophic haemorrhage control (tourniquets, direct pressure, haemostatic agents, pelvic and long bone splintage) and volume resuscitation. simultaneous oxygena tion optimisation should occur with proactive exclusion of tension pneumothoraces with bilateral open thoracostomies. cardiac ultrasound (us) should be used to help exclude cardiac tamponade and assist in prognostication. the us presence of true cardiac standstill versus low pressure state/pseudo-pea, and an etco 2 <1.3 kpa carries a grave prognosis in tca. given the high incidence of hypovolaemia, hypoxia and obstructive shock prior to tca, the role of adrenaline and chest compressions are limited. figure 2 shows a suggested algorithm for the management of penetrating tca requiring prehospital thoracotomy. conclusion the suggested algorithm is designed for a highly trained physician-led prehospital team and aims to maximise the number of neurologically intact survivors in out-of-hospital tca. little is known about the benefi t of physician winching in addition to a highly trained paramedic. we analysed the mission profi les and interventions performed during rescues involving the winching of a physician in the greater sydney area hems (gsa-hems). methods all winch missions involving a physician from august 2009 to january 2012 were identifi ed from the prospectively completed gsa-hems electronic database. a structured case-sheet review for a predetermined list of demographic data and physician-only interventions (poi) was conducted. we identified 130 missions involving the winching of a physician, of which 120 case sheets were available for analysis. the majority of patients were traumatically injured (90%) and male (85%) with a median age of 37 years. seven patients were pronounced life extinct on the scene. a total of 63 poi were performed on 48 patients. administration of advanced analgesia was the most common poi making up 68.3% of interventions. patients with abnormal rtsc 2 scores were more likely to receive a poi when compared with those with normal rtsc 2 (p = 0.03). the performance of poi had no effect on median scene times (45 vs. 43 minutes; p = 0.51). see tables 1 and 2 . conclusion our high poi rate of 40% coupled with long rescue times and the occasional severe injuries supports the argument for winching doctors. not doing so would deny a signifi cant proportion of patients time-critical interventions, advanced analgesia and procedural sedation. the aim was to assess the content and state of repair of equipment carried for transfer of critical care patients to other hospitals. by chance, several items of date-expired stock were identifi ed in the transfer kit whilst moving a patient to a tertiary centre. this raised the possibility of a more extensive problem with the equipment bags. due to the geographical location of our district general hospital we undertake around 70 transfers of critical care patients to other hospitals per year (16% by air) and it is clearly important that our equipment is well maintained for these journeys. methods we maintain two identical sets of equipment (syringes, fl uid, airway management items, and so forth) and drug bags to take on transfers; one equipment and one drug bag taken on each trip. the contents of all four bags were checked and itemised. by careful consideration of the aims of the bags (to provide emergency equipment and drugs for managing one patient during an en-route emergency) a new inventory was devised. excess items were removed to lighten the bags and improve accessibility to the essential items. expired stock was removed. a daily checking procedure and tamper-proof seals on the bags were instigated and the bags were reassessed 12 months later. results a total of 13.9% of drug items and 29.2% of equipment items had expired or would do so within 30 days of the initial assessment. the combined weight of one equipment and one drug bag was reduced from 14 to 9 kg (36% reduction) by introducing the new inventory. at reassessment in november 2012, only 10 items of equipment (3.2%) were expired or near to expiry and there were no expired drug items (4.1% near to expiry). in total, 0.3 kg (26 small items) of extraneous equipment had been added through over-restocking and was removed. conclusion these bags are designed for a clinician to manage a patient when an emergency arises during transfer of a critical care patient. by the introduction of simple measures, the risks posed by expired items or cluttered equipment bags have almost been eradicated. signifi cant weight savings have been made; this off ers improved ergonomics for staff and is also an important consideration for aeromedical operations. our department was surprised to discover the extent of decline of our equipment and it may be that other departments would fi nd themselves in a similar position. the anaesthetic registrars who routinely escort the transfer patients have a vested interest to maintain this equipment and this has secured their buy-in to the new checking procedure with clear results. conclusion prehospital hyperoxemia did not infl uence the functional neurological outcome. one of the reasons for this fi nding could be the short arrival time to the trauma center where repeated analyses of arterial blood gases were performed. therefore, correction of fraction of inspired oxygen according to the arterial blood gas analysis shortens the time of hyperoxemia, thus reducing neuronal brain damage. introduction severe burn patients are often noted to have subsequent neurocognitive problems. experimentally, we have found striking, prolonged elevations of infl ammatory markers in the brain (for example, il-6) even when the injury occurs in a remote anatomic location. this neuroinfl ammatory response can also be signifi cantly blunted by a single post-burn dose of estrogen. sonic hedgehog (shh), an important signaling protein found in the brain, controls and directs diff erentiation of neural stem cells, infl uencing brain regeneration and repair by generating new neurons throughout life. as estrogens not only blunt infl ammation but also exert an infl uence on a variety of stem cells, we hypothesized that 17β-estradiol (e2) might aff ect levels of shh in the post-burn rat brain. methods male rats (n = 44) were assigned randomly into three groups: controls/no burn (n = 4); burn/placebo (n = 20); and burn/e2 (n = 20). burned rats received a 40% 3° tbsa dorsal burn, fl uid resuscitation and one dose of e2 or placebo (0.5 mg/kg intraperitoneally) 15 minutes post burn. eight animals from each of the two burn groups (burn/placebo and burn/e2) were sacrifi ced at 24 hours and at 7 days, respectively (sham group at 7 days only), with four each of the two burn groups sacrifi ced at 45 days. brain tissue samples were analyzed by elisa for shh. results mean levels of shh levels were signifi cantly elevated within 24 hours as much as 45 days post injury in burned animals receiving the 17β-estradiol (>1,200 pcg/mg) as compared with the placebotreated burned animals (<700 pg/mg) and controls (<300 pcg/mg). see figure 1 . conclusion early, single-dose estrogen administration following severe burn injury signifi cantly elevated levels of shh in brain tissue. this fi nding may represent an extremely novel and important pathway for both neuroprotection and neuroregeneration in burn patients. introduction many proposed resuscitative therapies for cardiac arrest and trauma will require the earliest possible intervention and would occur under volatile circumstances, making true informed consent for clinical trials unfeasible. the purpose here was to report our experience using exception to informed consent during the inaugural pilot study of infusing estrogen for acute injury, the so-called rescue shock study. methods fifty patients were enrolled in rescue shock in which estrogen or placebo was infused as soon as possible in the emergency department for trauma patients with a low systolic blood pressure (<90 mmhg) at two level i trauma centers. they were all treated with a single-dose estrogen or placebo infusion within 2 hours using exception from informed consent following us federal guidelines. results investigator-initiated exception from informed consent studies is feasible, with our fda ind approval obtained in 31 days, irb 1 approval in 25 days, and irb 2 approval in 24 days. community consultation/notifi cation was successfully accomplished with no one opting out and 47/50 enrolled patients or their legal representatives were notifi ed of participation (one died unidentifi ed, two died with no known contact). the average number of days to verbal notifi cation of patients or advocates was 6.55 days (range 0 to 51 days) as the study team began notifi cation only after the patient or family was able to reasonably understand information about the study. no one decided against continued follow-up. overall, patients and their families were very enthusiastic about participation and the data safety monitoring board had no safety concerns after reviewing all study data. conclusion although delayed notice of participation occurs for many justifi able reasons, the use of exception from informed consent for novel, time-sensitive resuscitation studies is not only crucial, but can be feasible, and well accepted by patients, their advocates and communities at large. introduction patients with severe burn injury experience a rapid elevation in multiple circulating proinfl ammatory cytokines, with the levels correlating with both injury severity and outcome. in animal critical care 2013, volume 17 suppl 2 http://ccforum.com/supplements/17/s2 s109 models, accumulations of these cytokines have been observed in remote organs, including the heart, brain and lungs. however, data are lacking regarding the long-term levels of cytokines in the heart following severe burn injury and also how infusion of parenteral estrogen, a powerful anti-infl ammatory agent, would aff ect these levels. using a rat model, we studied the eff ects of a full-thickness thirddegree burn on cardiac levels of il-6 and tnfα over 45 days with and without 17β-estradiol infusion. methods a total of 168 male rats were assigned randomly to one of three groups: (1) conclusion following severe burn injury in an animal model, an early single dose of estrogen can decrease the prolonged let alone the early onset of cardiac infl ammation. based on these data, clinical studies of estrogen infusions should be seriously entertained as estrogen may not only be an inexpensive, simple adjunctive therapy in burn management, it may also obviate the need for many subsequent interventions altogether and even diminish mortality. conclusion the results of this study highlight the risk factors for the development of complications following blunt chest trauma. a risk stratifi cation tool has also been developed that could assist in the prediction of poor outcomes in this patient group. the next stage is to complete a prospective validation study. reference introduction we have reported the risk of chest drain insertion inferior to the diaphragm when using current international guidelines [1] . another complication is damage to signifi cant peripheral nerves, such as the long thoracic nerve causing winging of the scapula [2] . we assessed these risks using: the european trauma course method, a patient's handbreadth below their axilla just anterior to the midaxillary line; the british thoracic society safe triangle [3] ; and the advanced trauma life support (atls) course guidance [4] . methods we used the above guidelines to place markers (representing chest drains) in the thoracic wall of 16 cadavers bilaterally (32 sides), 1 cm anterior to the midaxillary line. subsequent dissection identifi ed the course and termination of the long thoracic nerve, the site of lateral cutaneous branches of intercostal nerves, and their relation to the markers. the long thoracic nerve was found in the fi fth intercostal space in 16 of 32 cases, always in or posterior to the midaxillary line. contrary to the description in grays' anatomy (40th edition) it terminated before the inferior border of serratus anterior. most commonly it was found to end by branching in the fourth (right) or fi fth (left) intercostal space (range third to sixth). lateral cutaneous branches of intercostal nerves were found in the fi fth intercostal space in 25 of 32 cases. contrary to the description in last's anatomy (12th edition) they always passed anterior to the midaxillary line (and marker). conclusion placement 1 cm anterior to the midaxillary line minimises risk to the long thoracic nerve and lateral cutaneous branches of intercostal nerves. we therefore conclude that not all areas of the british thoracic society safe triangle are indeed safe, and anteroposterior placement should follow the european trauma course and atls guidelines: just anterior to the midaxillary line (for example, 1 cm). introduction whole body computed tomography (wbct) appears to be useful for the early detection of clinically occult injury, although its indications have been controversial. the purpose of this study was to develop a clinical prediction score to clarify the indications for blunt trauma patients with multiple injuries (mi) who require wbct. methods we conducted a retrospective study of 173 patients with blunt trauma who underwent wbct at our emergency center between june 2011 and july 2012. we chose the presence or absence of mi (injury severity score ≥15) in need of surgical intervention as the outcome variable. we used bivariate analyses to identify variables potentially predicting the presentation of mi. the predictor variables were confi rmed by multivariate logistic regression analyses. we assigned a score based on the corresponding coeffi cients. results among the 173 patients enrolled, 53 were in the mi group. four predictors were found to be independently signifi cant by the logistic analysis: (1) body surface wound ≥3 regions, (2) positive focused assessment with sonography for trauma, (3) white blood cell count ≥11,000/μl, and (4) d-dimer ≥8 μg/ml. score 1 was assigned to predictor (1), score 2 was assigned to predictors (2), (3) and (4). a prediction score was calculated for each patient by adding these scores. the area under the receiver operating characteristic curve was 0.89. no patients with a score of 1 or less had mi (figures 1 and 2) . conclusion in patients with a score of 1 or 0, the presence of mi is less likely. these patients may not require wbct, and selective ct scans of body parts based on clinical presentation should be considered. (figure 1) . the most common intervention as a result of the ultrasound was initiation of a pressor infusion (33.3%), of which 71.4% were ionotropes. additional therapies included blood transfusion (4.8%), heparin (9.5%), tpa (4.8%), cardiac catheterization (4.8%), and surgery (9.5%). rosc was achieved in 37.5% of patients; average time to rosc was 13 minutes. a total 33.3% of patients who underwent als were alive at hospital discharge and 28.6% at 1 year. conclusion focused cardiac ultrasound is a feasible adjunct to als resuscitation and may assist in the early identifi cation of reversible causes of cardiac arrest. care must be taken to ensure no interruptions to cardiac compressions are made by performance during pulse checks. further studies are needed to examine the outcomes associated with its integration into resuscitations. introduction in this case report, we describe a patient who presented with a cardiac arrest as a result of an obstructive shock, which progressed into cardiac arrest, caused by an acute para-esophageal gastric herniation. methods our patient, with a medical history of a laparoscopic repair of a symptomatic diaphragmatic hernia 6 months prior, presented herself at the emergency department with pain in the upper abdomen and nausea. the physical examination, laboratory tests and x-ray of the thorax were normal and she was sent home. twenty-four hours later paramedics were summoned to our patient because of increased complaints. on arrival of the paramedics she had a normal electrocardiogram (ecg) and during the transfer from her bed to the stretcher she collapsed due to pulseless electric activity (pea), for which cardiopulmonary resuscitation was started. sinus rhythm and output was regained after several minutes and the patient was transported to the hospital. at arrival in the hospital, the x-ray of the thorax showed an intrathoracic stomach and a signifi cant mediastinal shift to the right. results after emergency laparotomy, which concerned correcting the gastric herniation and resection of an ischemic part of stomach, the patient remained hemodynamically stable. cardiac ischemia was ruled out based on ecg, laboratory fi ndings, cardiac ultrasound and cardiac computed tomography. the ultrasound in the emergency department did show a distended right ventricle and normal left function, which disappeared later (after repositioning the stomach), which is evidence for the mediastinal shift as a cause for the pea. conclusion we are the fi rst to describe a patient requiring cardiopulmonary resuscitation for progressive obstructive shock, due to an intrathoracic stomach. especially after a laparoscopic repair of a diaphragmatic hernia, this is a rare cause for shock and cardiac arrest, which requires a diff erent medical approach. is a key factor in improving survival from out-of-hospital cardiac arrest (ooh-ca). the alert algorithm, a simple and eff ective compression-only telephone cpr protocol, has the potential to help bystanders initiate cpr. this study evaluates the eff ectiveness of the implementation of this protocol in the liege dispatching centre. methods we designed a before-and-after study based on a 3-month retrospective assessment of the adult victims of ooh-ca in 2009, before the implementation of the alert protocol in the liege dispatching centre, and the prospective evaluation of the same 3-month period in 2011, immediately after the implementation of this protocol. data were extracted from ambulance, paramedical and medical intervention teams fi les, as well as the audio recordings of the dispatching centre. conclusion in ohca patients with unshockable initial rhythm, prehospital epinephrine administration signifi cantly increased the rate of survival at 1 month after cardiac arrest. the best single predictor for favorable neurological outcomes at 1 month following prehospital epinephrine administration after cardiac arrest was age (<66 years) followed by total dose of epinephrine (1 mg) and then by call-response time (<5 minutes). [3] . methods this was a single-center retrospective cohort study of patients who suff ered ohca and were transported to our hospital between april 2009 and march 2011. we investigated the patients' characteristics, whether they met the tor criteria, and their outcome at the time of hospital discharge. results a total of 195 patients (mean age, 69 years), 67% of whom were male, were transported to our hospital after suff ering ohca. cardiopulmonary arrest was witnessed in 52 cases (27%). the 2010 aha guidelines for cpr and ecc regarding the criteria for tor were applied in 126 cases (65%), of whom 113 (90%) were dead on arrival, and 13 were successfully resuscitated and admitted. the outcomes for these 13 patients were as follows: 10 died in the hospital, two patients were discharged with a glasgow pittsburgh cerebral performance category (cpc) score of 1, and one patient was transferred to another hospital with a cpc score of 3. conclusion in our study, 65% of the patients who were transported to the hospital after ohca met the criteria for tor. outcomes for patients who met the tor criteria were signifi cantly worse than those who did not meet the criteria (2.4% vs. 14.5%, p <0.005). in japan, eff orts are made to resuscitate almost all individuals who suff er ohca, but 75% of those patients die within a day. in light of the fact that even the medical cost for each of these patients who die within a day amounts to us$1,500 [4] , the introduction of tor will have a particularly strong impact in japan. introduction detection and treatment of cardiopulmonary arrest and their antecedents may be less eff ective at night and weekend than weekdays because of hospital staffi ng and response factors [1] . early detection and resuscitation of cardiopulmonary arrest are crucial for better clinical outcome. we conducted our study to evaluate event survival of in-hospital cardiopulmonary arrest after regular working hours in nonmonitored areas of a tertiary-care center. = 17) , hypoxia (n = 10), cardiac other (n = 5), sepsis (n = 4), arrhythmia (n = 3) and pe (n = 3). in two ihca patients more than one likely cause of arrest was reported and in 19 cases no cause was identifi ed. the presenting rhythm was ventricular fi brillation (vf) in 45.3% (n = 29), pulseless electrical activity in 32.8% (n = 21) and asystole in 20.3% (n = 13). a total of 9.4% (n = 6) were thrombolysed and one (1.6%) patient was referred for emergency pci. conclusion as previously reported [2] , ihca was associated with a worse prognosis than ohca. the ohca survival rate was better than reported elsewhere [3] . the percentage of ihca attributed to mi was low. only one ohca patient was referred for emergency pci. routine coronary angiography with ad hoc pci in vf ohca has been associated with increased survival [4] . greater availability of pci post ohca could further improve mortality in patients with a primary cardiac pathology. further investigation should include management of noncardiogenic cardiac arrest. introduction mild therapeutic hypothermia (mth) is the most powerful therapy to improve survival and neurologic outcome after out-ofhospital cardiac arrest. such benefi t may also occur for unconscious patients after in-hospital cardiac arrest. the aim is to compare 1-year evolution of neurological outcomes of patients treated with mth after in-hospital versus out-of-hospital cardiac arrest. methods a prospective study of patients treated with mth after cardiac arrest in a community hospital in são paulo, brazil. after return of spontaneous circulation, unconscious survivors received mth using topical ice and cold saline infusions in order to achieve a 32 to 34°c goal temperature, within 6 hours of cardiac arrest, and maintained in the management of out-of-hospital cardiac arrest (ohca) is not clear cut [1] . it has historically been used in patients with st elevation on post-resuscitation electrocardiogram (ecg) although this is a poor predictor of acute coronary occlusion after cardiac arrest [2] . this study investigates the benefi t of pci regardless of post-resuscitation ecg. benefi t is widely claimed for therapeutic hypothermia, so cooling parameters were included. methods we analysed all 41 consecutive adults admitted post ohca to a university hospital icu between january 2010 and december 2011. patients received pci regardless of ecg changes. a cox proportional hazards model was used to determine the relationship between pci, cooling and survival to discharge. routinely collected data such as demographics and details of resuscitation (ohca utstein data) were also included. results survival to hospital discharge was 41% with 29% of survivors discharged to a neurological rehabilitation centre. multivariate analysis using a cox proportional hazards model showed pci to be an independent predictive factor of survival, unrelated to ecg (hazards ratio, 0.0583; 95% ci, 0.0076 to 0.4485). cooling had no signifi cant impact on patient survival. see figure 1 . conclusion in this small retrospective study primary pci appears to be an independent predictor of survival after ohca. this is consistent with other studies suggesting benefi t for primary pci regardless of the post-resuscitation ecg [3] . cooling was not found to improve survival to discharge but further analysis is required to determine impact on neurological function. introduction sedation and therapeutic hypothermia (th) modify neurological examination and alter prognostic prediction of coma after cardiac arrest (ca). additional tools, such as eeg and evoked potentials, improve prediction of outcome in this setting, but are not widely available and require signifi cant implementation. methods using a new device for infrared pupillometry, we examined the value of quantitative pupillary light reactivity (plr) to predict outcome in comatose post-ca patients treated with th. twenty-four comatose ca patients treated with th (33°c, 24 hours) were prospectively studied. the percentage variation in plr was measured during th (12 hours from ca), using the neurolight algiscan® (idmed, marseille, france). for each patient, three consecutive measures were performed and the best value was retained for analysis. the relationship of plr with survival and neurological outcome (cpc scores) at 3 months was analyzed, and the predictive value of plr was compared with that of standard clinical examination (motor response and brainstem refl exes) performed at 48 hours from ca. results quantitative plr was strongly associated with survival (median left-eye plr 14% (11 to 16%) variation in survivors vs. 5.5% (4 to 8.5%) in nonsurvivors, p < 0.0001) and 3-month neurological outcome (14% (11 to 21%) in patients with cpc 1 to 2 vs. 5.5% (4 to 8.5%) in those with cpc 3 to 5, p <0.0001). comparable fi ndings were obtained using right-eye plr. a plr >10% was 100% predictive of patient prognosis, with false-positive and false-negative rates of 0% for outcome. clinical examination was signifi cantly associated with outcome; however, motor response (mr) and brainstem refl exes (brs) yielded higher falsepositive and false-negative rates than plr (table 1) . conclusion quantitative plr appears highly accurate and superior to standard neurological examination to predict outcome in patients with post-ca coma. further study is warranted to confi rm these promising fi ndings. acknowledgements supported by grants from the swiss national science foundation (fn 320030_138191) and the european critical care research network (eccrn). figure 1 . mv was associated with a signifi cant reduction of scto 2 from baseline (75% (73 to 76) to 69% (67.5 to 71.5), p <0.001). no signifi cant changes in scto 2 were found after ih (74 (72 to 76) vs. 75 (73 to 75.5), p = 0.24). conclusion moderate hv was associated with signifi cant reduction in cerebral saturation, whilst ih may be detrimental after ca and th, whilst increasing map to supranormal levels with vasopressors does not improve cerebral oxygenation. these data stress the importance of strict control of paco 2 following ca and th to avoid secondary cerebral ischemic insults. introduction after cardiac arrest, microcirculatory reperfusion dis orders develop despite adequate cerebral perfusion pressure. increased blood viscosity strongly hampers the microcirculation, resulting in plugging of the capillary bed, arteriovenous shunting and diminished tissue perfusion. the aim of the present study was to assess blood viscosity in relation to cerebral blood fl ow in patients after cardiac arrest. methods we performed an observational study in 10 comatose patients after cardiac arrest. patients were treated with hypothermia for 24 hours. blood viscosity was measured ex vivo using a contraves ls300 viscometer. mean fl ow velocity in the middle cerebral artery (mfvmca) was measured by transcranial doppler (tcd) at the same time points. <0.001) . there was a signifi cant association between viscosity and the mfvmca (p = 0.0019). see figure 1 . conclusion viscosity decreases in the fi rst 3 days after cardiac arrest and is strongly associated with an increase in cerebral blood fl ow. since viscosity is a major determinant of cerebral blood fl ow, repeated measurements may guide therapy to help restore cerebral oxygenation after cardiac arrest. in preliminary data, we report that sr >75 might correlate with bad outcome and that combining nse and sr might improve the predictive value. also, low nse and good initial bis values correlate with preserved cerebral potential and should encourage the clinician. introduction accurate prediction of neurological outcome after cardiac arrest is desirable to prevent inappropriate withdrawal of lifesustaining therapy in patients who could have a good neurological outcome, and to limit active treatment in patients whose ultimate neurological outcomes are poor. established guidelines to predict neurological outcome after cardiac arrest were developed before the widespread use of therapeutic hypothermia. the american association of neurology guidelines [1] currently recommend that absent or extensor motor scores on day 3 post arrest are reliable indicators or poor neurological outcome with a false positive rate of 0 to 3%. methods a review of existing literature was undertaken to examine whether the utility of motor scores to predict poor neurological outcome is infl uenced by the use of therapeutic hypothermia. results six studies were identifi ed [2] [3] [4] [5] [6] [7] that investigated the use of motor scores on day 3 post cardiac arrest in patients who had received therapeutic hypothermia. false positive rates (defi ned as 1 -specifi city) for predicting poor neurological outcome were calculable in fi ve of the six studies [2] [3] [4] [5] [6] and were 14%, 24%, 11%, 25% and 12% respectively. in all studies the fpr for motor scores of extension or worse were signifi cantly higher than the 0% (0 to 3% 95% cis) in the aan guidelines. conclusion motor scores at day 3 post cardiac arrest of extension or worse do not reliably predict poor neurological outcome when therapeutic hypothermia has been used. clinical neurological fi ndings may not be valid predictors of poor neurological outcome after therapeutic hypothermia. introduction it has been reported that the young are much more resistant to transient cerebral ischemia than the adult. methods in the present study, we compared the chronological changes of calcium binding proteins (cbps) (calbindin 28k (cb-d 28k), calretinin (cr) and parvalbumin (pv)) immunoreactivities and levels in the hippocampal ca1 region of the young gerbil with those in the adult following 5 minutes of transient cerebral ischemia induced by the occlusion of both the common carotid arteries. in the present study, we examined that about 90% of ca1 pyramidal cells in the adult gerbil hippocampus died at 4 days post ischemia; however, in the young hippocampus, about 56% of them died at 7 days post ischemia. we compared immunoreactivities and levels of cbps, such as cb-d 28k, cr and pv. the immunoreactivities and protein levels of all the cbps in the young sham were higher than those in the adult sham. in the adult, the immunoreactivities and protein levels of all the cbps were markedly decreased at 4 days post ischemia; however, in the young, they were apparently maintained. at 7 days post ischemia, they were decreased in the young; however, they were much higher than those in the adult. conclusion in brief, the immunoreactivities and levels of cbps were not decreased in the ischemic ca1 region of the young 4 days after transient cerebral ischemia. this fi nding indicates that the longer maintenance of cbps may contribute to a less and more delayed neuronal death/ damage in the young. delay in reaching target temperature [1] . we hypothesize that early and rapid induction of hypothermia will mitigate neuronal injury and improve survival in a swine model of tbi. methods twenty domestic cross-bred pigs (34 to 35 kg) were subjected to a 5 atm (100 ms) lateral fl uid percussion tbi. the brain temperature and icp were measured using camino®. serum biomarkers for neuronal injury -s-100β, neuron-specifi c enolase, glial fi brillary acid protein (gfap), and neurofi laments heavy chain -were measured daily using enzyme-linked immunosorbent assay. twelve of the injured animals were rapidly cooled to 32°c within 90 minutes of the injury using a transpulmonary hypothermia technique [2] . hypothermia was maintained for 48 hours. eight injured control animals were maintained at 37°c. in both groups, anesthesia (isofl urane 1%) was discontinued and the animals were weaned off the ventilator after 48 hours. five days post injury, the surviving animals were euthanized and necropsied. the data were analyzed using a log-rank (mantel-cox) test, and anova. results ten of the 12 hypothermia and four of the eight normothermia animals survived to the end of the 5-day study (χ 2 = 2.597, df = 1, p = 0.1071). although the probability of type i error between survival curves was 11%, the study was clinically signifi cant and showed a clear trend toward improved survival with hypothermia. the intracranial pressures were signifi cantly (p <0.05) lower in the hypothermia group. both interventions -that is, general anesthesia and hypothermiamitigated the rise of serum biomarkers following tbi. however, the suppression of biomarkers was sustained during the recovery period only in the hypothermia group. with the exception of the gfap levels, the curves of all biomarkers were signifi cantly diff erent between the groups. conclusion our preliminary fi ndings show early initiation, rapid induction, and prolonged maintenance (48 hours) of cerebral hypothermia to lower intracranial pressure, blunt the rise in serum biomarkers, and improve survival following tbi. references introduction traumatic brain injury (tbi) is a contributing factor to approximately one-third of all injury-related deaths in the usa annually. updated statistical records for tbi in egypt are lacking. the current research is aiming to estimate the prevalence of tbi in egypt in order to develop a comprehensive tbi prevention program. methods a 1-year period (one calendar month every quarter of 2010) descriptive epidemiological study of moderate and severe tbi cases admitted to the emergency department, cairo main university hospital. the data collection sheet included personal data (age, sex and residency), incident-related data (cause, nature and time of injury) and both clinical and radiological fi ndings. introduction one of the most used prognostic models for traumatic brain injury is the impact-tbi model, which predicts 6-month mortality and unfavorable outcome. our aim was to study whether adding markers of coagulation improves the model's predictive power when accounting for extracranial injury. methods patients with a tbi admitted to a designated trauma center in 2009/10 were screened retrospectively and included according to the impact study criteria. the predictive outcome was calculated for included patients using the full impact-tbi model. to assess coagulopathy and extracranial injury we used the prothrombin time percentage (pt), platelet count (10 9 ), and injury severity score (iss introduction evidence suggest that endogenous lactate, produced by aerobic glycolysis, is an important substrate for neurons, particularly in conditions of increased energy demand. this study aimed to examine brain lactate metabolism in patients with severe traumatic brain injury (stbi). methods a prospective cohort of stbi patients monitored with cerebral microdialysis (cmd) and brain tissue oxygen (pbto 2 ) was studied. brain lactate metabolism was assessed by quantifi cation of elevated cmd lactate samples (>4 mmol/l). these were matched to pyruvate and pbto 2 , and dichotomized as hyperglycolytic (cmd pyruvate >119 μmol/l) versus nonhyperglycolytic or as hypoxic (pbto 2 <20 mmhg) versus nonhypoxic. data were expressed as percentages per patient. global brain perfusion (categorized as oligemic, normal or hyperemic) was assessed with ct perfusion (ctp). results twenty-four patients (total 1,782 cmd samples) were studied. samples with elevated cmd lactate were frequently observed (41 ± 8% sem of individual samples). brain lactate elevations were predominantly hyperglycolytic (73 ± 8.2%), whilst only 14 ± 6.3% of them were hypoxic. trends over time of both lactate patterns are shown in figure 1 . on ctp (n = 17; average 48 hours from tbi) hyperglycolytic lactate was always associated with normal or hyperemic ctp, whilst hypoxic lactate was associated with oligemic ctp (table 1) . our fi ndings suggest predominant nonischemic lactate release after tbi and identify, for the fi rst time, an association between cerebral hyperglycolytic lactate production and normal to supranormal brain perfusion. our data support the concept that lactate may be used as energy substrate by the injured human brain. in the prehospital setting, it is diffi cult to use the glasgow coma scale (gcs) to evaluate the consciousness state using in pediatric patients with severe trauma. the japan coma scale (jcs) is a consciousness scale used widely in japan and, with its four grades, is simpler and quicker to use than the gcs. this study examined whether our study identifi ed a moderate relation between peep and osnd and a weaker one between ppeak, pm and osnd. thus, in selected cases osnd could serve as a bedside marker of eff ect of airway pressure to icp. yet, larger studies are needed to come to a safer conclusion. reference introduction following primary neurological insult, initial manage ment of traumatic brain-injured (tbi) patients has a clearly defi ned pathway [1] . however, after arrival at tertiary centers, further manage ment is not standardized. intracranial hypertension (ich), systemic hypotension, hypoxia, hyperpyrexia and hypocapnia have all been shown to independently increase mortality [2] . despite numerous studies, there is currently no level 1 evidence to support any specifi c management [3] . our objective was to provide an overview of the current clinical management protocols in the uk. methods thirty-one icus managing patients with severe tbi were identifi ed from the rain (risk adjustment in neurocritical care) study, and a telephone survey was conducted. results a total 97% of units used a cerebral perfusion pressure protocol for the initial management, with 83% targeting pressures of 60 to 70 mmhg and 17% aimed for >70 mmhg. ninety-one percent of units monitored co 2 routinely with 61% targeting co 2 of 4.5 to 5 kpa (figure 1 ). regarding osmotherapy, mannitol was still the preferred agent, with 48% of units using it as fi rst line; 32% used hypertonic saline, while 20% of units used either depending on clinicians' preference. sixteen percent questioned were currently enrolled on the eurotherm hypothermia trial, while 16% never used hypothermia and one unit used prophylactic hypothermia routinely. the remaining 65% of units used hypothermia only to manage refractory ich. conclusion there is no clear consensus on the initial targets used. the surviving sepsis campaign showed that protocol-led care can reduce mortality [4] . perhaps it is time for a similar approach to be adopted, with specialists coming to together to review the evidence and formulate guidelines that can then be tested. introduction traumatic brain injury (tbi) is a major cause of permanent disability and death in young patients. controversy exists regarding the optimal cerebral perfusion pressure (cpp) required in tbi management. a tool for monitoring autoregulation and determining an optimal cpp is the pressure reactivity index (prx), defi ned as a moving correlation coeffi cient between the mean arterial blood pressure (map) and intracranial pressure (icp) at a frequency of at least 60 hz. this requirement of high frequency has constrained its use to a few academic centers. an association was shown between outcome and continuous optimal cpp based on 4 hours of prx [1] . we present a novel low-frequency autoregulation index (lax), based on correlations between icp and map at a standard minute-by-minute time resolution. methods a total of 182 patients from the brain-it [2] multicentre european database had registered outcome and icp and map for the fi rst 48 icu hours. twenty-one tbi patients admitted to the university hospitals of leuven, belgium and tubingen, germany were continuously monitored using icm+ software (cambridge enterprise) allowing for continuous prx calculation. autoregulation indices versus cpp plots for prx and lax were computed to determine optimal cpp every minute during the fi rst 48 icu hours [1] . results on the brain-it database, lax resulted in an optimal cpp for 90% of the fi rst 48 hours. table 1 shows recommendations with respect to outcome. in the leuven-tübingen database, prx and lax resulted in 44% and 92% recommendations respectively. the average diff erence between methods was 5.26 mmhg. conclusion the diff erences in optimal cpps derived from prx and lax were not clinically signifi cant. lax allowed for recommendations to be computed for longer periods. signifi cantly better outcome (table 1) was observed in patients for whom optimal cpp derived from lax was maintained. introduction pediatric patients with altered mental status (ams) present with poor histories resulting in delayed testing and potential poor outcomes. non-invasive detection for altered cerebral physiology related to tbi would improve resuscitation and outcome. cerebral rso 2 (r c so 2 ) studies demonstrate its utility in certain neurological emergencies. methods a retrospective analysis of r c so 2 utility in ams. rcso 2 data were collected every 30 seconds for ams patients who had a head ct. patients with a negative head ct were compared with those with an abnormal head ct. roc analysis was performed to fi nd the auc for each summary statistic and performance characteristics. subgroup analysis was done to determine whether r c so 2 predicted injury and location. results r c so 2 readings across 5, 15, 20, and 30 minutes were stable (figure 1 ). r c so 2 readings with one or both sides <50% or a wide diff erence between l and r cerebrum was predictive of an abnormal ct scan. a mean diff erence of 4.2 was 82% sensitive for detecting a ct lesion with 62% specifi city, 88% ppv, and 52% npv; a mean diff erence of 12.2 was 100% specifi c for an abnormal head ct. lower mean r c so 2 readings localized to the ct pathology side, and higher r c so 2 readings trend toward the edh group. conclusion cerebral rcso 2 monitoring can non-invasively detect altered cerebral physiology and pathology related to tbi as the cause for pediatric altered mental status. the utility of r c so 2 monitoring has shown its potential for localizing and characterizing intracranial lesions among these altered children. further studies utilizing r c so 2 monitoring as an adjunct tool in pediatric altered mental status evaluation and management are ongoing. introduction fever is a dangerous secondary insult for the injured brain [1] . we investigated the cerebral and hemodynamic eff ects of intravenous (i.v.) paracetamol administration for the control of fever in neurointensive care unit (nicu) patients. methods the i.v. paracetamol (1 g in 15 minutes) was administered to nicu patients with a body temperature (temp.) >37.5°c. its eff ects on mean arterial pressure (map), heart rate (hr), intracranial pressure (icp), cerebral perfusion pressure (cpp), jugular venous oxygen saturation (sjvo 2 ) and temp. were recorded at the start of paracetamol infusion (t0) and after 30 (t30), 60 (t60) and 120 (t120) minutes. interventions for the maintenance of cpp >60 mmhg or icp <20 mmhg were recorded. (figure 1 ). in fi ve cases norepinephrine infusion was started for cpp <60 mmhg. in another two cases, for the same reason, the norepinephrine dosage was augmented. the proportion of patients who had infusion of norepinephrine increased from 42.8% at t0 to 78.6% at t120 (p = 0.02, chi-square for trends). conclusion use of i.v. paracetamol is eff ective in the maintenance of normothermia in acute brain-injured patients. however, adverse hemodynamic eff ects, which could represent a secondary insult for the injured brain, must be rapidly recognized and treated. reference introduction evaluating resource utilization is paramount in critically ill patients with traumatic brain injury (tbi), but little is known on readmissions after hospital discharge. we evaluated rates and determinants of unplanned readmission following tbi. methods we conducted a multicenter retrospective cohort study from april 1998 to march 2009. data were obtained from a canadian provincial trauma system, based on mandatory contribution from 59 trauma centres, and a hospital discharge database. patients aged ≥16 years with tbi (icd-9 or icd-10 codes of 850-854 and s06, respectively) were included. patients who died during the index hospitalization, who lived outside the province, who could not be linked with the hospital discharge database were excluded. we collected baseline and trauma characteristics, hospital admissions in the 12 months preceding index admission, and readmissions in the 12 following months. primary outcome was unplanned readmission 30 days, 3 months and 6 months post discharge. we evaluated sociodemographic and clinical factors associated with readmissions using a logistic regression model. results among 18,342 adult patients with tbi identifi ed in the registry, 14,777 patients were included among which 2,363 had severe, 1,106 moderate and 11,308 mild traumatic brain injury. most patients were young (mean age: 52 ± 23 years) and had no comorbidity (73.6%). overall, 1,032 patients (7.0%) were readmitted within 30 days, 12.7% within 3 months and 17.6% within 6 months. at 30 days post discharge, 311 (30.1%) were readmitted for a complication. the median length of stay was 8 days (q1 to q3: 3 to 20). more than 10% of patients aged ≥75 years with ≥1 comorbidity or with ≥1 admission prior to index hospitalisation were readmitted. the severity of the tbi was not an independent predictor of readmission. age, highest ais, number of comorbidities, number of admissions prior to index hospitalization, level of index trauma center and discharge destination were associated with readmissions on multivariate analysis. conclusion readmissions in the months following tbi are frequent, but were not found to be associated with the tbi severity. further studies evaluating reasons for readmission are warranted in order to develop strategies to prevent such events. introduction pituitary disorders following traumatic brain injury (tbi) are frequent, but their determinants are poorly understood. we performed a systematic review to assess the risk factors of tbiassociated pituitary disorders. methods we searched medline, embase, scopus, the cochrane library, biosis, and trip database, and references of narrative reviews for cohort, cross-sectional and case-control studies enrolling at least fi ve adults with tbi in whom ≥1 pituitary axis was tested and one potential predictor reported. two independent investigators selected citations, extracted data and assessed the risk of bias. we pooled the data from all studies assessing a specifi c predictor, regardless of the pituitary axis being evaluated. when more than one pituitary axis was assessed, we used the data related to hypopituitarism or the data from the most defective axis. when a pituitary axis was evaluated several times, we used assessment farthest from the injury. a meta-analysis was performed using random eff ect models and i 2 was used to evaluate heterogeneity. introduction prevention of secondary neurologic injuries is paramount for improved neurologic outcomes after traumatic brain injury (tbi). evidence suggests that although therapeutic hypothermia (th) lowers intracranial pressure and attenuates secondary cerebral insults after tbi [1] , it also induces hypotension. brief episodes of mild hypotension in brain-injured patients can trigger secondary injuries, which have been associated with increased mortality in patients with tbi [2] . vasopressin mitigates hypotension in septic shock and improves coronary perfusion in hypothermic cardiac arrest models [3] . we hypothesized that a lowdose vasopressin infusion may reduce the cumulative epinephrine dose in hypothermic, brain-injured swine. methods six domestic cross-bred pigs were subjected to epinephrine infusion after general anesthesia, standardized tbi and transpulmonary hypothermia (32°c for 48 hours). all animals received the same care, aiming for a mean arterial pressure >60 mmhg. at hour 24, animals received additional vasopressin infusion at 0.04 units/minute. we measured the cumulative epinephrine dose for each animal pre and post vasopressin infusion ( figure 1 ) and performed a twosample wilcoxon rank-sum test, comparing the median cumulative epinephrine doses in the two groups. the median cumulative epinephrine dose in the animals that received the vasopressin infusion was 715 mg with a 25th to 75th interquartile range (iqr) of 320 to 930 mg. the median cumulative epinephrine dose in the control group was 2,044 mg (iqr 1,640 to 2,344 mg). this was statistically signifi cant (p = 0.003), based on the wilcoxon rank-sum test. conclusion a low-dose infusion of vasopressin can signifi cantly reduce vasopressor requirements and improves hemodynamics in hypothermic, brain-injured swine. this hemodynamic stability may improve neurological outcomes. introduction severe traumatic brain injury (tbi) is a major cause of death and of severe neurologic sequelae. long-term functional outcome of tbi and its best timing of assessment are not well understood, and may be evaluated too prematurely in clinical studies because of resources required to do so without too much missing data. hence, we conducted a systematic review of studies in severe tbi patients to evaluate the long-term functional outcome. we hypothesized that functional impact measured by the glasgow outcome scale (gos), or the extended version (gose), may plateau after several months in patients with severe tbi. methods we performed a systematic review of randomized controlled trials and cohort studies (prospective and retrospective) in patients with severe tbi. we searched medline, embase, cochrane central, biosis, cinahl and trip database from their inception to december 2011. references of included studies were searched for additional studies. two reviewers independently determined study eligibility and collected data. the primary outcome measure was the proportion of unfavourable functional outcome (gos 1 to 3 or gose 1 to 4) at 6 to 12 months, 12 to 18 months, 18 to 24 months and more than 24 months after severe tbi. we calculated freeman tukey-type arcsine squareroot transformations and pooled data using random-eff ect models. heterogeneity was assessed with the i 2 test and sensitivity analyses were based on a priori hypotheses. in total, 4,432 studies were assessed for eligibility; 209 studies (n = 31,540) were included. in the 188 studies using the gos, a poor functional outcome was observed in 56.6% (95% ci = 54.0 to 59.1%, i 2 = 91%), 51.9% (95% ci = 38.0 to 59.0%, i 2 = 84%), 57.0% (95% ci = 48.2 to 55.5%, i 2 = 93%) and 56.9% (95% ci = 48.2 to 65.1%, i 2 = 93%) of patients at 6 to 12 months, 12 to 18 months, 18 to 24 months and beyond 24 months, respectively. in the 18 studies using gose, a poor functional outcome was observed in 62.9% of patients at 6 to 12 months (95% ci = 55.9 to 69.2%, i 2 = 90%) and 54.6% at 12 to 18 months (95% ci = 43.2 to 65.8%, i 2 = 90%). heterogeneity was present in most analyses and was not entirely explained by the planned sensitivity analyses. conclusion considering that the incidence of patients with an unfavourable outcome remained constant at diff erent assessments, a follow-up of severe tbi patients longer than 12 months does not provide incremental information. functional outcomes measured longer than 12 months after the injury may not be warranted in clinical studies. introduction prevention of secondary brain injury is the cornerstone in the management of patients with severe traumatic brain injury (tbi) and raised intracranial pressure (icp). although a variety of monitoring methods are available, due to lack of strong evidence their use varies considerably [1] . the objective of this survey was to provide an overview of the current practice in monitoring of patients with severe tbi in all neuro-icus across the uk. introduction pulmonary complications are frequently occurring medical complications after aneurysmal subarachnoid hemorrhage (asah) [1] . early respiratory deterioration (erd) may be associated with delayed cerebral ischemia (dci) or outcome and would then be a potential target for therapeutic interventions. we investigated whether respiratory deterioration within the fi rst 72 hours after admission predicted dci or poor outcome. methods we conducted a retrospective study in 137 consecutively admitted patients with asah, admitted between october 2007 and october 2011 to the icu of a university hospital. erd was defi ned as increased need for ventilatory support the second or third day after admission (table 1) . elective intubation for a surgical procedure was not included as erd. inclusion criteria were availability of detailed information on respiratory status and level of support, admission within 48 hours after hemorrhage and age ≥18 years. multivariable survival analysis was used to investigate associations of dci, death and glasgow outcome scale (gos) with erd adjusted for condition on admission, hijdra score, treatment of ruptured aneurysm and pulmonary comorbidity. gos was assessed at 3 to 6 months after the bleed. dci was defi ned as described recently [2] . results mean age of the patients was 55.9 (± 12.7) and 63.5% was female. a total 46.7% of the patients developed dci. mortality was 25.6%. forty percent of the patients were classifi ed as having erd. erd was not associated with dci (adjusted hr = 1.48; 95% ci = 0.88 to 2.49; p = 0.14). erd showed a trend towards an association with mortality (adjusted hr = 2.22; 95% ci = 0.96 to 5.14; p = 0.06; additionally adjusted for age, and rebleed). a clear association was found between absence of erd and functional outcome with ordinal logistic regression analysis (0.98 point increase in gos score at 3 to 6 months; 95% ci = 0.14 to 1.82; p = 0.02; additionally adjusted for age and rebleed). conclusion erd within 72 hours after admission is associated with increased risk of poor functional outcome after asah, but not dci. further investigations are required to assess whether prevention of erd may improve outcome. introduction elevated intracranial pressure (icp) may have deleterious eff ects on cerebral metabolism and mortality after aneurysmal subarachnoid hemorrhage (sah) [1, 2] , but its relevance has not yet been well explored. aims of this study are to track icp changes after sah, to identify clinical factors associated with it and to explore the relationship between icp and outcome. methods a total of 116 consecutive sah patients with icp monitoring were enrolled. episodes of icp >20 mmhg for at least 5 minutes and the mean icp value for every 12-hour interval were analyzed. the highest mean icp collected in every patient was identifi ed. icp values were analyzed in relation to clinical and ct fi ndings; 6-month outcome and icu mortality were also introduced in multivariable logistic models. results eighty-one percent of patients had at least one episode of elevated icp and 36% had a highest mean icp >20 mmhg. the number of patients with highest mean icp >20 mmhg or with episodes of hicp was maximum at day 3 after sah and decreased only after day 7. neurological status, aneurysmal rebleeding, amount of blood on ct and ct ischemic lesion occurred within 72 hours from sah were signifi cantly related to highest mean icp >20 mmhg in a multivariable model. patients with highest mean icp >20 mmhg showed signifi cantly higher mortality in icu. however, icp is not an independent predictor of 6 months unfavorable outcome. conclusion elevated intracranial pressure is a common complication in the fi rst week after sah. it is associated with early brain injury severity and icu mortality. . we systematically reviewed their prevalence, aiming particularly at studies with low risk of bias. methods we searched embase, medline, the cochrane library, trip database, references of included studies and narrative reviews. we included cohort studies, cross-sectional studies and rcts published in any language that tested the integrity of ≥1 pituitary axis in adults with asah. studies including more than 50% of non-aneurismal sah were excluded. studies were considered at low risk of bias if the authors defi ned inclusion/exclusion criteria, avoided voluntary sampling, and tested >90% of included patients with proper detailed diagnostic criteria. studies testing all pituitary axes were considered as evaluating hypopituitarism, which was defi ned as the dysfunction of ≥1 axis. we used a freeman tukey-type arcsine square-root transformation and pooled prevalences using the dersimonian-laird random-eff ect method. we determined the degree of heterogeneity with i 2 values. results among 12,363 citations, we included 28 studies (1,628 patients). patients were mostly female (64%) aged 50.5 ± 5.4. sixteen studies reported the severity of asah, 14 reported the procedure for securing the aneurysm and 13 reported the location of aneurysm. overall, hypopituitarism was observed in 53.4% of patients at shortterm (<3 months), 36.5% at mid-term (3 to 12 months) and 34.2% at long-term (>12 months) ( table 1 ). there was an insuffi cient number of studies with low risk of bias to perform sensitivity analyses according to study quality. conclusion the exact prevalence of pituitary disorders following asah remains uncertain, mainly due to high heterogeneity and the small number of studies with low risk of bias. however, the prevalence seems to decrease during the recovery phase. the prevalence, risk factors and clinical signifi cance of pituitary disorders in asah will require further rigorous evaluation. is associated with a high morbidity and mortality. although uk anaesthesia guidelines advocate early coiling or clipping of the aneurysm within the fi rst 72 hours of admission for all grades of asah, the optimal timing of treatment and whether this is linked with better neurological long-term outcome are a subject of debate [1] . we aimed to investigate whether the timing of the occlusion of the aneurysm translates into better outcome. methods a retrospective analysis of prospective collected data in a tertiary neuroscience centre from january to september 2012. all patients were managed according to the local guidelines for the management of asah. outcome was assessed at 3 months using the extended glasgow outcome scale (gose) defi ning good recovery as a gose ≥7 and poor outcome as gose ≤6. results a total of 28 patients were included within the study period. three patients were not expected to survive the fi rst 24 hours and were not included in the study. seventeen patients were classifi ed as good grade asah (wfns i to iii) and eight as poor grade (iv to v). twenty-two patients underwent successful coiling while the other three required clipping due to unsuccessful coiling. we did not fi nd any correlation between the timing of coiling/clipping and the 3-month gose (figure 1) . a total 44% of the patients had a poor 3-month gose while 56% had a good long-term functional outcome. the overall mortality rate was 21%. conclusion overall mortality in patients with asah is low when aneurysm is treated early post rupture of aneurysm. we did not fi nd any correlation between the timing of occlusion of aneurysm and the 3-month functional outcome. patients underwent neuropsychological evaluation at early (<3 days, 10 days) and delayed time points (1 month, 3 months). patients were tested for language, verbal fl uency, short-term and long-term memory, attention, executive functions, praxis, and neglect. impairments in activities of everyday life were assessed using the activities of daily living scale and the instrumental activities of daily living scale. the sf-36 was used to assess the quality of life at 3 months. since complications of aneurysm treatment in addition to asah severity may signifi cantly aff ect cognitive status, patients were evaluated according to the world federation of neurological surgeons score after treatment (wfnspt). all wfnspt 1 to 2 patients completed neuropsychological tests at each time point. wfnspt 3 and wfns 4 patients were testable in 80% and 50% of the cases respectively at early time points. wfns 5 patients were not testable at any time point. in all testable patients, cognitive functions were severely impaired at early time points. at 3 months in wfns 1 to 3 a good recovery of language defi cits while only a partial recovery of attention, memory and executive functions were observed; at the same time point 70% of wfns 4 patients became testable, but they had a worse recovery of all cognitive functions. at 1 month after sah less than 30% of patients return to work, at 3 months approximately 50%. despite a good recovery of everyday life activities at 3 months, for all patients quality of life was lower than a normal population. conclusion cognitive dysfunction has diff erent time courses after asah: signifi cant defi cits in diff erent cognitive domains, worse quality of life and diffi culties in return to work persist in more than 50% of patients at 3 months following sah. results pretreatment with 20 mg/kg, but not 10 mg/kg, of asa-da protected against ischemic neuronal death and damage, and its neuroprotective eff ect was much more pronounced than that of asa or da alone. in addition, treatment with 20 mg/kg asa-da reduced the ischemia-induced activation of astrocytes and microglia. conclusion our fi ndings indicate that asa-da, a new synthetic drug, prevents against transient focal cerebral ischemia, which provides a resource for the development of its clinical application for stroke. introduction acute neurological injury is a leading cause of morbidity and mortality in children. global prevalence and regional disparities of etiology, interventions, and outcomes are unknown. the aim of this point-prevalence study was to measure the burden of pediatric neurological injury and to describe variations in interventions and outcomes in icus. methods one hundred and three icus on six continents enrolled subjects on 4 specifi c days in a 1-year period. included subjects were between ages 7 days and 17 years who were diagnosed with acute traumatic brain injury, stroke, cardiac arrest, central nervous system infection or infl ammation, status epilepticus, spinal cord lesion, hydrocephalus, or brain mass. sites completed a secure web-based case report form that included subject and hospital demographics, details about the neurological disease, interventions, length of stay, and pediatric cerebral performance category (pcpc) score (good outcome = pcpc 1 to 3) and mortality at hospital discharge. results of 3,113 subjects screened, 1,009 (32%) met enrollment criteria. the mean number of subjects enrolled per site for each study day was 2.4. most sites were dedicated pediatric icus with a mean number of 22 icu beds (range 3 to 72). icus had resources to invasively monitor intracranial pressure (93%), continuous electroencephalography (14%), invasive and non-invasive brain tissue oxygenation (14% and 57%), and somatosensory evoked potentials (39%). there were on average 11 icu faculty and six fellows per site, and nearly one-half reported a neurocritical care icu team. subjects were 58% male and 52% white, and 60% had normal pre-admission pcpc scores (85%). status epilepticus and cardiac arrest (both 21%) had the highest prevalence. sixty-one per cent of subjects were mechanically ventilated during icu admission. icu length of stay was a mean 29 days (median 43 days) and hospital los was a mean 43 days (median 61 days). survival at hospital discharge was 87% with 58% of subjects discharged home and 17% to inpatient rehabilitation. conclusion acute neurological disease is a signifi cant pediatric health issue. these data suggest a vital need for increased research and healthcare resources to assist in the challenge of improving outcomes for these children. the newly approved oral anticoagulant dabigatran has no eff ective antidote. we therefore suspected an overall increase in mortality in patients presenting to the emergency department (ed) with a bleeding complication on dabigatran compared with warfarin or aspirin. methods we conducted a post hoc analysis on a database of all patients admitted to a tertiary-care ed with any kind of bleeding or suspicion of one from march 2011 to august 2012 who were taking dabigatran, warfarin, or aspirin. the primary endpoint was long-term survival. patients were censored at death or at the end of the study period (7 december 2012). we performed a cox proportional hazard model, controlled for age, to calculate the hazard ratio (hr) for dabigatran versus warfarin and one for warfarin versus aspirin. statistical signifi cance was set at α = 0.05 and results are presented with 95% ci. results in total, 943 patients met the inclusion criteria with a mean follow-up period of 1 year. the mean age was 74.3 years and 50.4% were men. a total of 108 deaths (11.5%) were recorded within the follow-up period; eight (25%) for dabigatran compared with 44 (12.6%) for warfarin and 56 (9.9%) for aspirin. the mortality risk for patients on dabigatran was signifi cantly higher than for patients on warfarin: hr = 2.1 (95% ci: 1.0 to 4.5), p = 0.05 after controlling for age. aspirin had a lower (but not statistically signifi cant) mortality risk compared with warfarin; hr = 0.75 (95% ci: 0.50 to 1.14), p = 0.18 after controlling for age. the results showed higher overall mortality in patients who presented to the ed with a bleeding complication and were taking dabigatran compared with warfarin or aspirin. physicians should be aware of the potential higher mortality with dabigatran over warfarin when treating a bleeding patient. however, this was a singlecentre retrospective analysis with a small number of patients taking dabigatran (n = 32), and further studies are needed to corroborate the results. introduction dose adjustments of low molecular weight heparin (lmwh) based on daily anti-xa measurement by chromogenic assay remain controversial in daily clinical practice. one of the major obstacles is the cost of such a test. an aff ordable and reliable bedside test could change practice to an individual tailored dosing of lmwh. the aim of our study was to evaluate whether a prophylactic dose regimen of 40 mg enoxaparine in cardiac surgical patients increases the anti-xa activity to the level necessary for effi cient prevention of a thromboembolic event [1] . secondarily we tested whether there was a reliable correlation between a bedside anti-xa measurement compared with a two-stage chromogenic assay at the laboratory [2] . this was an open, single-centre, prospective, nonrandomized clinical trial at a university hospital. all patients that needed prophylactic dosing of enoxaparine after cardiac surgery were duly informed and after giving written consent we included 44 patients with a mean euroscore of 1.66. the demographic specifi cations, medical and surgical history of all patients were collected. anti-xa activity was measured at three diff erent points in time. we determined baseline, peak and trough anti-xa activity: preoperatively, and respectively 4 hours after the third dose of enoxaparine and 30 minutes before the fourth dose. each measurement was done with both techniques, the two-stage chromogenic assay at the laboratory (biophen®) and the bedside assay (hemochron® jr). results our dose regimen of enoxaparine achieved in one-half of the included patients a suffi cient anti-xa activity for prevention of thromboembolic events. one-half of the patients with insuffi cient anti-xa activity had a body mass index over 30 kg/m 2 . comparison of the bedside assay with the two-stage chromogenic assay by means of the pearson's correlation coeffi cient showed correlation of the two tests if no variables were taken into account. in the bland-altman analysis we could not confi rm this correlation. conclusion the bedside anti-xa activity assay with a hemochron device tends to show some correlation with the two-stage chromogenic assay, but insuffi cient to be used as an alternative, in this small but uniform patient population. use of a standard dosing protocol for enoxaparine administration is prone for underdosage in post-cardiac surgery patients and may increase postoperative morbidity. references introduction we hypothesized that higher doses of enoxaparin would improve thromboprophylaxis without increasing the risk of bleeding. critically ill patients are predisposed to venous thromboembolism, leading to increased risk of adverse outcome [1] . peak anti-factor xa (anti-xa) levels of 0.1 to 0.4 iu/ml, 4 hours post administration of enoxaparin, refl ect adequate thromboprophylaxis for medico-surgical patients. methods the sample population consisted of 78 patients, randomized to receive subcutaneous (s.c.) enoxaparin: 40 mg ×1 (control group), versus 30 mg ×2, 40 mg ×2 or 1 mg/kg ×1 (test groups) for a period of 3 days. anti-xa activity was measured at baseline, and at 4, 12, 16 and 24 hours post administration on each day. patients did not diff er signifi cantly between groups. results on day 1 of administration, doses of 40 mg ×1 and 40 mg ×2 yielded similar mean peak anti-xa of 0.20 iu/ml and 0.17 iu/ml respectively, while a dose of 30 mg ×2 resulted in subtherapeutic levels of anti-xa (0.08 iu/ml). patients receiving 1 mg/kg enoxaparin achieved near-steady-state levels from day 1 with mean peak anti-xa levels of 0.34 iu/ml. steady-state anti-xa was achieved for all doses of enoxaparin at day 3. at steady state, mean peak anti-xa levels of 0.13 iu/ ml and 0.15 iu/ml were achieved with doses of 40 mg ×1 and 30 mg ×2 respectively. this increased signifi cantly to 0.33 iu/ml and 0.40 iu/ml for doses of 40 mg ×2 and 1 mg/kg enoxaparin respectively (p = 0.0000) (figure 1) . a dose of 1 mg/kg enoxaparin yielded therapeutic anti-xa levels for over 80% of the study period. there were no adverse eff ects. introduction unfractionated heparin is preferred over lmwh in icu patients but lmwh is used more frequently in many european icus. thromboprophylaxis with standard doses of nadroparin and enoxaparin has been shown to result in signifi cantly lower anti-xa in icu patients when compared with medical patients [1, 2] . methods icu patients (saps 44 ± 16, mv, n = 44; pressors n = 32) received 7,500 iu (group 1, n = 25) or 5,000 iu dalteparin s.c. (group 2, n = 29). twenty-nine medical patients receiving 5,000 iu dalteparin served as controls (group 3). results group 2 had signifi cantly lower areas under the xa curve (auc) compared with groups 1 and 3 (table 1) . diff erences were not signifi cant between groups 1 and 3. peak anti-xa activities (c max -anti-xa) were delayed (t max -anti-xa) in group 2 compared with groups 1 and 3 (table 1) . conclusion in icu patients a s.c. dose of 5,000 iu dalteparin results in signifi cantly lower xa activities when compared with normal ward patients. a s.c. dose of 7,500 iu dalteparin in icu patients resulted in kinetics and peak anti-xa activities comparable with medical patients receiving 5,000 iu dalteparin. introduction anemia is very frequently encountered on the icu. increased hepcidin production is one of the cornerstones of the pathophysiology of anemia of infl ammation. the fi rst-in-class hepcidin antagonist nox-h94, a pegylated anti-hepcidin l-rna oligonucleotide, is in development for targeted treatment of anemia of infl ammation. we investigated whether nox-h94 prevents the infl ammation-induced serum iron decrease during experimental human endotoxemia. methods a randomized, double-blind, placebo-controlled trial in 24 healthy young men. at t = 0 hours, 2 ng/kg e. coli endotoxin was administered intravenously (i.v.), followed by 1.2 mg/kg nox-h94 or placebo i.v. at t = 0.5 hours. blood was drawn serially after endotoxin administration for measurements of infl ammatory parameters, cytokines, nox-h94 pharmacokinetics, total hepcidin-25, and iron parameters. the diff erence of serum iron change from baseline at t = 9 hours was defi ned as the primary endpoint. results endotoxin administration led to fl u-like symptoms. infl ammatory parameters (crp, body temperature, leucocytes, and plasma levels of tnfα, il-6, il-10, and il-1ra) peaked markedly and similarly in both treatment groups. nox-h94 was well tolerated. plasma concentrations peaked at 0.7 ± 0.4 hours after the start of administration, after which they declined according to a two-compartment model, with a t 1/2 of 22.5 ± 4.28 hours. in the placebo group, serum iron increased from 19.0 ± 7.6 μg/l at baseline to a peak at t = 3 hours, returned close to baseline at t = 6 hours and decreased under the baseline concentration at t = 9 hours, reaching its lowest point at t = 12 hours. in the nox-h94 group, serum iron concentrations rose until t = 6 hours and then slowly declined until t = 24 hours. from 6 to 12 hours post lps, the serum iron concentrations in nox-h94-treated subjects were signifi cantly higher than in placebo-treated subjects (p <0.0001, ancova). conclusion experimental human endotoxemia induces a robust infl am matory response and a subsequent decrease in serum iron. treatment with nox-h94 had no eff ect on innate immunity, but eff ectively prevented the infl ammation-induced drop in serum iron concentrations. these fi ndings demonstrate the clinical potential of the anti-hepcidin drug nox-h94 for further development to treat patients with anemia of infl ammation. the association between haemoglobin concentrations and mortality has been studied in patients with various comorbidities [1, 2] . this study aims to determine the association between haemoglobin levels on admission to intensive care and patient length of stay and mortality. methods a retrospective collection of data from patient admissions to a single fi ve-bed icu over a 15-year period identifi ed 5,826 patients between april 1994 and november 2012. patients were split into groups according to haemoglobin concentration on admission. the data were analysed to determine whether there was any relationship between haemoglobin concentration at icu admission and any of our outcome measures (unit and hospital mortality, unit and hospital length of stay). results patients with haemoglobin concentrations ≤10 g/dl and >10.1 g/dl were used in mortality comparisons. patients with a haemo globin concentration ≤10 g/dl had an increase in icu mortality compared with those with haemoglobin levels >10 g/dl (or = 1.36, 95% ci = 1.30 to 1.71, p <0.0001). a similar diff erence was seen with hospital mortality (≤10 g/dl 37.7% vs. >10 g/dl 27.3%, p <0.0001). unit length of stay was signifi cantly longer in patients with admission hb ≤10 g/ dl (5.34 days) compared with an admission hb >10 g/dl (4.08 days), p <0.0001. hospital length of stay was also signifi cantly longer in patients with hb ≤10 g/dl versus hb >10 g/dl (21.6 days vs. 15.5 days, p <0.0001). there was seen to be an inverse correlation between haemoglobin concentration and patient age (r = -0.174; p <0.0001). conclusion haemoglobin concentrations ≤10 g/dl on admission to the icu are associated with an increase in icu mortality, hospital mortality, unit length of stay and hospital length of stay when compared with patients admitted with haemoglobin concentrations >10 g/dl. introduction according to many authors, acute necrotizing pancreatitis (anp) still remains one of the diffi cult problems of abdominal surgery. the complexity of the pathogenesis of the disease, features of the pancreas pathomorphology, abdominal hypertension, and high mortality (30 to 70%) necessitate a search for new ways to treat this disease. the study was conducted in 44 patients with anp, who were divided into two groups according to type of analgesia: epidural or opioids. patients from the fi rst group (n = 23) had epidural analgesia by ropivacaine 6 to 14 mg/hour during 7 to 10 days, and from the second group (n = 21) opioid analgesia by trimeperidine 20 mg three times a day during the same period. we monitored the level of septic and thrombohemorrhagic complications by clinical and instrumental data, during the month after treatment starting. the hemostatic system was evaluated using indicators of hemoviscoelastography (mednord-01m analyzer). results it was found that all patients with anp initially have hypercoagulation and fi brinolysis inhibition. levels of hemostatic disorders correlate with the level of septic complications, treatment in the icu, and mortality. in the fi rst group we noted a deep vein thrombosis, two pneumonia, seven pseudopancreatic cysts and abscesses, two deaths and time of stay in the icu as 15.4 days. in the second group: three cases of deep vein thrombosis, four pneumonia, 10 pseudopancreatic cysts and abscesses, two episodes of gastroduodenal bleeding, fi ve deaths and time of stay in the icu as 27.8 days. conclusion using epidural anesthesia in patients with anp reduced the number of septic complications on 36.6%, and reduced the mortality rate from 23.8% (second group) to 8.7% (fi rst group). we think that violations of blood coagulation and microcirculation are the basis for ischemia, necrosis in tissues and septic complications. epidural analgesia is an eff ective method to decrease the level of septic and thrombohemorrhagic complications and mortality in anp patients. methods after ethics approval and informed consent, we studied the functional state of hemostasis in a group of 57 healthy volunteers, who were not receiving drugs aff ecting coagulation, and 43 patients with postphlebothrombotic syndrome (ppts). in the ppts patients we conducted baseline studies of coagulation state and daily monitoring of dynamic changes in the functional state of hemostasis, a comparative evaluation of performance low-frequency piezoelectric vibration hemoviscoelastography (lpvh) and platelet aggregation test (pat), standard coagulation tests (sct), and thromboelastogram (teg). we found that lpvh correlated with sct, pat and teg. however, our proposed method is more voluminous: indexes icc (the intensity of the contact phase of coagulation), t1 (the time for the contact phase of coagulation), and ao (initial rate of aggregation of blood) are consistent with pat; indexes icd (the intensity of coagulation drive), cta (a constant thrombin activity) and cp (the clot intensity of the polymerization) are consistent with sct and teg. in addition, the advantage of this method is to determine the intensity of fi brinolysiswith the indicator iris (the intensity of the retraction and clot lysis). conclusion lpvh allows one to make a total assessment of all parts of hemostasis: from initial viscosity and platelet aggregation to coagulation and lysis of clots, as well as their interaction. these fi gures are objective and informative, as evidenced by close correlation with the performance of traditional coagulation methods. prophylaxis in orthopedics or in cases of acute coronary syndromes. the main drawback of fond is that routine monitoring is not currently available. this could be a problem during the management of critical and surgical patients, especially in cases of old patients and renal failure. the aim of this study is to evaluate the ability of thromboelastography (teg) to determine the level of anticoagulation due to fond in a surgical population. we prospectively analyzed all patients to whom elective major orthopedic surgery was consecutively performed in a 2-month period. all the patients received fond 2.5 mg in the postoperative period according to accp 2012 guidelines. native and heparinase (hep) teg (haemoscope corporation, niles, il, usa) tests activated with kaolin were performed using whole blood citrated samples at four times: t0, before fond administration; t1, 2 hours after administration; t2, 17 hours after administration (half-life); t3, 24 hours after administration. the following native and hep teg parameters were analyzed: reaction time (r), α angle, maximum amplitude (ma) and coagulation index (ci). these parameters were compared with levels of anti-xa. unvariate analysis and spearman's test were applied to our data. results eighteen patients were analyzed. ten patients met the inclusion criteria. the mean r value increased from t1 to t3. the mean r parameter was in the normal range at any phase of the study and there was no signifi cant diff erences between the r mean value at the diff erent phases. the lowest value of r was at t1, which coincides with plasmatic peak concentration of fond. this value did not correlate with anti-xa mean value at t1, which showed the highest value at that time. there was signifi cant diff erence between the mean native and hep r value only at t2 (p <0.05), native and hep α angle at t3, ma and ma hep at t2 (p <0.01) and ci and ci hep at t3 (p <0.02). only the parameter ma had signifi cant variation over time (p <0.02). conclusion r represents the time necessary to thrombin formation and in the presence of fond we hypothesized a prolonged r time. in our population, teg performed with citrated kaolin-activated whole blood was not able to detect prophylatic doses of fond in every phase. on the contrary, levels of anti-xa were able to reveal the exact pharmacokinetics of the drug. further studies including a large number of patients are necessary. introduction coagulopathy, particularly a trend toward hypercoagula bility and hypofi brinolysis, is common in critically ill patients and correlates with worse outcome. available laboratory coagulation tests to assess fi brinolysis are expensive and time demanding. we investigated whether a modifi ed thromboelastography with the plasminogen activator urokinase (ukif-teg) [1] may be able to evaluate fi brinolysis in a population of critically ill patients. methods ukif-teg was performed as follows: fi rst urokinase was added to citrate blood to give fi nal concentrations of 160 ui/ml, then thromboelastography (teg) analysis was started after kaolin activation and recalcifi cation with calcium chloride. basal teg (no addition of urokinase) was also performed. fibrinolysis was determined by the loss of clot strength after the maximal amplitude (ma), and recorded as ly30 (percentage lysis at 30 minutes after ma) and as ly60 (percentage lysis at 60 minutes after ma). results ukif-teg was performed on 17 healthy volunteers and 18 critically ill patients. ly60 was predicted by ly30 according to an exponential function, so we used ly30 as an indicator of clot lysis. basal teg showed increased coagulability and a trend toward less fi brinolysis in critically ill patients compared with healthy volunteers (reaction time 8.7 ± 3.4 minutes vs. 12.2 ± 1.9 minutes, p <0.001; α-angle 59.7 ± 9.4 vs. 47.2 ± 11.8, p <0.01). this reduction of fi brinolysis was more evident at a urokinase concentration of 160 ui/ml (figure 1 ). conclusion ukif-teg could be a feasible point-of-care method to evaluate fi brinolysis in critically ill patients. methods we performed a randomized, double-blind study in 37 patients who underwent cesarean section. patients were divided into two groups: the fi rst group (n = 19) received preoperative (30 minutes before operation) tranexamic acid 10 mg/kg; the second group (n = 18) received preoperative placebo. the condition of hemostasis was monitored by haemoviscoelastography. results all patients included in the study before surgery had moderate hypercoagulation and normal fi brinolysis: increasing the intensity of clot formation (icf) to 11.4% compared with normal rates; the intensity of the retraction and clot lysis (ircl) was 16.45 ± 1.40 in both groups. at the start of the operation in patients (group 1), icf decreased by 9.7% (p <0.05), and ircl decreased by 27.6% (p <0.05) compared with preoperatively. in group 2, there was icf decrease by 8.8% (p <0.05), and ircl increase by 11.4% (p <0.05) compared with preoperatively. at the end of the operation, the condition of hemostasis in both groups came almost to the same value -moderate hypocoagulation, depressed fi brinolysis. in both groups there were no thrombotic complications. intraoperative blood loss in the fi rst group was 300 ± 40.5 and in the second was 500 ± 60.6. conclusion using of tranexamic acid before surgery signifi cantly reduces intraoperative blood loss by 60%, without thrombotic complications. introduction rotational thromboelastography (rotem) can detect dilutive and hypothermic eff ects on coagulation and evaluate corrective treatments. the aim of this in vitro study was to study whether fi brinogen concentrate alone or combined with factor xiii could reverse colloid-induced and crystalloid-induced coagulopathies in the presence and absence of hypothermia. methods citrated venous blood from 10 healthy volunteers was diluted by 33% using 130/0.42 hydroxyethyl starch or ringer's acetate. rotem was used to evaluate the eff ect of addition of either fi brinogen concentrate corresponding to 4 g/70 kg, or this fi brinogen dose combined with factor xiii equivalent to 20 iu/kg. blood was analyzed at 33 or 37°c with rotem extem and fibtem reagents. results a signifi cant dilutive response was shown in both groups: hypocoagulation was greater in the starch group. hypothermia lengthened the following: extem clotting time (ct), clot formation time and α angle; fibtem maximal clot formation (mcf). irrespective of temperature, fi brinogen overcorrected ringer's acetate's eff ects on all rotem parameters and partially reversed starch's eff ects on extem ct and fibtem mcf. fibtem demonstrated that factor xiii provided an additional procoagulative eff ect in the ringer's acetate group at both temperatures but not the starch group. the only extem parameter to be improved by addition of factor xiii was mcf at 33°c. conclusion rotem shows that fi brinogen concentrate can reverse dilutive coagulation defects induced by colloid and crystalloid at both 33 and 37°c. some additional reversal was provided by factor xiii: higher doses of both fi brinogen and factor xiii may counteract starch's eff ects on clot structure. introduction natural colloid albumin induces a lesser degree of dilutional coagulopathy than synthetic colloids. fibrinogen concentrate has emerged as a promising strategy to treat coagulopathy, and factor xiii (fxiii) works synergistically with fi brinogen to correct coagulopathy following haemodilution with crystalloids. objectives were to examine the ability of fi brinogen and fxiii concentrates to reverse albumininduced dilutional coagulopathy. high and low concentrations of both fi brinogen and fxiii were used to reverse coagulopathy induced by 1:1 dilution in vitro with 5% albumin of blood samples from healthy volunteers, monitored by rotational thromboelastometry (rotem). results haemodilution with albumin signifi cantly attenuated extem maximum clot fi rmness (mcf), α angle (aa), clotting time (ct) and clot formation time (cft), and fibtem mcf (p <0.001). following haemodilution, both doses of fi brinogen signifi cantly corrected all rotem parameters (p ≤0.02), except the lower dose did not correct aa. compared with the lower dose, the higher dose of fi brinogen signifi cantly improved fibtem mcf and extem mcf, aa and cft (p <0.001). the lower dose of fxiii did not signifi cantly correct any of the rotem parameters, and the high dose only improved extem ct (p = 0.004). all combinations of high/low concentrations of fi brinogen/ fxiii signifi cantly improved all rotem parameters examined (p ≤0.001). fibrinogen concentration generally had a greater eff ect on each parameter than did fxiii concentration; the best correction of rotem parameters was achieved with high-dose fi brinogen concentrate and either low-dose or high-dose fxiii. conclusion fibrinogen concentrate successfully corrected initiation, propagation and clot fi rmness defi cits induced by haemodilution with albumin, and fxiii synergistically improved fi brin-based clot strength. results iocs was used in 70 severe pphs and 254 severe pph controls were managed without iocs. placenta accreta can be selected as the best indication for rbc restitution. in the 1,500 to 3,000 ml pph, allogeneic transfusion was decreased in the iocs group: 17.6 versus 56.3% (p = 0.006); prbc: 0 (0 to 3) versus 3 (0 to 6) (p = 0.045). iocs spared 87 blood bank prbc (17,374 ml); that is, 24.2% of the total transfusion need. no amniotic fl uid embolism has been observed in the group with iocs whereas one case appeared in the control group without iocs. conclusion regarding the literature [1] [2] [3] [4] and our study, iocs could be used safely in pph during cs. a leukocyte fi lter for retransfusion has been recommended and rhesus isoimmunization must be precluded and monitored by repeated fetal rbc testing. bleeding with the use of a protamine infusion and an abolishment of heparin rebound [1] . the aim of this study was to see whether the use of postoperative protamine infusions in our cardiac itu was associated with a reduction in heparin rebound and blood loss. methods data from 240 cardiac surgery patients were retrospectively analysed. of these, 157 had routine management with a bolus of protamine to correct the activated clotting time and then expectant management of subsequent bleeding, and 47 had the same but also a protamine infusion of 10 to 80 mg/hour for between 3 and 8 hours postoperatively. blood loss was measured at 1, 6, 12 and 24 hours. in all, excessive bleeding was investigated using thromboelastography (teg). rebound heparinisation was determined by a ratio of r-times (heparinase/plain) <0.8. the mann-whitney u test and the chi-squared test were used to assess statistical signifi cance. results there was no signifi cant diff erence in blood loss between the two groups. blood loss at 1 hour in the infusion and non-infusion group was 145 and 88 ml, respectively (p = 0.06); at 6 hours: 450 and 392 ml (p = 0.5); at 12 hours: 620 and 595 ml (p = 0.62); and at 24 hours: 971 and 872 ml (p = 0.12). there was also no signifi cant diff erence in those getting heparin rebound with 40% in the infusion group and 47% in the non-infusion group (p = 0.54). conclusion unlike teoh and colleagues [1] , we did not fi nd an advantage in using protamine infusions. that there were still cases of heparin rebound in the infusion group suggests that the infusion was not as eff ective as expected and/or the dose was inadequate. however, previous studies assessed heparin rebound using isolated clotting parameters [1, 2] . here, we used teg. as teg measures the thrombodynamic properties of whole blood coagulation, perhaps it is a more reliable indicator of heparin activity? as a retrospective study, there are limitations; namely, the nonstandardised management of the patients and the potential bias in the anaesthetists' selection of patients for an infusion. this group may be inherently higher risk for bleeding. however, heparin rebound is common and protamine is a simple, relatively safe and low-cost intervention compared with transfusion and so further study is needed. introduction the purpose of this study was to evaluate whether a restrictive strategy of red blood cell (rbc) transfusion was superior to a liberal one for reducing mortality and severe clinical complications among patients undergoing major cancer surgery. methods the trial was designed as a phase iii, randomized, controlled, parallel-group, superiority trial. the inclusion criteria were adult patients with cancer who were undergoing major abdominal surgery requiring postoperative care in an icu. the patients were randomly allocated to treatment with either a liberal rbc transfusion strategy (transfusion when hemoglobin levels decreased below 9 g/dl) or a restrictive rbc transfusion strategy (transfusion when hemoglobin levels decreased below 7 g/dl). the primary outcome was a composite endpoint of death or severe complications. the patients were monitored for 30 days. results a total of 1,521 patients were screened for eligibility and 248 met the inclusion criteria. after exclusions for medical reasons or a lack of consent, 198 patients were included in fi nal analysis, with 101 allocated to the restrictive group and 97 to the liberal group. the primary composite endpoint -all-cause mortality, cardiovascular complications, acute respiratory distress syndrome, acute kidney injury requiring renal replacement therapy, septic shock or reoperation at 30 days -occurred in 19.6% of the patients in the liberal strategy group and in 35.6% in the restrictive group (p = 0.012). the liberal strategy group had a signifi cantly lower 30-day mortality rate as compared with the restrictive group (8.2% (95% ci, 4.2 to 15.4%) vs. 22.8% (95% ci, 15.7 to 31.9%), respectively, p = 0.005). the occurrence of cardiovascular complications was lower in the liberal group than in the restrictive group (5.2% (95% ci, 2.2 to 11.5%) vs. 13.9% (95% ci, 8.4 to 21.9%), respectively, p = 0.038). the restrictive strategy group had a higher 60day mortality rate as compared with the liberal group (23.8% (95% ci, 16.5 to 32.9%) vs. 11.3% (95% ci, 6.5 to 9.2%), respectively, p = 0.022). conclusion the liberal rbc transfusion strategy with a hemoglobin trigger of 9 g/dl was associated with fewer major postoperative complications in patients undergoing major cancer surgery compared with the restrictive strategy. introduction red blood cell (rbc) transfusion is associated with morbidity and mortality in critically ill patients. congenital cardiac surgeries are associated with high rates of bleeding and consequently with high rates of allogeneic transfusion. we aimed to evaluate the association of transfusion with worse outcomes in children undergoing cardiac surgery. methods we performed a prospective cohort study of 205 patients undergoing cardiac surgery for congenital heart disease. we recorded baseline characteristics, rachs-1 score, intraoperative data, transfusion requirement and severe postoperative complications as need for reoperation, acute kidney injury, arrhythmia, severe sepsis, septic shock, bleeding, stroke, and death during 30 days. we performed univariate analysis using baseline, intraoperative and postoperative variables. selected variables (p <0.10) were included in a forward stepwise multiple logistic regression model to identify predictive factors of a combined endpoint including 30-day mortality and severe complications. results one hundred and thirty-six patients (66.3%) were exposed to rbc transfusion. in the intraoperative room, 63.4% of patients received at least one rbc unit, and in the icu, 11.2% of children were transfused. from all patients, 66 (32.1%) presented the combined endpoint. patients with complications had higher rachs-1 score, were younger (69 months (0 to 137) vs. 73 months (37 to 138), p <0.001), had a lower weight (13 kg (3 to 23) vs. 20 kg (12 to 36), p <0.001), a longer time of surgery (475 minutes (410 to 540) vs. 353 (275 to 433), p <0.001), a longer duration of cardiopulmonary bypass (205 minutes (175 to 235) vs. 106 minutes (73 to 123), p = 0.003), a lower svo 2 at the end of surgery (59% (iqr 39 to 80) vs. 78% (71 to 83), p <0.001), a higher arterial lactate at the end of surgery (6.9 mmol/l (4.3 to 9.2) vs. 2.7 mmol/l (73 to 123), p = 0.003), a lower intraoperative hematocrit (26.2 ± 5.6% vs. 29.5 ± 6% (p <0.001)) and a lower hematocrit at the end of surgery (33.4 ± 6.7% vs. 36.9 ± 6.9% (p <0.001)) as compared with patients without complications. patients with complications were more exposed to rbc transfusion in the intraoperative room (75% vs. 57%, p = 0.011) and in the icu (21% vs. 6.4%, p = 0.002). in an adjusted model of logistic regression, rbc transfusion is an independent risk factor of combined endpoint (or 4.25 (95% ci, 1.359 to 13.328), p = 0.013). conclusion blood transfusion after pediatric cardiac surgery is a risk factor for worse outcome including 30-day mortality. avoiding blood transfusion must be a goal of best postoperative care. introduction we do not have enough criteria to make a judgment of the need for a massive transfusion (mt) in severe blunt traumatic patients. as a scoring system to predict the need for a mt, we usually use the assessment blood consumption score (abcs) and/or the trauma-associated severe hemorrhage score (tashs). however, for these scoring systems, the procedure is slightly complicated. the aim of this study was to establish a predictor of a mt using coagulation or fi brinolysis markers. methods a retrospective analysis of mt was conducted in patients with severe blunt traumatic injury, which was defi ned as injury severity score (iss) of 16 or more admitted to the icu between 1 june 2009 and 31 december 2010. blood samples were collected from patients immediately after arriving at our level i trauma center. we defi ned the patients who received more than 10 unit packed red blood cells (prbcs) within the fi rst 24 hours as a mt group and who received less than 9 units prbcs as a non-mt group. after the demographic data, number of units of prbcs and the need for massive transfusions were recorded and analyzed in each groups, we compared data between two groups. results there were 114 patients who met the inclusion criteria. fifty patients received blood transfusions (43.9%; 50/114). there were 27 patients in the mt group (23.7%; 27/114) and 87 in the non-mt group. the mt group was signifi cantly higher in the ratio of females (p <0.001), iss (p <0.01), pt-inr (p <0.001), aptt (p <0.05), abcs (p <0.001) and tashs (p <0.001) than in the on-mt group. on the other hand, the mt group was signifi cantly lower in ps (p <0.05) and fi brinogen level (p <0.001) than the non-mt group. in the receiver operating characteristics (roc) analysis, the area under the curve (auc) to distinguish a mt was the highest for tashs (0.831, p <0.001), followed by fi brinogen (0.758, p <0.001), and abcs (0.732, p <0.001). fibrinogen was only a predictor of a mt without a scoring system such as abcs and tashs, and the optimal cutoff value was 205 mg/dl. conclusion we found that the level of fi brinogen was the most valuable predictor of a mt in the coagulation or fi brinolysis markers. it is certain that the level of fi brinogen at admission was not as useful as the tashs about predicting a mt in this study. whereas the scoring systems require the assessment of several factors, the measurement of fi brinogen is simple, easy and quick. we strongly suggest that the level of fi brinogen will be a useful predictor of a mt at in severe blunt traumatic patients. introduction red blood cell (rbc) transfusions are frequent in critically ill children. their benefi ts are clear in several situations. however, issues surrounding their safety have emerged in the past decades. it is important to identify the potential complications associated with rbc transfusions, in order to evaluate their risk-benefi t ratio better. methods a single-center prospective observational study of all children admitted to the pediatric intensive care unit (picu) over a 1-year period. the variables possibly related to rbc transfusions were identifi ed before the study was initiated, and their presence was assessed daily for each child. in transfused cases (tcs), a variable was considered as a possible outcome related to the transfusion only if it was observed after the fi rst transfusion. results during the study period, 913 admissions were documented, 843 of which were included in the study. among them, 144 (17%) were transfused. when comparing tcs with nontransfused cases (ntcs), the odds ratio (or) of new or progressive multiple organ dysfunction syndrome (npmods) was 2.39 (95% ci = 1.58 to 3.62, p <0.001). this association remained statistically signifi cant in the multivariate analysis for children with admission prism score ≤5 (or = 2.41, 95% ci = 1.08 to 5.37, p = 0.032). tcs were ventilated longer than ntcs (14.1 ± 32.6 days vs. 4.3 ± 9.6 days, p <0.001). this diff erence was still signifi cant after adjustment using a cox model. moreover, we observed an adjusted dose-eff ect relationship between rbc transfusions and length of mechanical ventilation. the picu length of stay was signifi cantly increased for tcs (12.4 ± 26.2 days vs. 4.9 ± 10.2 days, p <0.001), even after multivariate adjustment (hazard ratio of picu discharge for tcs: 0.61, 95% ci = 0.5 to 0.74, p <0.001). we also observed an adjusted dose-eff ect relationship between rbc transfusions and picu length of stay. the paired analysis for comparison of pre-transfusion and posttransfusion values showed that the arterial partial pressure in oxygen was signifi cantly reduced after the fi rst transfusion (mean diff erence 42.8 mmhg, 95% ci = 27.2 to 58.3, p <0.001). the paired analysis also showed an increased proportion of renal replacement therapy, while the proportions of sepsis, severe sepsis and septic shock did not diff er. conclusion rbc transfusions were associated with prolonged mechanical ventilation and prolonged picu stay. the risk of npmods was increased in some transfused children. moreover, our study questions the ability of stored rbcs to improve oxygenation in critically ill children. these results should help to improve transfusion practice in the picu. introduction microcirculatory alterations during sepsis impair tissue oxygenation, which may be further worsened by anemia. blood transfusions proved not to restore o 2 delivery during sepsis [1] . the impact of storage lesions and/or leukocyte-derived mediators in red blood cell (rbc) units has not yet been clarifi ed [2] . we compared the eff ects of leukoreduced (lr) versus nonlr packed rbcs on microcirculation and tissue oxygenation during sepsis. methods a prospective randomized study. twenty patients with either sepsis, severe sepsis or septic shock requiring rbc transfusion randomly received nonlr (group 1, n = 10) or lr (group 2, n = 10) fresh rbcs (<10 days old). before and 1 hour after transfusion, microvascular density and fl ow were assessed with sidestream dark-fi eld imaging sublingually. thenar tissue o 2 saturation (sto 2 ) was measured using near-infrared spectroscopy and a vascular occlusion test was performed. results the de backer score (p = 0.02), total vessel density (p = 0.08), perfused vessel density (p = 0.04), proportion of perfused vessels (p = 0.01), and microvascular fl ow index (p = 0.04, figure 1 ) increased only in group 2. the sto 2 upslope (figure 2 ) during reperfusion increased in both groups (p <0.05). in group 1 the baseline sto 2 and sto 2 downslope during ischemia increased, probably refl ecting a lower o 2 consumption. conclusion unlike nonlr rbcs, the transfusion of fresh lr rbcs seems to improve microvascular perfusion and might help to restore tissue oxygenation during sepsis. introduction obstetric haemorrhage remains a leading cause of maternal mortality and severe morbidity. cardiovascular and haemostatic physiology alters in pregnancy and massive transfusion protocols have been implemented for obstetric haemorrhage based on limited evidence. the objective of this study was to examine the pattern and rate of blood products used in massive transfusion for obstetric haemorrhage in a tertiary obstetric hospital. methods massive transfusion was defi ned as 5 or more units of red blood cells within 4 hours in accordance with the australian massive transfusion registry defi nition. following ethics approval, all cases fi lling this criterion were identifi ed in the hospital's birthing and blood bank systems. data were extracted from the medical histories and analysed using spss. p <0.05 was considered statistically signifi cant. results twenty-eight women in three years (2009 to 2011) underwent a massive transfusion for obstetric haemorrhage, with nine receiving more than 10 units of rbcs in 24 hours. eleven (39%) were admitted to the icu and 11 underwent a hysterectomy, of which six were admitted to the icu. the median estimated blood loss was 4,335 ml (iqr 3,000 to 5,000). median blood product delivery was rbc 8 units (iqr 6 to 13); ffp 4 units (iqr 4 to 8); platelets 4 units (iqr 0 to 8) and cryoprecipitate 3 units (iqr 0 to 10). one-half of the women received the fi rst four units of rbcs in less than 34 minutes. other blood products were started a median of 49 minutes, 44 minutes and 75 minutes after the rbc transfusion commenced, respectively. eight women had a fi brinogen level <0.8 g/l on the initial coagulation test during the haemorrhage. the remaining 20 women had a median fi brinogen level of 3.7 g/l (iqr 3.15 to 4.9). there was no diff erence in the transfusion of rbcs (p = 0.20), ffps (p = 0.96) and platelets (p = 0.48) in women who showed an initial low fi brinogen and those who did not, although there was a diff erence in the number of units of cryoprecipitate (p <0.05). the median lowest hb during the haemorrhage was 66 g/l (iqr 51 to 80) and median discharge hb was 103 g/l (iqr 96 to 113). no blood product reaction was noted and there was one death. conclusion massive transfusion for obstetric haemorrhage involved rapid blood product administration with no consistent pattern in the ratio of products administered. introduction blood transfusions are associated with longer icu and hospital inpatient durations, and an increase in mortality [1] . this study was undertaken to investigate whether the practice of packed red cell critical care 2013, volume 17 suppl 2 http://ccforum.com/supplements/17/s2 s139 (prc) transfusions in the icu was in accordance with the best clinical evidence. a number of studies, most notably the tricc study [2] , have shown that indications for icu blood transfusions are a haemoglobin (hb) level of <7 g/dl or evidence of acute haemorrhage [3] . these criteria were therefore employed. methods this study prospectively examined episodes of prc unit transfusions over a 2-month period in the icu of a large level 1 trauma centre and a tertiary cardiac unit. the number of prc units transfused in each episode was recorded by nurses, along with the proposed indication and concurrent hb level. the data were analysed to assess the number of transfusions administered contrary to the guidelines, along with the average hb level at which a prc unit was transfused and the average number of units administered per episode. results a total 175 units of prc were transfused in the icu, over 105 episodes during the 2-month period (excluding immediately postoperative transfusions). ninety-four units (53.7%) administered in 64 transfusion episodes (61.0%) occurred contrary to the guidelines. in 89.3% of these cases the recorded reason for transfusion was an apparently low hb level. the median (iqr (range)) hb level at which patients were transfused: within guidelines was 6.9 g/dl (6.6 to 7.7 (4.8 to 13.9)); within guidelines, excluding cases of acute blood loss, was 6.6 g/dl (6.5 to 6.8 (5.5 to 6.9)); and outside the guidelines was 7.7 g/dl (7.4 to 8.2 (7.0 to 9.7)). one unit of prc was transfused in 57 episodes (54.3%), 2 units of prc were transfused in 36 episodes (34.3%), and 3 to 6 units were transfused in 12 episodes (11.4%), with two-thirds of the latter due to acute haemorrhage. our results indicate a liberal transfusion threshold currently exists in the icu. patients are frequently receiving excessive prc transfusions for hb levels above the recommended concentration. in the 2-month study period, these were associated with a cost of approximately £12,220. we recommend increased staff awareness of the guidelines to reduce the number of unnecessary transfusions. this would decrease exposure of icu patients to unnecessary risks of blood transfusion, reduce cost of treatment and help to preserve a valuable resource. introduction transfusion-related acute lung injury (trali) has a high incidence in critically ill and surgical patients and contributes to adverse outcome, while specifi c therapy is absent. recently it was demonstrated that complement activation plays a pivotal role in trali. we aimed to determine whether a c1 inhibitor is benefi cial in a two-hit mouse model of antibody-mediated trali. methods balb/c mice were primed with lipopolysaccharide (lps, from e. coli 0111:b4) that was administered intraperitoneally in a dose of 0.1 mg/kg, after which trali was induced by injecting mhc-i antibody against h2kd (igg2a,k) at a dose of 2 mg/kg. mice infused with pbs or lps served as controls. concomitantly, mice infused with the mhc-i antibody were treated with c1 inhibitor (cetor®; sanquin, amsterdam, the netherlands) in a dose of 400 iu/kg intravenously. after infusion, mice were mechanically ventilated with a lung-protective pressurecontrolled mode for 2 hours and then sacrifi ced, after which a bronchoalveolar lavage (bal) was done. statistics were analyzed by one-way anova, values expressed as mean and standard deviation. results injection of lps and mhc-i antibodies resulted in trali, indicated by increased levels of protein in the bal fl uid, wet/dry ratios and levels of kc, mip-2 and il-6. c1 inhibitor cetor® signifi cantly reduced total protein in bal fl uid from 792 (169) to 421 (230) μg/ml (p <0.001) and tended to reduce the wet/dry ratio from 5.3 ± 0.3 to 4.9 ± 0.5 (p = 0.09). cetor® also reduced balf levels of mip-2 from 214 (54) to 127 (22) pg/ml (p <0.01). kc and il-6 levels were not aff ected. conclusion in a model of antibody-mediated trali, c1 inhibitor attenuated pulmonary infl ammation. c1 inhibition may be a potential benefi cial intervention in trali. introduction transfusion-related acute lung injury (trali) is a syndrome that presents as a sudden onset of respiratory distress 6 hours after transfusion of blood products. the diagnosis is based on clinical and radiographic fi ndings. particularly at risk for trali are cardiac surgery patients. however, specifi c patient risk factors and data on outcome are largely unknown. the aim of this study was to investigate incidence, risk factors and outcome of trali in cardiac surgical patients on cardiopulmonary bypass. methods all thoracic surgery patients from a university hospital in the netherlands of 18 years and older admitted to the icu from january 2009 until december 2011 were screened. included patients were observed during surgery and the fi rst 24 hours on the icu for the onset of possible trali. the canadian consensus conference trali defi nition was used. two independent physicians blinded to the predictor variables scored the chest radiographs for the onset of bilateral interstitial abnormalities on 2k monitors. when interpretation diff ered, chest radiographs were reviewed by a third physician to achieve consensus. the european system for cardiac operative risk evaluation (euro score) and the american association of anesthesiology (asa) were scored before surgery. by calculating the acute physiology and chronic health evaluation (apache) ii and iv scores the severity of illness was determined on arrival in the icu. in total, 1,787 cardiac surgical patients were included. a total of 19 (1.1%) patients developed trali within 24 hours following surgery. patients developing trali were older compared with patients not developing trali, mean age respectively 71 and 65 years (p = 0.035). furthermore, patients developing trali had higher apache ii, apache iv, euro and asa score (p = 0.000, p = 0.000, p = 0.000 and p = 0.37 introduction volume resuscitation is essential to restore normovolemia during hemorrhagic shock, burns and sepsis. however, synthetic colloids cause dilutional coagulopathy. the aims were to determine whether the natural colloid albumin induces a lesser degree of coagulopathy compared with synthetic colloids, and the comparative eff ectiveness of fi brinogen concentrate to reverse coagulopathy following dilution with these solutions. methods rotational thromboelastometry-based tests were used to examine coagulation parameters in samples from 10 healthy volunteers, in undiluted blood and samples diluted 1:1 with saline, was seen for samples diluted with synthetic colloids (p <0.001) but not albumin (p = 0.10). following addition of fi brinogen, fibtem mcf, extem mcf and extem aa were signifi cantly higher, and extem cft was signifi cantly shorter in samples diluted with albumin versus those treated with hes or dextran (p ≤0.001). conclusion hemodilution using albumin induced a lesser degree of coagulopathy compared with the synthetic colloids hes and dextran. in addition, albumin-induced coagulopathy was more eff ectively reversed following addition of fi brinogen concentrate compared with coagulopathy induced by synthetic colloids. comparative assessment of the diff erent fl uid modalities is hampered by a paucity of direct trials. we present a network meta-analysis for assessing the relative eff ectiveness of two fl uid treatments in sepsis when they have not been compared directly in a randomized trial but have each been compared with a common treatment. methods a systematic review of trials sepsis yielded 13 trials for assessment in network meta-analysis. the indirect comparison between albumin, hes and crystalloid was conducted using bayesian methods for binomial likelihood, fi xed-eff ects network meta-analysis with a monte carlo gibbs sampling method. studies in septic patients with crystalloid as a reference treatment compared with any formulation of the colloid treatments albumin or hes were included, as were direct head-to-head trials between the two colloids. results odds ratios between the diff erent treatments were obtained ( figure 1 ). ranking the interventions [1] demonstrated that albumin ranked highest in lowering mortality at a 96.4% probability compared with 3.6% and 0.01% for crystalloid and hes, respectively. conclusion albumin as a fl uid therapy in sepsis is associated with the lowest mortality of the three modalities studied. (sap), sv and co were recorded directly before the administration of any colloid (t0) and every 5 minutes for the next 1 hour (t1 to t12). kolmogorov-smirnov was used to test normal distribution of data and anova was used for the statistical analysis. p <0.05 was considered statistically signifi cant. results demographic data and asa classifi cation did not diff er statistically signifi cant among the six groups of the study. co, sv, hr and sap did not show any statistically signifi cant evolution compared with their baseline value during the study period. moreover, there were no statistically signifi cant diff erences among the six study groups with regard to any of the recorded parameters. conclusion according to our results, volume replacement with the six colloids tested in our study did not result in any hemodynamic response. within comparison of these six colloids did not reveal any statistically signifi cant diff erence in any of the parameters recorded according to our protocol. the biochemical characteristics of infused fl uids may be important in regulating acid-base balance, by modifying plasmatic volume and strong ion diff erence. in vitro and animal studies [1, 2] have shown that volume and strong ion diff erence of infused fl uids (sidin) as well as the arterial baseline bicarbonate concentration (hco 3 -a) infl uence acid-base variations. our aim was to verify these changes in critically ill patients after surgery. methods an electronic-dedicated database was created to retrospectively collect volume, type of fl uids infused and plasmatic acidbase balance variations in postoperative icu patients from admission to 9:00 am of the day after. sidin was calculated as the average sid of all fl uids infused during the whole study period (crystalloids, colloids and blood products). arterial base excess variation (δbea) was computed as the diff erence between values at 9:00 am on the day after and those at entry. we report data from all patients admitted in 2006 and 2007 (650 patients). results nine patients not receiving intravenous infusions were excluded. the remaining population was divided into three groups according to sidin distribution (group 1, 18 ± 12; group 2, 47 ± 6; group 3, 55 ± 0 meq/l). we observed a progressive increment in δbea between the groups (1.1 ± 2.0 vs. 2.8 ± 2.9 vs. 3.0 ± 2.8 mmol/l, p <0.001). we further subdivided each group by the median value of baseline hco 3 -a (24.3 (22.3 to 26.1) mmol/l) and we analyzed the δbea: we observed a greater increase in patients with lower baseline hco 3 -a (group 1, 1.8 ± 2.9 vs. 0.2 ± 2.6, mmol/l, p <0.001; group 2, 4.0 ± 2.7 vs. 1.5 ± 2.6, mmol/l, p <0.001; group 3, 4.4 ± 2.8 vs. 1.7 ± 2.0 mmol/l, p <0.001), as compared with those with higher baseline levels. when the study population was divided into quartiles of the diff erence between sidin and hco 3 -a, δbea appeared to increase with the rise of such diff erence (p <0.001). conclusion sidin aff ects the acid-base status per se and in relationship with hco 3 -a. we verifi ed this hypothesis in critically ill patients, highlighting the importance of the diff erence between sidin and hco 3 -a, which better describes and predicts the acid-base modifi cations to fl uid therapy. introduction fluid resuscitation should improve tissue oxygenation in hypovolemia, besides restoring macrohemodynamic stability [1] . we evaluated the microvascular response to fl uid challenge with diff erent colloid solutions and its relation to macrohemodynamics. methods an observational study of patients receiving a fl uid challenge (500 ml colloids in 30 minutes) according to the attending physician's decision. before and after the infusion, sublingual microcirculation was evaluated with sidestream dark-fi eld imaging (microscan; microvision medical, amsterdam, the netherlands). microvascular fl ow and density were assessed for small vessels [2] . the cardiac index (ci), intrathoracic blood volume index (itbvi) and extravascular lung water index (elwi) were measured in seven patients with picco2 (pulsion medical system, munich, germany). results ten patients (two sepsis, four trauma, three intracranial bleeding, one post surgery) received either saline-based hydroxyethyl starch (hes) 130/0.4 (amidolite®; b.braunspa; n = 5) or balanced hes 130/0.42 (tetraspan®; b.braunspa; n = 5). the ci (p = 0.02) and itbvi (p = 0.07) tended to increase, the evlwi did not change. microvascular fl ow and density improved in the whole sample. no correlation was found between macro-circulatory and micro-circulatory parameters. balanced hes led to a greater increase in capillary density than nacl hes (figure 1 ). conclusion balanced hes may be more effi cacious than saline-based hes in recruiting the microcirculation, thereby improving tissue o 2 delivery. introduction are safety guidelines being followed when administering procedural sedation in the emergency department? between november 2004 and november 2008, the npsa received 498 alerts of patients being given the wrong dose of midazolam for procedural sedation [1] . in the fi rst 5 years of midazolam use there were 86 deaths, most related to procedural sedation [2] . methods we searched through the controlled drugs book in resuscitation over a 2-month period and found a list of patients who had received midazolam or fentanyl. from this, we could make a search for the relevant a and e notes for these patients. from these notes, we looked for (see shorthand in table 1 ): verbal consent documentation (consent), past medical history recorded (pmhx), safe initial dose of midazolam (midaz), pre-procedure monitoring (pre), post-procedure monitoring (post), and monitoring for 1 hour before discharge (1hr). following introduction of a reminder in the controlled drugs book/ sedation room and staff education, the case notes were analysed over another 2-month period (24 sets of notes) to assess practise against safety guidelines. results see table 1 (key for shorthand in methods). conclusion the re-audit notices within the procedural sedation room and controlled drug book front cover served as a reminder of good practise. the visibility of this reminder (within the cd book) helped ensure better adherence to the audit standard. this reminder will now be kept within the cd book. introduction daily sedation interruption and protocol implementation have been recommended to reduce excessive sedation; however, their use has been inconsistent. we hypothesized that the use of an age, kidney and liver function adjusted sedation protocol would be associated with reduced doses and improved outcomes compared with a standard protocol. methods this was a prospective cohort study comparing 3 months of a standard protocol (control group) with 3 months of an adjusted protocol (intervention group). in the adjusted protocol, patients were divided into three categories: category 1 (age <60 years, and normal kidney and liver function), category 2 (age = 60 to 70 years, or moderate kidney or liver function impairment), and category 3 (age >70 years, or severe kidney or liver function impairment). the upper limits of analgesics and sedatives doses were determined by age, and kidney and liver function, being lowest in category 3, and lower in category 2 than category 1. all consecutive adults mechanically ventilated patients who required infusion of analgesics and/or sedatives for >24 hours were included in the study. we compared the main outcomes of both groups including average daily doses of analgesics and sedatives; average sedation-agitation scale (sas), pain and gcs scores; mechanical ventilation duration (mvd); sedation-related complications during icu stay; icu and hospital length of stay (los), and icu and hospital mortality. results two hundred and four patients were included in the study (control group = 105; adjusted protocol group = 99). there was no diff erence in baseline characteristics between the two groups. the adjusted protocol group, compared with the control group, received signifi cantly lower average daily doses of fentanyl (2,162 ± 2,110 μg vs. 3,650 ± 3,253 μg, p = 0.0001), nonsignifi cant lower average daily doses of midazolam and dexmedetomidine, and a trend toward higher average daily doses of propofol. pain score was higher in the adjusted protocol group (0.98 ± 0.72 vs. 0.16 ± 0.35, p <0.0001) with no diff erence in sas or gcs scores. sedation-related complications during icu stay were not diff erent between the two groups; however, agitation (sas = 5) was less frequent in the adjusted protocol group (3% vs. 30%, p <0.0001). icu mortality was signifi cantly lower in the introduction the aim of this research was to provide clinically relevant evidence for y-site compatibility of drug infusion combinations used in the picu. pharmacists and clinicians regularly have to interpret limited published data, particularly when more than two drugs are y-sited. the risk of potential incompatibility must be balanced against that of additional line insertion. methods a full 28-factorial design (total 256 combinations) was used to investigate chemical and physical compatibility of fi ve drugs (clonidine, morphine, ketamine, midazolam and furosemide). the drugs were studied at their highest commonly infused concentrations and exposed to three variations in environmental conditions (diluent: sodium chloride 0.9% or glucose 10%; temperature 25 or 37°c; and normal room lighting or blue light phototherapy). chemical stability was assessed using hplc; >10% reduction in concentration indicated incompatibility. physical incompatibility was confi rmed by precipitation, ph or colour change. results environmental conditions had no eff ect on the drug mixtures. the precipitation observed in incompatible combinations was due to either a change in ph, or with ketamine the presence of benzethonium chloride. of 31 possible drug combinations, 12 were incompatible. a further three combinations were incompatible at extreme ph, or were of concern and so should be avoided. the incompatible formulations all contained furosemide. all combinations of the sedative agents studied were chemically and physically compatible. conclusion this work provides evidence for y-site compatibility of morphine, midazolam, clonidine and ketamine in any combination, which will potentially reduce the need for extra intravenous lines. furosemide is incompatible with any of these sedative drugs and must be infused via a separate line. these results will aid clinical decisionmaking and help satisfy the requirements of recent uk department of health legislation relating to the mixing of medicines. reference introduction in light of the interest in the relationship between glycemia control in critically ill subjects and outcome, we set up a study to investigate whether benzodiazepine, commonly used in anesthesia and icus, interferes with glucose metabolism and to explore the mechanism. methods a total of 40 sedated and paralyzed sprague-dawley rats (301 ± 55 g) were investigated in four consecutive studies. (1) to investigate the eff ects of diazepam on blood glucose, 15 rats were randomly assigned to intraperitoneal anesthesia with tiopenthal 80 mg/kg (dzp0), tiopenthal 40 mg/kg + diazepam 5 mg/kg (dpz5) or tiopenthal 40 mg/kg + diazepam 15 mg/kg (dzp15). blood levels of glucose (gem premier 3000; il) were measured at time intervals over 2 hours. (2) ten animals randomized to dzp0 or dzp5 underwent an intravenous glucose tolerance test with glucose bolus (0.5 g/kg). acute insulin response, the mean value of blood insulin (insulin elisa kit; millipore) from 2 to 10 minutes after glucose bolus, was measured as index of insulin secretion. (3) a hyperinsulinemic euglycemic clamp obtained by a continuous intravenous infusion of insulin (130 mui/ kg/minute) was run in 10 animals randomized to dzp0 or dzp5 and the glucose infusion rate (gir, mg/kg/minute) was assessed [1] . (4) introduction we report our experience in the use of isofl urane for prolonged sedation in severe ards patients. prolonged sedation in the icu may be diffi cult because of tolerance, drug dependence and withdrawal, drug interactions and side eff ects. inhaled anesthetics have been proposed for sedation in ventilator-dependent icu patients. anaconda is a device that allows a safety and easy administration of inhaled anesthetics in the icu. methods from january 2009 to june 2012, 15 patients were sedated with isofl urane by means of the anaconda device. we consider administration of isofl urane as a washout period from common sedative drugs in patients with (at least one of ): high sedative drug dosage (propofol ≥300 mg/hour or midazolam ≥8 mg/hour) to reach the target richmond agitation sedation score (rass) or inadequate paralysis; two or more hypnotic drugs to reach the target rass (propofol, midazolam, hydroxyzine, haloperidol, diazepam, quetiapine); and hypertriglyceridemia. during isofl urane administration previous hypnotic drugs were interrupted. we retrospectively collected data before, during and after administration of isofl urane: hemodynamic parameters, renal and hepatic function, level of sedation (rass) and sedative drug dosage. all data are reported as mean ± standard deviation, otherwise as median (minimum to maximum). results mean age was 43 ± 12 years and saps ii was 35.7 ± 11; 13 patients were treated with ecmo for severe ards and four had a history of drug abuse; median icu length of stay was 41 (15 to 127) days and they were ventilated for 41 (12 to 114) days. due to severe critical illness, target rass was -4 for all patients, most of which were also paralysed. isofl urane was administered in nine patients because of a high level of common sedative drugs, in fi ve patients due to the use of two or more hypnotic drugs and in one patient because of hypertrigliceridemia. isofl urane administration lasted 5.6 ± 1.8 days. during isofl urane administration no alteration in renal function or hemodynamic instability was recorded. after the isofl urane washout period we observed a reduction in sedative drug dosage in 10 patients while two patients were quickly weaned from mechanical ventilation and the target rass raised to 0. in two patients isofl urane was precautionarily interrupted because of concomitant alteration of liver function and suspected seizures respectively. conclusion inhaled anesthetics could be successfully used in the icu especially in case of an inadequate sedation plan; for example, in patients with a history of drug abuse or young severe ards patients that required deep sedation and paralysis for a long period. introduction pharmacological agents used to treat critically ill patients may alter mitochondrial function. the aim of the present study was to investigate whether fentanyl, a commonly used analgesic drug, interacts with hepatic mitochondrial function. methods the human hepatoma cell line hepg2 was exposed to fentanyl at 0.5, 2 or 10 ng/ml for 1 hour, or pretreated with naloxone (an opioid receptor antagonist) at 200 ng/ml or 5-hydroxydecanoate (5-hd; a specifi c inhibitor of mitochondrial atp-sensitive k + (katp) channels) at 50 μm for 30 minutes, followed by incubation with fentanyl at 2 ng/ml for an additional hour. the mitochondrial complex i-dependent, ii-dependent and iv-dependent oxygen consumption rates of the permeabilized cells were measured using a high-resolution oxygraph (oxygraph-2k; oroboros instruments, innsbruck, austria). the respiratory electron transfer capacity of intact cells was evaluated using fccp (carbonyl cyanide p-trifl uoromethoxyphenylhydrazone) to obtain the maximum fl ux. results incubation of hepg2 cells with fentanyl (1 hour, 2 ng/ml) induced a reduction in complex ii-dependent and iv-dependent respiration ( figure 1 ). cells pretreated with 5-hd before the addition of fentanyl exhibited no signifi cant changes in complex activities in comparison with controls. pretreatment with naloxone tended to abolish the fentanyl-induced mitochondrial dysfunction. treatment with fentanyl led to a reduction in cellular atp content (0.24 ± 0.06 in controls vs. 0.17 ± 0.14 μmol/mg cellular protein in stimulated cells; p = 0.02). we did not observe any diff erence in basal or fccp-uncoupled respiration rates of cells treated with fentanyl at 2 ng/ml compared with controls (data not shown). conclusion fentanyl reduces cultured human hepatocyte mitochondrial respiration by a mechanism that is blocked by a katp channel antagonist. in contrast, antagonism with naloxone does not seem to completely abolish the eff ect of fentanyl. introduction endothelial dysfunction during endotoxemia is responsible for the functional breakdown of microvascular perfusion and microvessel permeability. the cholinergic anti-infl ammatory pathway (cap) is a neurophysiological mechanism that regulates the infl ammatory response by inhibiting proinfl ammatory cytokine synthesis, thereby preventing tissue damage. endotoxemia-induced microcirculatory dysfunction can be reduced by cholinergic cap activation. clonidine improves survival in experimental sepsis [1] by reducing the sympathetic tone, resulting in the parasympatheticmediated cap activation. the aim of this study was to determine the eff ects of clonidine on microcirculatory alterations during endotoxemia. methods using fl uorescent intravital microscopy, we determined the venular wall shear rate, macromolecular effl ux and leukocyte adhesion in mesenteric postcapillary venules of male wistar rats. endotoxemia was induced over 120 minutes by intravenous infusion of lipopolysaccharide (lps). control groups received an equivalent volume of saline. clonidine 10 μg/kg was applied as i.v. bolus in treatment groups. animals received either (i) saline alone, (ii) clonidine 10 minutes prior to saline administration, (iii) clonidine 45 minutes prior to lps administration, (iv) clonidine 10 minutes prior to lps administration, (v) clonidine 30 minutes after lps administration or (vi) lps alone. results all lps groups (iii to vi) showed a signifi cantly reduced venular wall shear rate compared with the saline group after 120 minutes. there were no signifi cant diff erences between the numbers of adhering leukocytes in the clonidine/lps groups (iii, iv, v) and the lps group after 120 minutes. macromolecular effl ux signifi cantly increased in all groups over the time period of 120 minutes. after 120 minutes there was no diff erence between the lps group and the clonidine 10 minutes prior to lps administration group (iv) whereas all other groups (i, ii, iii, v) showed a signifi cantly reduced macromolecular effl ux compared with the lps group. conclusion clonidine has no positive eff ect on microhemodynamic alterations and leukocyte-endothelial interaction during endotoxemia. the reduction of capillary leakage in clonidine-treated groups depends on the time interval relative to the initiation of endotoxemia. endothelial permeability and leukocyte activation are regulated by diff erent pathways when stimulated by clonidine during endotoxemia. we conclude that clonidine might have an important time-dependent anti-infl ammatory and protective eff ect on endothelial activation during infl ammation. introduction delivering analgesics via conjunctival application could provide rapid and convenient pain relief in disaster medicine. there are sporadic reports from the usa concerning inhalation administration of aerosol with various drugs producing a wide variety of eff ects from anxiolysis, sedation, and loss of aggressiveness to immobilisation. we attempted to determine in an animal experiment whether conjunctival administration of s+ketamine could produce signifi cant eff ect without side eff ects. methods after ethic committee approval, 10 rabbits were administered conjunctival s+ketamine 2.5 mg/kg. measured parameters were spo 2 , blood pressure (bp) and heart rate (hr) before administration and in 1-minute intervals and immobilisation time (loss of righting refl ex [1] . we can speculate that the reason for stability of cardiorespiratory parameters was due to the sympathoadrenergic eff ect of ketamine or due to the method of administration. there were no signs of conjunctival irritation in any animal (s+ketamine is a preservative-free solution). conclusion conjunctival s+ketamine 2.5 mg/kg in rabbits produced rapid onset without changes in cardiorespiratory parameters and without signs of irritation of the eye. the results of our project warrant further research to increase the variety of drugs and methods of their administration for anxiolysis, sedation and analgesia in disaster medicine. introduction procedural sedation is used in the emergency department (ed) to facilitate short but painful interventions. many patients are suitable for discharge after completion. ideally, the agent used to achieve sedation should not have a prolonged eff ect, allowing safe discharge in the shortest time frame. we hypothesised that propofol, with its short onset and off set, may reduce length of stay (los) in comparison with traditional benzodiazepines. methods data from a prospective registry were analysed for the period 1 august 2011 to 31 january 2012. patients who underwent procedural sedation and who were discharged from the ed were identifi ed. individuals were grouped as having received propofol, midazolam or a combination of the two. all were discharged when fully alert and able to eat and drink. demographic details and the type of procedure undertaken were extracted. anova was performed to identify diff erences in the length of stay between groups, in addition to descriptive analysis. results during the study period 75 patients underwent procedural sedation and were discharged from the ed. the median age was 40 years and 57% were male. the commonest procedure performed was shoulder reduction (52%). in the propofol group (n = 20) the mean los was 100 minutes compared with 165 minutes in those receiving midazolam (n = 40) and 141 minutes in those receiving a combination (n = 15), p = 0.004. there was no diff erence in adverse events between groups. see figure 1 . conclusion propofol is increasingly used in eds for procedural sedation due to its short duration of action. this study suggests that a shorter duration of action and faster recovery may result in a reduced los in the ed. the use of propofol for sedation in intensive care has been associated with the propofol infusion syndrome (pris) characterised by cardiac dysfunction, metabolic acidosis, renal failure, rhabdomyolysis and hyperlipidaemia. we prospectively monitor biochemical markers that we believe demonstrate early signs of this dangerous, often fatal syndrome. when this pre-pris state is identifi ed, propofol is withdrawn whilst the syndrome is still reversible. methods we prospectively audited our monitoring of these markers over a 4-month period in propofol-sedated patients: propofol infusion rate, creatine kinase (ck), triglycerides (tg), creatinine, lactate, ph and base defi cit. we defi ned the criteria for pre-pris as requiring a ck ≥320 mmol/l that had doubled from its base level and a rise in tg ≥1.7 iu/l; both that followed a trend with propofol dose. conclusion we propose that a paired rise in ck and tg that can be attributed to propofol alone represents a pre-pris state that is at risk of developing into full pris. we noted this in 22% of our patients, all on modest doses of propofol. it is unclear what proportion of patients will develop the full syndrome as it is not ethically possible to continue propofol in this situation. we advocate daily monitoring of ck and tg to identify pre-pris so that propofol can be reduced or substituted to avoid the morbidity and mortality of the full syndrome. introduction until recently there were no guidelines for the reporting of adverse events (aes) during procedural sedation [1, 2] . a consensus document released in 2012 by the world siva international sedation task force proposed a benchmark for defi ning aes [3] . we analysed 1,008 cases of procedural sedation in the emergency department. methods the study is based on 1,008 patients who received procedural sedation with propofol in the emergency department between december 2006 and march 2012. patients were selected and sedated to a strict protocol by ed consultant staff . we applied the ae tool by performing a search through patient records, discussion with consultants performing the sedation and consensus opinion. results from 1,008 cases we identifi ed 11 sentinel (six of hypotension, fi ve cases of hypoxia), 34 moderate, 25 minor and three minimal risk adverse events. the study shows a 1% adverse event rate. this supports use of propofol sedation by emergency physicians but within the limits of a strict governance framework. our safety analysis using the world siva adverse events tool provides a reference point for further studies. introduction physical restraints are used to facilitate essential care and prevent secondary injuries. however, physical restraint may be regarded as humiliating. it may lead to local injury and increase the risk of delirium and post-traumatic stress syndrome. research on physical restraint is scarce. the aim of this study is to investigate the scope of physical restraint use. methods twenty-one icus ranging from local hospitals to academic centres were each visited twice and 327 patients were included. we recorded characteristics of restrained patients, motives and awareness of nurses and physicians. results physical restraint was applied in 74 (23%) patients, ranging from 0 to 54% in diff erent hospitals. frequent motives for restraint use were 'possible threat to airway' (36%) and 'pulling lines/probes' (31%). restrained subjects more often had a positive cam-icu (34% vs. 16%, p <0.001), could less frequently verbally communicate (14% vs. 49%, p <0.001), and received more often antipsychotics (49% vs. 28%, p <0.001), or benzodiazepines (55% vs. 36%, p = 0.003). the use of physical restraint was registered in the patient's fi les in 48% of cases. of the 310 interviewed nurses, 258 (83%) were familiar with a physical restraint protocol and 89 (29%) used it in any situation. thirty percent of the 60 interviewed physicians were aware of the physical restraint status of their patients. conclusion physical restraint is frequently used in dutch icus, but the frequency diff ers strongly between diff erent icus. attending physicians are often not aware of physical restraint use. introduction physical restraint (pr) use in critically ill patients has been associated with delirium, unplanned extubation, prolonged icu length of stay, and post-traumatic stress disorder. our objectives were to defi ne prevalence of pr use, and to examine patient, treatment, or institutional factors associated with their use in canadian icus. measures aimed at delirium prevention (psychohygiene and early mobilization) were carried only in a small minority or were not documented. to implement protocolled delirium care in the region at study, a multifaceted tailored implementation program is needed. introduction the objective of this study is to investigate the eff ect of intraoperative administration of dexamethasone versus placebo on the incidence of delirium in the fi rst four postoperative days after cardiac surgery. methods within the context of the large multicenter dexamethasone for cardiac surgery (decs) trial [1] for which patients were randomized to 1 mg/kg dexamethasone or placebo at induction of anesthesia, a monocenter substudy was conducted. the primary outcome of this study was the incidence of delirium in the fi rst four postoperative days. secondary outcomes were duration of delirium, use of restrictive measures and sedative, antipsychotic and analgesic requirements. delirium was assessed daily by trained research personnel, using the richmond agitation sedation scale and the confusion assessment method. medical, nursing and medication charts were evaluated for signs of delirium and use of prespecifi ed medication. analysis was by intention to treat. results of 768 eligible patients, complete data on delirium could be collected in 738 patients. the incidence of delirium was 14.2% in the dexamethasone group and 14.9% in the placebo group (odds ratio = 0.95, 95% ci = 0.63 to 1.43). no signifi cant diff erence was found on the duration of delirium between the intervention (median = 2 days, interquartile range 1 to 3 days) and placebo (median = 2 days, interquartile range 1 to 2 days) group (p = 0.45). the use of restrictive measures and administration of sedatives, haloperidol, benzodiazepine and opiates were comparable between both groups. conclusion intraoperative injection of dexamethasone seems not to aff ect the incidence or duration of delirium in the fi rst 4 days after cardiac surgery, suggesting this regimen is safe to use in the operative setting with respect to psychiatric adverse events. reference introduction the beliefs, knowledge and practices regarding icu delirium among icu professionals may vary. this may interfere with the implementation of the dutch icu delirium guideline. we aimed to get insight into potential barriers and facilitators for delirium guideline implementation that may help to fi nd an eff ective implementation strategy. methods an online survey was sent to healthcare professionals from the six participating icus. respondents included icu physicians, nurses and delirium experts (psychiatrists, neurologists, geriatricians, nurse experts). the survey consisted of statements on beliefs, knowledge and practices towards icu delirium. agreement with statements by more than 75% of respondents were regarded as facilitating items and agreement lower than 50% as barriers for implementing protocolled care. of the 565 surveys distributed, 360 were completed (63.7%). the majority of respondents were icu nurses (79%). delirium was considered a major problem (83%) that requires adequate treatment (99%) and is underdiagnosed (81%). respondents considered that routine screening of delirium can improve prognosis (95%). however, only a minority (20%) answered that delirium is preventable. only 39% of the respondents had received any training about delirium in the previous 3 years and 77% of them found training useful. the mean delirium knowledge score was 6.6 out of 10 (sd = 1.54). when all groups were mutually compared, nurses scored lower than delirium experts (anova, p = 0.013). the respondents (58%; n = 210) from three icus indicated that cam-icu assessment was department policy. however, 50% (n = 106) of these respondents felt unfamiliar with cam-icu and only 47% (n = 99) of them indicated that a positive cam-icu was used for treatment decisions. haloperidol was the fi rst-choice pharmacological treatment. only 21% of all respondents knew that a national icu delirium guideline existed, but in-depth knowledge was generally low. conclusion our survey showed that healthcare professionals considered delirium an important but underdiagnosed form of organ failure. in contrast, screening tools for delirium are scarcely used, knowledge can be improved and protocolled treatment based on positive screening is often lacking. these results suggest that the focus of implementation of icu delirium management should not be on motivational aspects, but on knowledge improvements, training in screening tools and implementation of treatment and prevention protocols. introduction delirium is an acute disturbance of consciousness and cognition. it is a common disorder in the icu and associated with impaired long-term outcome [1, 2] . despite its frequency and impact, delirium is poorly recognized by icu physicians and nurses using delirium screening tools [3] . a completely new approach to detect delirium is to use monitoring of physiological alterations. temperature variability, a measure for temperature regulation, could be an interesting parameter for monitoring of icu delirium, but this has never been investigated before. the aim of this study was to investigate whether temperature variability is aff ected during icu delirium. methods we included patients in whom days with delirium could be compared with days without delirium, based on the confusion assessment method for the icu and inspection of medical records. patients with conditions aff ecting thermal regulation, including infectious diseases, and those receiving therapies aff ecting body temperature were excluded. twenty-four icu patients were included after screening 334 delirious icu patients. daily temperature variability was determined by computing the mean absolute second derivative of the temperature signal. per patient, temperature variability during delirious days was compared with nondelirium days using a wilcoxon signed-rank test. with a linear mixed model, diff erences between delirium and nondelirium days with regard to temperature variability were analysed adjusted for daily mean richmond agitation and sedation scale scores, daily maximum sequential organ failure assessment score, and within-patient correlation. results temperature variability was increased during delirium days compared with days without delirium (mean diff erence = -0.007, 95% ci = -0.004; -0.011, p <0.001). adjusting for confounders did not alter our fi ndings (adjusted mean diff erence = -0.005, 95% ci = -0.008; -0.002, p <0.001). conclusion temperature variability is increased during delirium in icu patients, which refl ects the encephalopathy that underlies delirium. opportunities for delirium monitoring using temperature variability should be further explored. particularly, in combination with electroencephalography it could provide the input for an objective tool to monitor delirium. in icu patients, little research has been performed on the relationship between delirium and long-term outcome, including health-related quality of life (hrqol), cognitive functioning and mortality. in addition, results seem to be inconsistent. furthermore, in studies that reported increased mortality in delirious patients, no proper adjustments were made for severity of illness during icu admission. this study was conducted to investigate the association introduction we aimed to clarify the diff erences between primary and secondary acute gi injury. methods a total of 2,690 consecutive adult patients were retrospectively studied during their fi rst week in the icu. pathology in the gi system or laparotomy defi ned the primary gi insult. if gi symptoms developed without primary gi insult it was considered secondary gi injury. absent bowel sounds (bs), vomiting/regurgitation, diarrhoea, bowel distension, gi bleeding, and high gastric residuals (grv >1,000 ml/24 hours) were recorded daily. results in total, 2,690 patients (60.4% male), median age 59 years (range 16 to 92), were studied. eighty-four per cent of them were ventilated, 72% received vasopressor/inotrope. median (iqr) apache ii score was 14 (9 to 21) and sofa on the fi rst day was 6 (3 to 10). a total 35.5% had primary gi pathology. during the fi rst week 34% of patients had absent bs, 38% vomiting/regurgitation, 9% diarrhoea, 7% bowel distension, 6% high grv and 5% gi bleeding. all symptoms except diarrhoea occurred more often (<0.001) in patients with primary gi insult. eighty-fi ve per cent of patients with primary gi insult versus 46% without developed at least one gi symptom. the incidence of gi symptoms was signifi cantly higher in nonsurvivors. icu mortality was lower in patients with primary than secondary gi injury (43.6% vs. 61.2%, p = 0.046). nonsurvivors without primary gi insult developed gi symptoms later (figure 1 ). conclusion primary and secondary acute gi injury have diff erent incidence, dynamics and outcome. ventilation with relative risk of 9 to 27% and with mortality of 25 to 50% [1, 2] . one of the promoting factors of vap is the increased ph of the gastric acid, which occurs when h2-receptor antagonists (h2ra) or proton pump inhibitors (ppi) are used for stress ulcer prophylaxis. the results of this pilot study suggest that there may be no diff erence in the incidence of vap and gi bleeding if stress ulcer prophylaxis is performed by h2ra or ppi. as the latter is more expensive, its use as fi rst choice in critical care should be questioned. conclusion depending on resection size liver resection acutely increases portal venous pressure and induces neurohumoral activation resulting in compromised renal function and increased risk of developing aki. introduction severe acute pancreatitis (sap) requiring admission to an icu is associated with high mortality (hospital mortality reached 42%) and long lengths of stay [1] . survival among patients with predicted sap at admission has been shown to correlate with the duration of organ failure (of) [2] . the systemic determinant of severity in a new classifi cation of acute pancreatitis (ap) is also based on identifi cation of patients with transient or persistent of [3] . methods the aim of the study was to retrospectively determine the predictors of early persistent of in icu patients with sap. the analysis involved 152 patients. the median time interval between the onset of ap and admission was 24 (9; 48) hours. the patients were divided into two groups: the fi rst group (n = 46) had transient of and the second group (n = 106) had persistent of. the ability of the apache ii score, total sofa score and number of organ/system failure to discriminate transient from persistent of was explored with receiver operating characteristic (roc) curves. results hospital mortality was signifi cantly higher in the second group as compared with the fi rst group (45% vs. 7%, p = 0.000); while infectious complications were 39% versus 11% (p = 0.001) and median lengths of icu stay were 8 (5; 18) days for the second group and 6 (4; 7) days for the fi rst group (p = 0.001). optimum cutoff levels (by roc curve analysis) were apache ii score ≥12 (sensitivity 0.790; 1 -specifi city 0.119), total sofa score ≥4 (sensitivity 0.829; 1 -specifi city 0.190), and failure ≥2 organs/systems (sensitivity 0.819; 1 -specifi city 0.214). see table 1 . introduction the aim of this study was to evaluate the accuracy of thrombopoietin (tpo) plasma levels as a biomarker of clinical severity in patients with acute pancreatitis (ap). tpo is a humoral growth factor that stimulates megakaryocyte proliferation and diff erentiation [1] . furthermore, it favors platelet aggregation and polymorphonuclear leukocyte activation [2] . elevated plasmatic concentrations of tpo have been shown in patients with critical diseases, including acs, burn injury and sepsis [2] . in particular, clinical severity is the major determinant of elevated tpo levels in patients with sepsis [3] . ap is a relatively common disease whose diagnosis and treatment are often diffi cult, especially in the clinical setting of the emergency department (ed introduction renal ischemia-reperfusion injury (iri) is a common cause of acute kidney injury and occurs in various clinical conditions including shock and cardiovascular surgery. renal iri releases proinfl ammatory cytokines within the kidney. atrial natriuretic peptide (anp) has natriuretic, diuretic and anti-infl ammatory eff ects [1] and plays an important role of regulating blood pressure and volume homeostasis. the hypothesis was that renal iri induces infl ammation not only in the kidney but also in remote organs such as the lung and heart and anp attenuates renal injury and infl ammation in the kidney, lung and heart. methods male sprague-dawley rats were anesthetized with pentobarbital. tracheostomy was performed and rats were ventilated at vt 10 ml/kg with 5 cmh 2 o peep. the right carotid artery was catheterized for blood sampling and continuous blood pressure measurements. the right femoral vein was catheterized for infusion of saline or anp. rats were divided into three groups; iri group (n = 10), left renal pedicle was clamped for 30 minutes; iri+anp group (n = 10), left renal pedicle was clamped for 30 minutes, anp (0.2 μg/kg/minute, for 3 hours 25 minutes) was started 5 minutes after clamp; and sham group (n = 6), the shamoperated rats. hemodynamics, arterial blood gas, and plasma lactate levels were measured at baseline and at 1 hour, 2 hours and 3 hours after declamp. the mrna expression of il-6 in the kidney, lung, and heart were measured. the kidney, lung and heart were immunostained to examine the localization of il-6 and nf-κb and assigned an expression score. the wet/dry ratio of the lung was also measured. results renal iri induced metabolic acidosis, pulmonary edema, mrna expression of il-6 in the kidney, lung and heart. renal iri increased immunohistochemical localization of il-6 in the proximal convoluted tubule of the left kidney and nf-κb in the bronchial epithelial cells of the lung. anp attenuated metabolic acidosis, pulmonary edema and expression of il-6 mrna in the kidney, heart, and lung. anp decreased immunohistochemical localization of il-6 in the left kidney and nf-κb in the lung. conclusion these fi ndings suggested that infl ammation within the kidney after renal iri was extended into the lung and heart. anp attenuated metabolic acidosis and infl ammation in the kidney, lung and heart in a rat model of renal iri. anp may attenuate organ crosstalk between the kidney, lung and heart. reference increase in urinary ngal in patients receiving bicarbonate infusion was observed compared with control (p = 0.011). the incidence of postoperative rrt was similar but hospital mortality was increased in patients treated with bicarbonate compared with chloride (11/174 (6.3%) vs. 3/176 (1.7%), or 3.89 (1.07 to 14.2), p = 0.031). see figure 1 . conclusion on this basis of our fi ndings we do not recommend the use of perioperative infusions of sodium bicarbonate to reduce the incidence or severity of aki in this patient group. figure 1 ). an excellent predictive value was found for ungal/uhepcidin ratio (auc 0.90, figure 1 ). this ratio combines an aki prediction marker (ngal) and a marker of protection from aki (hepcidin), potentiating their individual discriminatory values. contrarily, at icu admission, none of the plasma biomarkers was a good early aki predictor with auc-roc ≥0.80. conclusion several urinary markers of acute tubular damage predict aki after cardiac surgery and the biologically plausible combination of ngal and hepcidin provides excellent aki prediction. introduction furosemide is one of the most employed diuretics in the icu for its ability to induce negative water balance. however, one common side eff ect is metabolic alkalosis [1] . we aimed to describe the time course of urinary excretion and changes in plasmatic acid-base balance in response to the administration of furosemide. methods we connected the urinary catheter of 39 icu patients to a quasi-continuous urine analyzer (kidney instant monitoring®), allowing measurement of ph (phu), sodium, chloride, potassium and ammonium concentrations (na+u, cl-u, k+u, nh4+u) every 10 minutes. the study period lasted 3 hours after a single intravenous bolus of furosemide (time 0). in 13 patients receiving two or more administrations over a longer period (46 (26 to 49) hours), according to clinical needs, we reviewed data on fl uid therapy, hemodynamics and acid-base balance from the beginning to the end of the observation. results ten minutes after furosemide administration, na+u and cl-u rose from 65 ± 6 to 140 ± 5 and from 109 ± 6 to 150 ± 5 meq/l respectively, while k+u fell from 60 ± 5 to 39 ± 4 meq/l (p <0.001 for all electrolytes vs. time 0) with a consequent increase in urinary anion gap (agu = na+u + cl-u -k+u). urinary output increased from 10 (5 to 19) to 53 (29 to 71) ml/10 minutes (p <0.05). after the fi rst hour cl-u remained higher than na+u, which progressively decreased, leading to a reduction in agu and phu over time. in parallel, a progressive increment in nh4+u was observed. in patients receiving more than one administration we observed an increase in arterial base excess (1.8 ± 0.8 vs. 5.0 ± 0.6 mmol/l, p <0.001) and plasmatic strong ion diff erence (sidpl) (31 (30 to 33) vs. 35 (34 to 36) meq/l, p = 0.01) during the study period. these changes were due to a decrease in plasmatic clconcentration (109.0 ± 1.1 vs. 106.6 ± 0.9 meq/l, p = 0.009). plasmatic sodium and potassium concentrations did not change. in these patients, considering the total amount of administered fl uids and urine, a negative water and chloride balance was observed (-460 ± 403 ml and -48 ± 48 meq, respectively). conclusion furosemide acts immediately after administration, causing a rise in urinary output, na+u and cl-u concentrations. loop-diureticinduced metabolic alkalosis may be due to an increased urinary chloride loss and the associated increase in sidpl. reference introduction given the signifi cant morbidity and mortality associated with acute kidney injury (aki), there is a need to fi nd factors to help aid decision-making regarding levels of therapeutic support. as a prognostic biomarker, the red cell distribution width (rdw) has attracted interest in the setting of critical care when added to existing scoring systems [1] . by examining rdw in a previously studied aki cohort, we aimed to evaluate the utility of this routine blood test. methods a cohort of 209 mixed critical care patients who received renal replacement therapy for aki had their demographic and biochemical data retrieved from electronic databases. outcomes were gathered for icu and hospital mortality. incomplete datasets were discarded, leading to 153 complete sets. rdw data were taken from the fi rst sample after admission to the icu, as were all other biochemical values apart from pre-rrt creatinine and potassium. overall cohort characteristics were gathered, and two groups were created: those with a rdw value within normal range (≤14.5%) and those with a greater than normal value (>14.5%). we then further subgrouped rdw to assess the correlation between rising levels and icu mortality. results a total 77.1% of our cohort had a rdw greater than the normal laboratory range at time of icu admission. key baseline characteristics (age, apache ii score, length of stay, icu mortality) did not diff er signifi cantly between patients with normal and abnormal rdw. when subgroup analysis was performed, no statistically signifi cant correlation between rising rdw and icu mortality was found (spearman correlation = 0.426, p = 0.233). conclusion in this cohort of critically ill patients with aki, rdw was not found to be a predictor of mortality. our results contradict those of recent studies [1, 2] . however, both groups of rdw patients in our study suff ered a higher icu mortality than in other studies. to further explain these fi ndings, we intend to perform multivariate logistic regression analysis and assess the eff ect of social deprivation on rdw. introduction intra-abdominal hypertension (iah) is an independent predictor of renal impairment and mortality [1] . organ dysfunction caused by the pressure eff ect of iah is well understood, but how this is modifi ed in the presence of bowel obstruction is unclear. the aim of this study was to determine how diff erent iah models cause renal dysfunction in a pig model. methods twenty-four pigs were divided into three groups; a control group (n = 5), a pneumoperitoneum (pn) (n = 10), and an intestinal occlusion (oc) model (n = 10). iap was maintained for 3 hours at 20 mmhg during which time creatinine, urea, urine output, potassium, and glomerular fi ltration pressure (gfp) were measured. statistical analysis was performed using repeated-measures anova. results over the fi rst 3 hours there was a statistically signifi cant diff erence between the control group and both iah models for conclusion as expected the iah models resulted in signifi cantly worse renal function after 3 hours. this early renal dysfunction may be as a result of an early infl ammatory process that has been associated with the pathophysiology of acute kidney injury. potassium was signifi cantly elevated in the pn group as compared with the oc group. early changes in potassium levels with iah may be a marker of early renal dysfunction and the usefulness of other renal biomarkers, such as ngal, prompts further investigation. reference introduction oliguria is common in septic patients and is frequently therapeutically addressed with loop diuretics; that is, furosemide. diuretic treatment in shock and hypovolemia is not rational, but can be tried in oliguric patients with normovolemia or hypervolemia and without hypotension. in such patients it still does not always increase dieresis and can also be harmful. the resistive index is a measure of pulsatile blood fl ow that refl ects the resistance to blood fl ow caused by the microvascular bed distal to the site of measurement. it can refl ect functional status of the tissue distal to the point of measurement. we investigated whether measuring the renal resistive index (ri) could be helpful in determining which patients will respond to furosemide treatment. methods we included medical icu patients with sepsis and oliguria (urine output <1 ml/kg/hour) who were prescribed i.v. furose mide. patients with known chronic renal failure, hypovolemia (cvp <10 mmhg) or severe hypotension (map <80 mmhg) were excluded. resistive index (1 − (end diastolic velocity / maximum systolic velocity)×100) was measured in at least three segmental arteries of both kidneys, the average of all measurements was reported as the result. repeated assessments were viewed as independent if separated by more than 24 hours. furosemide was given intravenously in the dose of 40 mg after ri measurement. positive response to furosemide was defi ned as doubling of hourly dieresis or achieving urine output >1.5 ml/kg/hour after drug administration. we included 47 patients with a total of 59 measurements. in 28 cases patients had positive response to furosemide. median ri in responders was 0.67 (range 0.55 to 0.78) and in nonresponders 0.79 (range 0.58 to 0.81); p = 0.027. construction of receiver operating characteristic curve showed 83% sensitivity and 81% specifi city for the cutoff ri 0.73. no other measured patient characteristic was found to be predictive of response to diuretic treatment. conclusion our results show that the ri could be used to guide diuretic treatment in nonhypovolemic, nonhypotensive septic patients. further studies are needed to confi rm those preliminary results. introduction as a proof of concept, the potential added value of chitinase 3-like 1 (chi3l1) as a more early and specifi c diagnostic parameter for acute kidney injury (aki) was investigated in adult icu patients that underwent elective cardiac surgery. . conclusion sdma appears to be an accurate and precise estimate of gfr and a more sensitive biomarker of renal dysfunction than scr. we predict sdma will perform better than scr as a biomarker of aki. this forms the basis of a future study. introduction growing evidence hints that bidirectional interaction between heart failure and kidney disease and renal insuffi ciency is a strong predictor of mortality as well as causally linked to the progression of heart failure. neutrophil gelatinase-associated lipocalin (ngal) is an early predictor of acute kidney injury (aki). we evaluated the impact of ngal on morbidity and mortality in patients with acute heart failure. methods seventy-six patients presenting with symptoms consistent with acute heart failure (median age 72 years, 56% male) were enrolled. plasma ngal levels were measured by an elisa at admission and compared with the glomerular fi ltration rate (egfr) and b-natriuretic peptide (bnp) levels. the primary outcome was aki development defi ned by rifle criteria (fall in gfr >25% or creatinine rise ≥50% from baseline, or a fall in urine output <0.5 ml/kg/hour) and secondary outcomes were duration of hospital stay and in-hospital mortality. conclusion ngal is emerging as a promising biomarker of aki in the setting of acute heart failure and elevated ngal levels indicate a poor prognosis in this population regarding morbidity and mortality. introduction aki is a common occurrence in sick hospitalized patients, in particular those admitted to intensive care. published data suggest that 4 to 5% of all critically ill patients develop severe aki and require initiation of renal replacement therapy (rrt) [1, 2] . such patients have high mortality rates often exceeding 60% [2] . we aimed to review the outcomes of patients admitted to the icu and required renal replacement therapy for aki. we examined whether aetiology of aki, comorbidity burden, hospital length of stay and treatment in icu had any signifi cant association with survival in the study cohort. methods during 2009, 56 patients were identifi ed to have received rrt with aki who were admitted to the icu at the royal wolverhampton hospitals nhs trust. computerised and paper-based case records were examined for these patients to collect the data. akin classifi cation was used to classify the severity of aki. conclusion individuals who develop dialysis-dependent aki in the icu setting in general terms either die or recover. sepsis is the most common association with death. the need for mechanical ventilation and inotropic therapy are both associated with increased incidence of death. introduction this study was to evaluate the effi ciency of the early start of intermittent substitutive renal therapy in patients with polytrauma complicated by multiple organ failure syndrome. methods forty-two patients with polytrauma complicated by multiple organ failure syndrome were included in the study. the age of the patients was from 20 to 60 years (38.3 ± 1.6 years average). all patients were divided into two equal groups. in the control group (cg) the criteria for the start of the substitutive renal therapy were: hyperkalemia ≥6 mmol/l, plasma creatinine ≥280 μmol/l, diuresis ≤20 ml/hour. in the investigation group (ig) there were subtests to carry out the substitutive renal therapy, allowing one to start it in the earlier period of the multiple organ failure progression. these are increase of na + >150 mmol/l, osmolarity >300 mosm/l, elevation of the plasma toxicity according to the average molecule concentration ≥1.0, diuresis decrease ≤40 ml/hour. these were examined: lethality, quantity of the substitutive renal therapy procedures, mechanical lung ventilation duration (mlv), intensive care and hospital duration. the substitutive renal therapy was carried out by ak-200-ultra apparatus (gambro, sweden). the statistical analysis was realized using statistica 6.1 and the mann-whitney u test. the average quantity of the substitutive renal therapy procedures in the cg was 13.4 ± 0.7, in the ig it was 8 ± 0.6 (p <0.05). the recuperation of the renal excretory functions was on 19 ± 1 day in 12 patients of the cg, and on 11 ± 1.3 day in the ig, from the moment of substitutive renal therapy start (p <0.05). lethality in the cg was 43% (nine patients), and in the ig it was 29% (six patients, p <0.05). the duration of the mlv in the cg and ig was 21 ± 1.2 days and 16 ± 1.2, respectively (p <0.05). in the ig the duration of the icu was lower by 23%, hospitality duration was lower by 17% (p <0.05). conclusion the effi ciency of the substitutive renal therapy depends directly on the hydroelectrolytic and metabolic changes and toxicosis degrees in the polytrauma complicated by multiple organ failure syndrome. the early start of the dialysis methods treatment allows one to achieve the earlier recuperation of the renal functions and to decrease the lethality level by 14%. can treatment with the molecular adsorbent recirculation system be the solution for typeintroduction it has been suggested that fl uid balance is a biomarker in critically ill patients [1] . there is a paucity of randomized trials examining the eff ect of daily fl uid balance on outcomes in patients on continuous renal replacement therapy (crrt). the renal trial did not fi nd mortality diff erence with higher crrt dose [2] , but did not investigate the eff ect of daily fl uid balance on patient outcomes. a post hoc analysis suggested survival benefi t in patients with negative fl uid balance [3] . in this study, we hypothesize that daily fl uid balance is an independent predictor of mortality in critically ill patients. we conducted a retrospective cohort study in eight icus of a tertiary academic center. we constructed a robust clustered linear regression model of daily fl uid balance and all-cause hospital mortality among 595 critically ill patients receiving crrt. we adjusted the model for the charlson comorbidity score, the daily sofa scores in the fi rst week after initiation of crrt as well the type of icu. results after adjusting for the type of icu and the daily severity of illness, patients who died had on average 779 ml higher daily fl uid balance compared with patients who survived (p <0.001, 95% ci = 385 to 1,173 ml, figure 1 ). severity of illness predicted daily fl uid accumulation; each additional point of the sofa score predicted an additional 57 ml of extra daily fl uid (p = 0.002). balance and intradialytic hypotension with mortality and recovery of renal function. methods we conducted a retrospective cohort study among patients aged ≥16 years who had rrt initiated and continued for ≥2 days in a level 2 or 3 icu at two academic centres, and had fl uid balance data available. patients with end-stage kidney disease, within 1 year of a renal transplant or who had rrt initiated to treat a toxic ingestion were excluded. we used multivariable logistic regression to determine the relationship between mean daily fl uid balance over the fi rst 7 days following rrt initiation and the outcomes of mortality and rrt dependence in survivors. introduction acute kidney injury (aki) is a common complication of critical illness and sepsis [1] . dosing of antibacterial agents in septic patients is complicated by altered pharmacokinetics due to both acute renal failure and critical illness [2] . current dosing regimens for administration of gentamicin and vancomycin to septic patients with aki on continuous venovenous hemofi ltration (cvvh) at a fi ltration rate of 45 ml/kg/hour are missing. methods seventeen septic patients with aki treated with vancomycin and seven patients with gentamicin on cvvh were included. in the vancomycin group, patients received the fi rst dose of 1.0 g intravenously followed by 1.0 g/12 hours if not adjusted. in the gentamicin group, patients received a loading dose of 240 mg followed by a maintenance dose every 24 hours. the vancomycin maintenance dose was optimized to achieve auc 0-24 /mic ≥400 (cmin >10 mg/l), gentamicin target was cmax/mic of 8 to 10. maintenance doses were adjusted according to drug level simulation using a pharmacokinetic programme. the median vancomycin total clearance (cltot) was 0.89 and 0.55 ml/minute/kg on the fi rst and second day of the study. crrt clearance accounted for about 50 to 60% of vancomycin cltot found in a population with normal renal function (0.97 ml/minute/kg). vancomycin serum concentrations after the fi rst dose were below the required target of 10 mg/l as early as 6 hours in 10 patients. auc 0-24 / mic ≥400 ratio was achieved in 67% of patients on the fi rst day. the median gentamicin cltot was 0.68 and 0.79 ml/minute/kg on the fi rst and second day of the study. crrt clearance accounted for about 50% of gentamicin cltot found in a population without renal impairment (0.73 ml/minute/kg). the target cmax/mic ratio was achieved in 78% of patients after the fi rst dose. conclusion cvvh at a fi ltration rate of 45 ml/kg/hour leads to high removal of both antibiotics. due to rapid change in patient's clinical status it was impossible to predict a fi xed dosage regimen. we recommend administration of unreduced loading dose and: blood sampling as early as 6 hours after fi rst vancomycin dose; blood sampling 30 to 60 minutes after gentamicin administration and before the next dose; and the maintenance dose should be based on druglevel monitoring. crrt. the aim was to evaluate the eff ects on electrolyte and acid-base status of a new rca-cvvh protocol using an 18 mmol/l citrate solution combined with a phosphate-containing replacement fl uid, compared with a previously adopted rca-cvvh protocol combining a 12 mmol/l citrate solution with a conventional replacement fl uid. methods until september 2011, rca-cvvh was routinely performed in our centre with a 12 mmol/l citrate solution and a postdilution replacement fl uid with bicarbonate (hco 3 -32, ca 2+ 1.75, mg 2+ 0.5, k + 2 mmol/l) (protocol a). in cases of metabolic acidosis, not related to inappropriate citrate metabolism and persisting after optimization of rca-cvvh parameter setting, bicarbonate infusion was scheduled. starting from september 2011, in order to optimize buff er balance and to reduce the need for phosphate supplementation, a new rca-cvvh protocol has been designed using an 18 mmol/l citrate solution combined with a recently introduced phosphate-containing replacement fl uid with bicarbonate (hco 3 conclusion protocol b provided a buff er balance more positive than protocol a and allowed one to adequately control acid-base status without additional bicarbonate infusion and in the absence of alkalosis, despite the use of a standard bicarbonate concentration replacement solution. furthermore, the combination of a phosphate-containing replacement fl uid appeared eff ective to prevent hypophosphatemia. introduction the aim of this study was to establish the intraobserver and interobserver variation of ultrasonographic measurements of the rectus femoris muscle cross-section area (rf-csa). muscle wasting is frequent in the icu, aff ecting more than one-half of the patients with severe sepsis [1] . muscle mass reduces rapidly, and 15 to 20% is lost within the fi rst week [1] . to monitor muscle mass, ultrasound has the benefi ts of being both readily available in the icu and non-invasive. ultrasonographic measurement of rf-csa has an almost perfect correlation with mri (mean interclass correlation (icc) = 0.999) [2] and rf-csa is linearly related to maximum voluntary contraction strength in both healthy subjects and copd patients (r = 0.78) [3] . methods the study had two purposes: to determine the intraobserver variation for rf-csa by one observer scanning 15 healthy adult volunteers three times each at 2-day intervals; and to determine the interobserver variation for rf-csa by two observers each scanning 15 adult icu patients on the same day. patients were in a supine position, legs in passive extension. the transducer was placed perpendicular to the long axis of the right thigh over the rf, two-thirds of the distance from the anterior superior iliac spine to the superior patellar border [1] . rf-csa was calculated by planimetry. at each scan, three measurements were made. for intraobserver variation, the 3×3 scans were analyzed using the interclass correlation coeffi cient. for interobserver variation, the three measurements from each observer were averaged and compared using bland-altman statistics. results intraobserver variation: 15 healthy adults, age 39.6 ± 2.4 years, weight 66.8 ± 2.3 kg, sex three male/12 female. icc: 0.996 (95% ci: 0.990 to 0.998). interobserver variation: 15 icu patients, age: 77 ± 8.3 years, weight: 71.3 ± 9.1 kg, sex nine male/six female. bland-altman: bias: -0.07 cm 2 , 95% limits of agreement -0.188 to 0.048 cm 2 . conclusion ultrasonographic measurement of rf-csa is easily learned and quickly performed. it has a very low intraobserver and interobserver variation and can be recommended as a reliable method for monitoring muscle wasting in the icu. in artifi cially fed critically ill patients, adipose tissue reveals an increased number of small adipocytes and accumulation of m2-type macrophages [1] . we hypothesized that nutrient-independent factors of critical illness explain these fi ndings, and also that m2macrophage accumulation during critical illness may not be limited to adipose tissue. methods we performed a randomized investigation in a septic mouse model of critical illness and a study of icu patient biopsies. in the critically ill mouse, we compared the eff ect of parenteral nutrition (n = 13) with fasting (n = 11) on body composition, adipocyte cell size, and macrophage accumulation in adipose tissue, liver and lung. fed healthy control mice (n = 11) were studied for comparison. in vivo adipose tissue was harvested after 1 week of illness from human patients (n = 40) who participated in a rct on early parenteral nutrition versus tolerating nutrient restriction [2] , adipose tissue morphology was characterized and compared with healthy controls (n = 13). results irrespective of nutritional intake, critically ill mice lost body weight, total fat and fat-free mass. part of the fat loss was explained by reduced ectopic fat accumulation. adipocyte cell number and the adipogenic markers peroxisome proliferator-activated receptor γ and ccat/enhancer binding-protein β increased with illness, again irrespective of nutritional intake. macrophage accumulation with predominant m2-phenotype was observed in adipose tissue, liver and lungs of critically ill mice, further accentuated by fasting in visceral tissues. macrophage m2-markers correlated with chemoattractant factor expression in all studied tissues. in human subcutaneous adipose tissue biopsies of critically ill patients, increased adipogenic markers and m2 macrophage accumulation were present irrespective of nutritional intake. conclusion adipogenesis and accumulation of m2-macrophages are hallmarks of critical illness, irrespective of nutritional management in humans and mice. critical illness evokes macrophage polarization to the m2-state not only in adipose tissue but also in liver and lungs, which is further accentuated by fasting. introduction intravenous magnesium sulfate is commonly used in obstetric patients with pre-eclampsia. following a case of acute symptomatic hypocalcemia we retrospectively examined a cohort of patients to investigate the frequency of hypocalcemia. methods obstetric patients were identifi ed from the icu admissions database and divided into two groups -those treated with magnesium (for suspected pre-eclampsia) and those admitted for other obstetric indications (postpartum hemorrhage, infection, etc.). the baseline calcium values were compared, as well as the lowest and discharge values. albumin and magnesium values were also compared. all comparisons used student's t test. results data were collected on 88 parturients admitted over 2 years including 40 (45%) who received magnesium and 48 (55%) who did not. magnesium-treated women were younger (age: 31 ± 7 vs. 36 ± 5 years, p = 0.02). the baseline calcium concentrations were similar for the two groups (2.2 ± 0.2 vs. 2.2 ± 0.1 mmol/l, p = 0.85). patients receiving magnesium had signifi cantly higher magnesium concentrations (2.1 ± 0.4 vs. 0.7 ± 0.2 mmol/l, p <0.001), and signifi cantly lower calcium concentrations during therapy (1.6 ± 0.3 vs. 1.9 ± 0.3 mmol/l, p <0.001). at discharge, the calcium levels were closer (magnesium treated 1.9 ± 0.2 vs. untreated 2.1 ± 0.1 mmol/l, p = 0.02). the albumin concentrations did not diff er between the two groups (magnesium treated 27 ± 13 vs. nontreated 33 ± 23 g/l, p = 0.134). normal values: calcium 2.15 to 2.55 mmol/l, magnesium 0.7 to 0.95 mmol/l, albumin 35 to 50 g/l. conclusion magnesium therapy was associated with hypocalcemia. potential causative mechanisms include a renal excretion interaction and magnesium-induced suppression of parathyroid hormone secretion. physicians should be aware of the potential for symptomatic hypocalcemia during magnesium therapy. introduction disorders of sodium (na + ) and water homeostasis are common in hospitalised patients. hyponatremia in particular has been associated with worse hospital outcome and length of stay [1] . we aimed to defi ne the incidence of hyponatremia (serum na + ≤134 mmol/l) in our intensive care population and to determine whether it was associated with icu outcome or length of stay. methods demographics, apache ii score, outcome data and admission sodium were retrieved from the ward watcher system in the victoria infi rmary icu for 2,440 consecutive admissions from january 2005 to present. we divided patients into three groups depending on serum na + (≤134 mmol/l, 135 to 144 mmol/l, ≥145 mmol/l) and compared apache ii score, length of stay and icu outcome between patients with a low versus a normal serum na + . data were analysed using the chi-squared test, student's t test and the mann-whitney test where appropriate. results of the 2,440 patients studied, 1,993 had apache ii data and serum na + recorded and so were included for analysis. in total, 453 patients (22.7%) had a serum na + ≤134 mmol/l and 1,388 patients (67.1%) had a serum na + of 135 to 144 mmol/l. patients with a low na + had a higher mortality (or = 1.48, 95% ci = 1.16 to 1.90, p <0.001), a higher apache ii score (22 vs. 19, p <0.001) and higher mean age (60 years vs. 58 years, p <0.001) than patients with a normal serum na + . mean length of stay of patients with low serum na + was also longer (5.1 days vs. 4.6 days) although this was not statistically signifi cant (p = 0.09). conclusion in summary, hyponatremia is a useful index of severity of illness in our icu population. whether this is a direct adverse eff ect of low serum sodium levels, or if hyponatremia is simply a marker for 'sicker' patients, is not known. reference introduction the anion gap (ag) is used routinely in the assessment of metabolic acidosis, but can be misleading in patients with hypoalbuminemia and other disorders commonly encountered in intensive care. this approach to acid-base analysis relies on assessment of ph, pco 2 , sodium, bicarbonate and chloride, and can lead to underestimation or overestimation of the true electrochemical status of a patient, as it does not include important ions such as lactate, calcium, magnesium, and albumin. the strong ion gap (sig) is an alternative to the ag and is based upon stewart's physical chemistry approach. however, the sig is cumbersome to calculate. as such, a number of shortcut equations have been developed in an eff ort to approximate the sig. we sought to compare three such equations, the kellum corrected anion gap (kellagc), the moviat equation, and ezsig, in an eff ort to evaluate precision and accuracy [1] [2] [3] . methods we conducted a retrospective chart review of consecutive patients admitted to the icu of george washington university medical center from september 2010 to march 2011. of the 1,516 patients screened, 200 met inclusion criteria, which included availability of all laboratory components to calculate the sig, obtained within 1 hour of each other. demographic data and serum values for ph, pco 2 , albumin, lactate, sodium, potassium, chloride, bicarbonate, magnesium, phosphate, and calcium were collected. the ag, sig, kellagc, ezsig, and moviat equations were subsequently calculated and compared using pearson correlation and bland-altman analysis. results the mean sig was 3.25 ± 3.5. mean values for kellagc, moviat, and ezsig were 4.5 ± 5.0, 1.77 ± 2.2, and 3.6 ± 3.7, respectively. pearson correlation coeffi cients for kellagc, moviat, and ezsig when compared with the sig were r = 0.77, p = 0.0001; r = 0.88, p = 0.001; and r = 0.89, p = 0.001, respectively. in bland-altman analysis, the mean bias for the test equations versus the sig were: kellagc (1.25), moviat (-1.48), and ezsig (0.40). conclusion while all three equations correlated highly with the sig, the ezsig and moviat outperformed the kellagc in pearson and bland-altman analysis. the ezsig had a smaller bias than the moviat equation and a slightly better correlation (0.89 vs. 0.88). in the assessment of critically ill patients, ezsig is a candidate scanning equation for the measurement of the sig when all sig components are not available. university-affi liated teaching hospital in tunis. patients admitted within the fi rst 24 hours post burn with greater than 10% total body surface area (tbsa) burned were enrolled in this study from 1 january 2009 to 30 june 2010. exclusion criteria were pregnancy, history of adrenal insuffi ciency, or steroid therapy within 6 months prior to burns. a short corticotrophin test (250 μg) was performed, and cortisol levels were measured at baseline (cs t0) and 60 minutes post test. adrenal insuffi ciency was defi ned by a response ≤9 μg/dl. relative adrenal insuffi ciency was further defi ned by a baseline cortisol >20 μg/dl. results patients were assigned into two groups: g1 (rai, n = 7) and g2 (absence ai, n = 11). comparative study of the two groups shows the results presented in table 1 . conclusion rai is common in severely burned patients during the acute phase, and is associated with shock. further prospective controlled studies will be necessary to establish risk factors of rai in severely burned patients and its impact on their prognosis. albumin-adjusted calcium concentration should not be used to identify hypocalcaemia in critical illness t steele 1 , r introduction hypocalcaemia is common in critical illness and accurate assessment is crucial. small studies have shown that albumin-adjusted calcium (adjca) does not accurately predict the ionised calcium (ica) concentration in critically ill patients, yet adjca continues to be widely used [1] . we investigated the reliability of using adjca to identify hypocalcaemia in a large, diverse population requiring intensive care. methods in a retrospective study of patients admitted to the icus of a tertiary care hospital between january 2008 and 2012, ica and ph were extracted from routine blood gas results and total calcium, albumin and phosphate from routine biochemistry results. adjca was calculated using a formula derived from and validated on the local population [2] . sensitivity, specifi city, positive and negative predictive values (ppv and npv) and area under the curve (auc) of adjca for predicting hypocalcaemia (ica <1.1 mmol/l) were calculated. results in total, 18 patients were included. the mean age was 69 ± 2 years, mean weight 76 ± 2 kg, apache ii score 23 ± 2 and most patients suff ered from pneumosepsis. on the fi rst day of intubation, total and free testosterone levels were extremely low in most patients and remained low during the fi rst week (figure 1 ). 17β-estradiol levels were elevated on day 1 and decreased during the fi rst week. lh and fsh levels were inappropriately low. all lipoprotein fractions and their apo-proteins were reduced as well as 17-oh-progesterone, dhea and dheas. in contrast, androstenedione (adione) levels were elevated. this suggests preferential and stimulated synthesis of androstenedione ( figure 2 ). the high 17β-estradiol levels indicate that androstenedione is shunted into the estrogen pathway, a process that requires high aromatase activity. the high estradiol/total testosterone ratio supports this conclusion. conclusion hyperestrogenic hypotestosteronemia is a frequent fi nding in the acute phase of severe sepsis in male patients with respiratory failure. it is suggested to be caused by decreased androgen production and shunting of androgen to estrogen synthesis as a result of increased aromatase activity. the clinical relevance of gonadal hormone substitution needs further study. introduction melatonin could have a meaningful role in critically ill patients, because of its immunomodulatory, antioxidant and sleep regulation properties; it is reduced in critical illness. the purpose of this study is to describe the endogenous blood melatonin values in icu patients and their correlation with clinical parameters. methods seventy-three high-risk critically ill patients mechanically ventilated for >48 hours were enrolled. blood samples for melatonin assay were collected between the 3rd and the 8th day of the icu stay. melatonin was determined by radioimmunoassay and elisa. the peak and the area under the curve (auc) calculated for each patient were correlated with the clinical parameters using the regression for quantiles test. results endogenous melatonin was found lower in critically ill patients compared with healthy subjects (figure 1) , although it showed a great individual variability and it generally maintained a night-time increase. in the univariate analysis the peak was found related to: blood creatinine (p = 0.034); patients in coma (p = 0.024); hospital mortality (p = 0.016). the auc was found related to: saps ii (p = 0.047); creatinine (p <0.001); ast (p <0.001); alt (p <0.001); hospital mortality (p <0.022). peak and auc were found higher in nonsurvivor patients. in accord with previous studies, the endogenous blood melatonin was found reduced in icu patients. the higher melatonin peak in renal failure may be due to an increased distribution volume; greater auc in patients with liver failure could be due to a less effi cient removal of the hormone from the systemic circulation. the fi nding of increased peak and auc in nonsurvivor patients could be due to a hormonal response increased by the body stress reaction, potentially similar to cortisol [1], or to a higher production of a physiological antioxidant [2] with a decreased ability to use it. introduction metformin intoxication inhibits mitochondrial complex i and oxygen consumption (vo 2 ). succinate bypasses complex i by donating electrons to complex ii. the aim of this study was to clarify whether succinate ameliorates mitochondrial vo 2 of metforminintoxicated human platelets. methods platelet-rich-plasma was incubated for 72 hours with metformin at a fi nal concentration of 0 mg/l (control), 1.66 mg/l (therapeutic dose) or 166 mg/l (toxic dose). platelet vo 2 was then measured with a clark-type electrode, in the presence of glutamate plus malate (complex i electron donors) (fi nal concentration: 20 mmol/l for both) or succinate (complex ii electron donor) (30 mmol/l), before and after adding cyanide (40 mmol/l). mitochondrial (cyanide-sensitive) and extra-mitochondrial (cyanide-insensitive) vo 2 were corrected for platelet count. the main results, from four preliminary experiments, are shown in figure 1 . in the presence of glutamate plus malate, only platelets incubated with a high dose of metformin had a mitochondrial vo 2 signifi cantly lower than controls. in the presence of succinate, mitochondrial vo 2 of controls did not change signifi cantly whereas that of platelets incubated with metformin did. the eff ect of succinate tended to become larger as the dose of metformin was increased from 0 up to 166 mg/l (0.3 ± 0.2 vs. 0.6 ± 0.3 vs. 1.0 ± 0.3 nmol/minute*10 6 cells) (p = 0.068). even so, mitochondrial vo 2 of platelets incubated with the highest dose of metformin did not return to the levels of controls. extra-mitochondrial vo 2 was always the same. introduction metformin, widely used as an antidiabetic drug, activates the amp activated protein kinase, a key regulator of the metabolism providing protection under fuel defi ciency. chronic metformin therapy has been shown in long-term follow-up clinical studies to reduce cardiovascular mortality [1] . in animal experiments, acute metformin pretreatment has been shown to reduce ischemia-reperfusion injury on cardiomyocytes [2] . we want to evaluate whether outcomes are aff ected in coronary artery bypass grafting (cabg) surgery. introduction metformin, an oral hypoglycemic drug, belongs to the biguanide class and is now generally accepted as fi rst-line treatment in type 2 diabetes mellitus, especially in overweight patients [1] . in some predisposing conditions, the use of metformin may result in metforminassociated lactic acidosis (mala), a rare adverse event associated with a high mortality rate [2] . the aim of this study is to assess risk factors and prognostic factors in patients with mala. [4] . in our study, a higher plasma concentration of lactate represents the main negative prognostic factor, as pointed out by other studies [5] . the prothrombin activity, which is considered to be a decisive prognostic factor in the study of peters and colleagues [6] , was not impaired in patients with poor outcome. introduction stress hyperglycemia in the critically ill is a complex process in which insulin signaling is systematically hijacked to provide energy substrate for metabolic priorities such as cell healing or infection containment. fluctuating levels of plasma glucose are associated with increased mortality in the icu [1] . we develop a multiscale mathematical model that can characterize the severity of stress hyperglycemia based on a fundamental understanding of the signaling molecules involved. methods insulin resistance following insult has been shown to be driven primarily by the immune response via the cytokine il-6 [2] . we created a multiscale mathematical model that links circulating glucose and insulin concentration dynamics from the extended minimal model [3] to a cellular insulin response model [4] that captures insulinmediated glucose uptake in an insulin-responsive cell. results inhibitory dynamics driven by il-6 were incorporated into the cellular model to attenuate an insulin signaling intermediate (insulin receptor substrate 1) according to the proposed biological mechanisms. the percentage reduction in glucose uptake as a function of il-6 concentration was fi t to data from patients who underwent elective abdominal surgery [2] , shown in figure 1 . the overall multiscale model captures decreased insulin signaling as a result of increased il-6 levels and the subsequent hyperglycemia that may ensue. introduction hyperglycemia is frequently encountered in critically ill patients, and associated with adverse outcome. improvement of glucose protocol adherence may be accomplished using electronic alerts. we confi gured a non-intrusive real-time electronic alert, called a glyc sniff er, as part of our intensive care information system (icis) that continuously evaluates the occurrence of persistent hyperglycemia and hypoglycemia. conclusion a real-time electronic persistent glycemia sniff er resulted in a signifi cantly higher proportion of normoglycemia, without increasing the variability. furthermore, hypoglycemic events occurred less frequently, and were resolved more timely. smart alerting is able to improve quality of care, while diminishing the problem of alert fatigue. introduction a recent study showed that hyperglycaemia (blood glucose ≥7.8 mmol/l) in nondiabetic patients hospitalised in a medical icu is associated with increased risk of diabetes [1] . we investigated a large mixed icu population to confi rm these results. methods this study retrospectively included patients with negative history of diabetes admitted to icus during the year 2007. we excluded patients receiving steroids, with newly diagnosed diabetes and those with end-stage disease. patients were followed-up 5 years after index admission. diagnosis of diabetes within 6 months from the index admission was presumed as revealing dm at inclusion, which excluded the patient. patients who were taking glucocorticoids during the followup period were excluded. diabetics were identifi ed from icd-9 documentation. propensity score for death (pdead) was computed from either sap1 (mimicii) or apache iii (hidenic) to assess the risk of death. hypoglycemia was defi ned as avg ≤60 mg/dl. avg was computed as the area under the glucose curve throughout icu admission. mortality was examined within bins (each bin is categorized by a 10 mg/dl increase in avg) and was compared between adjacent categories using a chi-square test. the same method was repeated among diabetics, nondiabetics, patients with lower (pdead greater than median) and higher (pdead lower than the presence of decubiti on admission to the icu is associated with longer hospitalizations even after adjusting for age, acuity, and organ supportive therapies. du on admission to icu provide a unique, unambiguous marker of increased resource utilization. introduction the aim was to analyze the prognosis of aids patients with organ dysfunctions at icu admission. methods a prospective cohort study, including all patients with hiv/ aids diagnosis, who were admitted to a specialized icu from november 2009 until may 2012. patients with less than 24 hours of icu stay were excluded. demographics and nutritional status were collected. the organ dysfunctions were classifi ed according to the sofa score, and categorized as absent (0 sofa point), mild (1 to 2 points) and severe (3 to 4 points). we expressed numeric variables as median and interquartile interval (25% to 75%). we performed a multivariate analysis of possible variables associated with hospital mortality (p <0.2), and we explored the 7-day, 28-day and 60-day survival of patients with and without independent risk factors. we included 139 patients with hiv/aids admitted to the icu. median age was 40 (31 to 48) years and 71% were male. severe malnutrition was common (34%). the cd4 cell count was 84 (25 to 274) cells/mm 3 and viral load was 17,733 (67 to 174,214) copies/ml; 57% had at least one opportunistic infection; 55% had used antiretroviral therapy previous to icu admission. mechanical ventilation was used by 46% of patients and hospital mortality was 42%. total sofa score was 5 (2 to 9) points. cardiovascular dysfunction was the most common on the fi rst day of stay (51%), followed by respiratory (42%), neurological (40%), renal (35%), hematological (27%) and hepatic (17%). cardiovascular and renal dysfunctions presented with higher rate of severe dysfunction (30% and 15%, respectively). rates of neurological (p = 0.002), renal (p = 0.009) and hematological (p = 0.003) dysfunctions were higher in nonsurvivors. age, cd4 cell count, malnutrition, and opportunistic infections were included in the multivariate analysis. neurological dysfunction was the independent risk factor for hospital mortality (odds 3.2 (1.4 to 7.2)). the presence of neurological dysfunction was dichotomized: associated or not with primary neurological diagnosis; survival was lower in the patients with neurological dysfunction and without primary neurological diagnosis (log-rank test 0.001 in the 7-day and 0.02 in the 28-day analysis). sixty-day survival was similar in primary and secondary neurological dysfunction, but it remained lower than in patients without neurological impairment. conclusion neurological dysfunction was independently associated with hospital survival, mainly in those aids critically patients without primary neuropathy. results a total of 273 charts were reviewed. in total, 242 were categorized into a (n = 126), b (n = 79) or c (n = 37). d (n = 31) consisted mainly of patients with hematological malignancies (n = 12) and patients with chemotherapy or immunosuppressive treatment (n = 14). the groups diff ered in length of stay with a< b< c. during the fi rst 3 days the sofa score was higher in a compared with c and in b compared with c. the duration of antibiotic therapy was longer in both b and c compared with a. there were no diff erences in 28-day mortality (a: 34/126 = 27%, b: 30/79 = 38%, c: 15/37 = 40%); however, the proportions of patients dying between days 8 and 28 were higher in b (14/63 = 22%) and c (7/29 = 24%) compared with a (5/95 = 5%). conclusion in this retrospective material it was possible to categorize 88.6% of all patients as having primary, secondary or tertiary sepsis. the categories diff ered in clinical picture at presentation as well as in outcome. a prospective study is warranted to validate the results of this study. conclusion older people represent a growing proportion of the population although their representation in the critical care population remained constant in this 10-year study. these patients had a slightly higher median apache ii score and 14.5% greater critical care mortality than the younger patients. the majority of survivors were able to go home; however, 31% died within 22 months with signifi cant life expectancy curtailment, surviving on average only 7.4 months after discharge; this has not changed in the last 10 years. those who survived this initial period (69%) had a much better outlook. this information may be vital to patients and physicians when discussing admission to critical care. reference methods potential risk factors for psychological problems were prospectively collected at icu discharge. two months after icu discharge 252 icu survivors received the questionnaires post-traumatic stress symptom scale-10 (ptss-10) and hospital anxiety and depression scale (hads) to estimate the degree of post-traumatic stress, anxiety and depression. of the 150 responders, 31% had adverse psychological outcome, defi ned as ptss-10 >35 and/or hads subscales ≥8. after analysis, six predictors with weighted risk scores were included in the screening instrument: major pre-existing disease, being a parent to children younger than 18 years of age, previous psychological problems, in-icu agitation, being unemployed or sick-listed at icu admission and appearing depressed in the icu. each predictor corresponded to a given risk score. the total risk score, the sum of individual risk scores, was related to the probability for adverse psychological outcome in the individual patient. the predictive accuracy of the screening instrument, as assessed with area under the receiver operating curve, was 0.77. when categorizing patients in three risk probability groups -low (0 to 29%), moderate (30 to 59%) and high (60 to 100%) risk -the actual prevalence of adverse psychological outcome in respective groups was 12%, 50% and 63%. conclusion the preliminary screening instrument may aid icu clinicians in identifying patients at risk for adverse psychological outcome after critical illness. prior to wider clinical use, external validation is needed. the multiorgan dysfunction syndrome (mods) is a dynamic process involving simultaneously or consecutively two or more organ systems [1] . the organ dysfunction's degree can be assessed by three severity scores (sofa [2] , mods [3] , lods [4] ), but they have some limitations: they do not allow the evaluation of the clinical course of a patient, they are not reliable in populations diff erent from the reference one, and they do not support clinicians' decisions. because mods implies a systemic infl ammatory reaction leading to microcirculatory dysfunction, our hypothesis was that organ failures follow a predictable sequence of appearance. our aims were to verify the presence of more likely organ failure sequences and to assess an online method to predict the evolution of mods in a patient. the high mortality and morbidity rate of mods in icus can in fact be reduced only by a prompt and well-timed treatment [5] . methods we selected 73 patients consecutively admitted to the icu of sant'andrea hospital from january to june 2012. the inclusion criteria were at least two organ systems with sofa ≥2, icu length of stay >48 hours. for each patient we calculated the sofa since the beginning of the inclusion criteria and daily for 8 days. for the statistical analysis we used dynamic bayesian networks (dbns) [6] . dbns were applied to model sofa changes in order to identify the most probable sequences of organs failures in a patient who experienced a fi rst known failure. we created a dbn for the analysis of mods studying the relations between organ failures at diff erent times. the dbn was made so that each organ failure is dependent on the previous one. we also considered a corrective factor to take account that not all patients completed the observation. using software (genie) we obtained the probabilities of the organ failure sequences. conclusion the use of dbns, although with our limited set of data, allowed us to identify the most likely organ dysfunction sequences associated with a fi rst known one. capability to predict these sequences in a patient makes dbns a promising prognostic tool for physicians in order to treat patients in a timely manner, or to test a treatment effi cacy. introduction assessing whether a critically ill patient should be admitted to an icu remains diffi cult and mortality amongst icu patients is high. to render intensive care with no prospect of success is an immense emotional burden for both patient and relatives, and a great socioeconomic burden for society as well. therefore, validated strategies that can help identify patients who will benefi t from intensive care are in demand. this study seeks to investigate whether preadmission quality of life can act as a predictor of mortality amongst patients admitted to the icu. methods all patients (>18 years) admitted to the icu for more than 24 hours are included. in order to assess preadmission quality of life, the patient or close relatives complete the short-form 36 (sf-36) within 72 hours after icu admission. mortality is evaluated from icu admission until 30 days hereafter. logistic regression and receiver operating characteristic analyses are employed to assess predictive value for mortality using fi ve models: introduction long-term compromise after traumatic injury is signifi cant; however, few modifi able factors that infl uence outcome have been identifi ed. the aim of this study was to identify acute and early post-acute predictors of long-term recovery amenable to change through intervention. methods adults (>17 years) admitted to the icu, princess alexandra hospital, australia following injury were prospectively followed. data were collected on demographics, pre-injury health, injury characteristics and acute care factors. psychosocial measures (selfeffi cacy (se), illness perception (ip), post-traumatic stress disorder (ptsd) symptoms and psychological distress) and health status (sf-36) were collected via questionnaire 1, 6, 12, and 24 months post injury. outcomes of interest were the physical function (pf) and mental health (mh) subscales of the sf-36. regression models were used to estimate predictors of physical function and mental health over a 2-year period. a subject-specifi c intercept in a mixed model was used to account for repeated data from participants over time. results participants (n = 123) were young (median 37, iqr 22 to 55 years), predominantly male (83%) and spent on average 3 days in the icu and 3 weeks in hospital. response rates were over 55% at each follow-up, with responders similar to nonresponders except for being generally older. pf and mh scores improved over time, although the averages remained below the australian norms at 24 months. predictors of pf included ip (β = -1.5, 95% ci = -3.1 to -1.1, p <0.01), se (β = 1.8, 95% ci = 1.3 to 2.6, p <0.01), hospital length of stay (β = -1.7, 95% ci = -2.0 to -0.8, p <0.01), never having been married (β = 1.8, 95% ci = 0.3 to 5.5, p = 0.03), and having injury insurance (β = -2.7, 95% ci = -6.9 to -1.9, p <0.01). predictors of mh included ptsd symptoms (β = -2.4, 95% ci -3.4 to -1.4, p <0.01), psychological distress (β = -6.9, 95% ci = -8.9 to -5.2, p <0.01), se (β = 0.6, 95% ci = 0.2 to 1.1, p <0.01), and unemployment (β = -2.3, 95% ci = -5.0 to -0.2, p = 0.04). conclusion trauma icu patients experience compromised physical function and mental health 24 months after injury. psychological distress, self-effi cacy and illness perception infl uence outcomes and are potentially amenable to change in response to interventions initiated during hospital stay. introduction swiss diagnosis related groups (swissdrg) have been eff ective since 1 january 2012. the infl uence of this new system on patients' discharge characteristics from a large icu is not known. with the introduction of the drg we expect patients to be discharged after a shorter length of stay on the icu and with higher severity of illness. methods the icu of the city hospital triemli in zurich has an interdisciplinary organization with surgical and internal medical patients, with a maximum occupancy of 18 beds and a center function for the surrounding hospitals. in this ongoing prospective observational study, we collect and analyze the anonymized data of all patients discharged from our icu prior to and after the introduction of the swissdrg. the primary endpoint was the length of stay on the icu in hours. the secondary endpoints were the severity of illness of the patients at the time of discharge, detected by the scoring system saps ii as well as measured by the number of readmissions to the icu. initially all patients were analyzed and in a second step only patients within percentiles 6 to 94 were considered. we also analyzed the subgroups of patients referred internally, patients sent back to referring hospital and patients regionalized to a homebase hospital. the statistics have been done with spss and p <0.05 was considered signifi cant. results we present the results of an 18-month period, 9 months prior to and 9 months after the introduction of the swissdrg. data of 1,491 and 1,492 patients were analyzed, respectively. when all patients were included, we found prior to and after the introduction of the drgs a comparable length of stay on the icu (mean ± sd of 52.1 ± 2.2 hours vs. 50.82 ± 2.2 hours), no diff erence in the severity of illness at discharge detected by the saps ii (mean ± sd of 27.9 ± 0.3 vs. 28.4 ± 0.3) and the number of readmissions (91 vs. 92). there was also no signifi cant diff erence when only percentiles 6 to 94 were included or when the three subgroups were analyzed. conclusion up to now, the introduction of the swissdrg has no infl uence on patients' discharge characteristics from a large icu. data assessment will continue and further data analysis has to be performed. there are only few data on the infl uence of drg on icu patients [1, 2] . we expect that the introduction of the drg in switzerland will change the number of admissions from external hospitals to a large icu with a centre function and will infl uence the severity of disease of the admitted patients. the icu of the triemli city hospital in zurich has an interdisciplinary organisation with surgical and internal medical patients, with a maximum occupancy of 18 beds and a centre function for the surrounding hospitals of the region. in this prospective ongoing observational study, we collect and analyse the anonymised data of all patients admitted to our icu from an external hospital during 12 months prior to (1 january to 31 december 2011) and after (1 january to 31 december 2012) the introduction of the drg in switzerland. exclusion criteria are admissions by the emergency department, self-assignments into the hospital and internal relocations. the primary endpoint is the number of admissions from an external hospital to our icu. secondary endpoints are the severity of the disease of the admitted patients, detected by the scoring systems saps ii and apache ii as well as the length of stay in external hospitals before admission. the statistical analysis is descriptive. results we present the preliminary data for 10 months (in each case january to october) before and after the introduction of the drg. we observed an increase of 9.2% (391 vs. 427 patients) of admissions to our icu after the introduction of the drg. the severity of disease determined by the saps ii score is unchanged (mean 26.7 vs. 26.0 points, p = 0.466). the severity of disease determined by the apache ii score is signifi cantly lower (15.4 vs. 14 points, p = 0.017). we also noted that after the introduction of the drg the patients were earlier transferred from an external hospital to our icu (mean time until transfer 29.9 vs. 18.7 hours), but this value was not signifi cant (p = 0.55). conclusion up to now the introduction of the drg in switzerland has had a complex infl uence on the number and the kind of patients (lwp, n = 300); and patients whose waiting time was equal to or less than that period, short waiting period (swp, n = 113). results in total, 413 patients were included, 300 of which belonged to the lwp group (65.4%). for the entire cohort, the mean apache ii score was 19 ± 7, the mean age was 52 ± 22 years, and 211 patients were male (51.1%). the lwp group did not show diff erence in the apache ii score (19 ± 7 vs. 18 ± 8, p = 0.13), but was older (55 ± 20 vs. 49 ± 23, p = 0.01). lwp also had a higher incidence of primary bloodstream infection (23.8% vs. 10.4%, p = 0.01) and catheter-associated urinary tract infection (10.2% vs. 1.9%, p = 0.01). lwp patients had higher mortality (37.8% vs. 25.9%, p = 0.02) and longer icu los (21 ± 47 vs. 14 ± 18 days, p = 0.01). relative risk for death in the lwp was 1.74 (95% ci: 1.11 to 2.72). conclusion despite showing no signifi cant diff erences on apache ii scores from the swp group, patients from the lwp group presented greater incidence of primary bloodstream infection, catheterassociated urinary tract infection, higher mortality outcomes and longer icu los. references intensivists are expected to have many roles during and after a major disaster/catastrophe; that is, triage, intensive care, education for people, and so forth. the roles of intensivists against special disaster or nuclear disaster are studied based on actual experiences. methods several disasters are studied. the fukushima daiichi nuclear plant explosion after the higashinihon earthquake 2011 was medically reviewed based on the total 30-day stay on-site in addition to several days around the site. the chernobyl incident 1986 was inspected 15 years after the incident. other nuclear disasters are included. results many serious problems were revealed in the medical teams, which are as follows: inappropriate basic preparedness against large special disasters, including nuclear disaster; lack of appropriate education and training for medical teams against nuclear disasterthat is, most members of japan dmat or the disaster medical assistance team are still laypersons; incorrect standard/rules of japan dmat, which were excessively focused upon cure of the usual type of injury and planned short period or nearly 48 hours, which should be abandoned; and insuffi cient consideration to the weak/vulnerable people or cwap, children, (pregnant) women, aged people, and the poor people/sicker patients. many of them died because of an insuffi cient emergency transportation system from their contaminated houses or hospital. conclusion in order to cope with the special disasters, such as nbc or nuclear, biological and chemical disaster, it is insuffi cient to take makeshift measures or use cheap tricks. working out the systematization of disaster medicine, based upon the academic viewpoints and philosophy/reliability, is essential to protect the people and the nation. variation in acute care burden and supply across diverse urban settings s murthy 1 , s austin 2 , h wunsch 3 , nk adhikari 4 , v karir 2 , k rowan 5 , st jacob 6 , j salluh 7 , f bozza 8 , b du 9 , y an 10 , b lee 2 , f wu 2 , c oppong 11 , r venkataraman 12 , v velayutham 13 , d angus 2 the world bank has warned that the rapid growth of the world's urban population can only be accommodated safely if cities adequately develop key infrastructure, such as the provision of acute care resources. yet, even basic descriptive information on urban acute care supply and demand is extremely limited. we therefore conducted a pilot assessment across seven diverse urban settings across the world. we selected a convenience sample of seven large cities with varying geographical and socioeconomic characteristics: boston, paris, bogota, recife, liaocheng, chennai, and kumasi. to estimate acute care supply, we developed an instrument to collect data on acute and critical care infrastructure. we collected data from municipal authorities and local research collaborators. we expressed the burden of acute disease as the number of deaths due to acute illnesses, estimated from the 2008 global burden of disease study. results were expressed as acute care supply and acute deaths per 100,000 population and acute care supply per 100 acute deaths. the supply of hospital beds varied from 72.4/100,000 population in kumasi to 245.8/100,000 in boston. icu beds with capacity for invasive mechanical ventilation and intensive nursing services ranged from 0.4/100,000 in kumasi to 19/100,000 population in boston. the number of ambulances varied 70-fold between cities. the gap between cities widened when demand was estimated based on disease burden, with a 70-fold diff erence between cities in icu beds/acute deaths. in general, most of the data were unavailable from municipal authorities. conclusion the provision of acute care services, a key aspect of urban infrastructure, varied substantially across the seven diverse urban settings we studied. furthermore, the local municipal authorities generally appeared to have little knowledge of their acute care infrastructure, with implications for future planning and development. resources may not always be allocated by severity of illness, but by custom or habit, particularly if diff erent groups administer bed control and triage. specialty-specifi c diff erences may exist even when a single team controls triage. variability in resource utilization has important implications for cost-containment and triage. methods patients admitted to a single, closed medical/surgical icu with full-time intensivists and unifi ed triage control in a large, university-affi liated hospital were evaluated during 2011 to 2012. patients who died in the icu were excluded. the day of discharge (d/c) and severity using apache iv and its related acute physiology score (aps) component were calculated daily for the fi rst 7 days. trend was assessed across days by cuzick's test. results a total of 719 surgical and 925 medical patients met inclusion criteria. in total, 20.2% of surgical and 21.3% of medical patients had an icu los <1; p = 0.58. admission severity was correlated with length of stay, p = 0.014 for both medical and surgical patients. medical patients are sicker on admission and d/c from the icu than surgical patients (p <0.05) (figure 1 ). conclusion icu utilization diff ered by patient type even with unifi ed triage control within a single unit. surgical patients were less severely ill on admission to and d/c from the icu. a signifi cant percentage of medical and surgical patients are d/c within 1 day and may be more effi ciently served in a less resource-intensive environment. the reasons for the diff erences in icu utilization for surgical versus medical patients require clarifi cation and may have implications for both resource utilization and cost. introduction interest in safety and clinical outcomes of inpatients has been growing in japan, because the 100,000 lives campaign was introduced under the japanese patient safety act in 2008. in this act, an introduction of the rapid response system (rrs) was one of the mainstreams to inpatients' care. however, many japanese healthcare providers cannot understand how to achieve the introduction of the rrs, because there are few who have knowledge of the system. therefore, we developed a new introductory training course for the rrs. the educational eff ectiveness was analyzed through the surveillance questionnaires after the course. methods the educational program includes a lecture series con cerning the outline and management methods, introduction of facilities that have already deployed, small group discussions, and teaching methods-of-training for the medical emergency team using a simulator. evaluation was made in the fi ve-point scale by 82 participants (58 physicians, 16 nurses and eight other professions) throughout seven courses. the questionnaires are: a. understanding of rrs, b. knowledge acquisition about patient safety, c. expectation for decreasing the cardiopulmonary arrest by rrs, and d. expectation for decreasing the psychological burden by rrs. results seventy-three participants (89.0%) answered the questionnaires. the numbers of participants who scored more than four points were as follows: a. was 71 (97.2%), b. was 70 (95.9%), c. was 64 (87.7%), and d. was 68 (93.2%), respectively. the majority of participants obtained the correct knowledge, and had a solid understanding for the rrs. it was evident that providing abundant material and didactic lectures traced from the introduction to management, and collecting and resolving the questions, promoted comprehension. however, there is a limitation of whether or not the participants introduce the rrs into their own institutions. it is essential to improve the course and continue to support the activities of the participants. conclusion our training course may promote the introduction and dissemination of the rrs in japan. introduction teaching of medical ethical issues including confi dentia lity and consent have long been a small part of the medical curriculum. these issues are more complex in an icu where patients may lack capacity. documents such as good medical practice 1995, confi dentiality 2009 and the mental capacity act 2005 give guidance to medical professionals in these matters in the uk. methods a questionnaire was distributed amongst staff in four icus in south london. results were analysed according to level of experience and background (medical/nursing or allied health professional (ahp)). of 225 questionnaires distributed, the response rate was 66% (31% doctors, 56% nurses and 13% ahp). staff with either less than 1 year experience or greater than 10 years experience had the greatest exposure to the mental capacity act and data protection act, suggesting a gap in knowledge in staff with intermediate experience. knowledge of the caldicott principles were unaff ected by experience, with many experienced respondents having 'no idea' . the majority of respondents (unaff ected by experience) felt that when giving information to relatives face to face, relatives should be kept fully informed. when giving information over the telephone, most doctors felt the response should be tailored to the knowledge of the person being spoken to whilst nurses were split between tailoring the response, giving full information, setting up a password system and not giving any information at all. most respondents felt date of birth and hospital number constituted 'patient identifi able information' . however, experienced staff did not appreciate the importance of unusual diagnosis and clinical photographs as also being able to identify patients. similarly, the majority knew that the patient themselves identifi ed the 'next of kin' but 7% (unaff ected by experience) felt this was decided by the family and felt the family could decide on resuscitation status. when consent is required for an elective procedure in a patient who lacks capacity, doctors tended to have a better understanding of the need to delay the procedure where possible than nurses, the majority of which felt this could be decided by the next of kin or two consultant doctors. most doctors felt that 'acting in the patient's best interests' would mean doing what would give the patient the best outcome rather than doing what the patient would have wanted (unaff ected by experience). the majority of staff , on answering this questionnaire, felt that they lacked suffi cient knowledge on the subject and most felt annual reminders would be useful. the icu is an environment where issues of consent, confi dentiality and disclosure of information occur daily. staff feel they lack knowledge in these areas that is unaff ected by their experience. we need to ensure that all staff have the necessary knowledge to deal with these situations. introduction alcohol-related hospital and icu admissions are known to have a huge impact on healthcare resources in the uk. excessive use of alcohol is independently associated with sepsis, septic shock and hospital mortality among icu patients. this study assesses the relationship between alcohol abuse and intensive care resource utilisation in a mixed medical, surgical and neurosurgical icu. methods a prospective survey of emergency alcohol-related admissions over a 1-year period was undertaken at a tertiary university adult general and neurosurgical icu. all patients were screened for acute and chronic alcohol abuse on admission. acute alcohol abuse was defi ned as being intoxicated with alcohol at the time of admission and chronic alcohol abuse was defi ned as chronic alcohol use exceeding recommended uk national guidelines on consumption. the amount of alcohol consumption was obtained, diagnosis on admission, icu and hospital mortality, length of stay, and total cost were recorded. all patients were screened for alcohol-related comorbidities. comparative retrospective data were obtained for the same time period for nonalcohol-related emergency icu admissions. data were analyzed using spss. results in total, 7.7% of patients were admitted with a history of acute/chronic alcohol excess. sixty-seven per cent of alcoholrelated admissions were due to acute alcohol excess. neurosurgical patients admitted due to alcohol excess had higher itu mortality than nonalcohol-related neurosurgical patients: 32.1% versus 14.39% (p = 0.02), respectively. ninety-three per cent of alcohol-related neurosurgical admissions were caused by acute alcohol intoxication. the intensive care cost was signifi cantly higher for alcohol-related (£12,396 per patient) compared with nonalcohol-related neurosurgical admissions (£7,284 per patient). of the medical patients admitted, 60% of these admissions were due to acute alcohol excess. the cost of intensive care treatment was lower for alcohol-related medical admissions. conclusion this is one of the largest studies of alcohol-related admissions to critical care. our survey confi rms that alcohol-related admissions to the icu are commonplace; however, our frequency is signifi cantly less than previously reported. our study reveals interspecialty variations in demographic data, apache ii scores, mortality and cost of admission. neurosurgical alcohol-related admissions bear higher mortality and result in greater resource utilisation relative to nonalcohol-related neurosurgical admissions. alcohol continues to burden both our patients and critical care. during the fi rst three postoperative days, preoperative ahi >30 was associated with a prolonged weaning time, a reduced oxygenation index (arterial po 2 /fio 2 ), an impaired kidney function, an augmented infl ammatory response and an overall increased length of stay in the icu. the observed association of high preoperative ahi values with postoperative clinical characteristics remained statistically signifi cant throughout the fi rst three postoperative days. conclusion undiagnosed sdb is highly prevalent among cardiac surgical patients. clinical trajectories of individuals with severe sdb are described by a prolonged recovery of pulmonary function, delayed weaning and a pronounced infl ammatory response after surgery. screening for sdb might identify patients that are susceptible for a complicated postoperative course. introduction a literature review was performed to assess whether massage benefi ts patients postoperatively following coronary bypass grafts (cabg) and or valve replacement/repair. a case study on a patient who had suff ered a hypoxic brain post cardiac arrest was conducted. methods a review on medline and cochrane using search terms massage, cardiac and icu identifi ed nine research papers on the benefi ts of massage postoperatively for the aforementioned patient group. other papers were listed but unrelated to cardiac surgery. none of the nine papers identifi ed for this review were icu specifi c in the title but the icu was mentioned in the main text body. for the purpose of this review the selected papers are researching the eff ects of massage on physiological parameters, anxiety, pain, calm and perceived stress indicators in the cabg and/or valve repair/replacement. out of these nine papers, one is british (2002). five are american (2006 to 2012), two are brazilian (2010) and one is an indian paper (2010). all papers are randomised control trials (rcts). papers written prior to 1999 were excluded from this literature review. introduction vap has continued to be a major cause of morbidity and mortality in critically ill patients in thailand for decades. previous research found that the implementation of vap care bundles and the educational program can reduce vap incidence in the icu [1] . in this research we aimed to observe the reduction of vap incidence after the implementation of vap care bundles to icu medical personnel. methods inclusion criteria: all adult surgical patients (>18 years old) who are on ventilatory support in the surgical icu at siriraj hospital. there are two groups, divided into pre-educational group (group i) and post-educational group (group ii) (n = 220/group). we also observed the adherence rate to vap care bundles according to the educational program. the pretest and post-test to determine the effi cacy of the educational program were done. the vap care bundles consisted of weaning according to weaning protocol, sedation vacation, headof-bed elevation, measurement of cuff pressures four times/day, 2% chlorhexidine use for mouth care and emptying of ventilator circuit condensate. results there were 45.38 and 25.25 episodes of vap per 1,000 ventilatordays in group i and group ii, respectively (p = 0.020). the incidence of vap was 21.82% in group i and 9.09% in group ii (p = 0.000). there was signifi cant reduction in the length of ventilatory support per person (group i = 2, group ii = 1 (median), p = 0.013, 95% ci = 0.319 to 0.936) and mortality rate (group i = 15.5%, group ii = 8.2%, p = 0.017). there was no signifi cant diff erence in loi, loh and atb cost. the pretest scores were 15.53 and 17.53 on average from 40 medical personnel in group i and group ii, respectively (p = 0.000). the head-of-bed elevation adherence rate was improved after the educational program (group i = 50.1%, group ii = 70.36%, p = 0.017). but the adherence to other bundles was not improved. see tables 1 and 2 . introduction following our study of severe sepsis care across three centres [1] , we aimed to introduce a rapid feedback mechanism into our rolling audit programme. whilst previous audits raised awareness of severe sepsis, only whole organisation performance was reported and no feedback was given to individual clinicians. it is recognised that such feedback loops can improve clinical practice [2] . methods patients admitted to critical care (58 beds, four units) with a primary admission diagnosis of infection were screened for severe sepsis. pre-icu care was then audited against the surviving sepsis guidelines [3] . time zero is defi ned as when criteria for severe sepsis were fi rst met. an individualised traffi c-light report was then generated and emailed to the patient's consultant and other stakeholders involved in care (figure 1 ). we aimed to report cases within 7 days of critical care admission. a cumulative report is generated monthly to track organisation-wide performance. since november 2011, 153 cases of severe sepsis have been audited and reported back to clinicians. compliance with antibiotics in <1 hour has risen from 35 to 75% and compliance with the pre-icu elements of the resuscitation bundle has risen from 20 to 70% ( figure 2 ). feedback from clinicians has been encouraging as our reports highlight both positive and negative examples of practice. conclusion individualised feedback on sepsis care has led to substantial improvements in guideline compliance. this concept could be translated to other time-dependent patient pathways. introduction when we talk about safety culture, we speak of being aware that things can go wrong. we must be able to recognize mistakes and learn from them, sharing that information fairly and impartially to try to prevent its recurrence. organizations such as the agency for healthcare research and quality (ahrq) have developed tools to help organizations measure their safety culture and there is little information about our country. methods a descriptive survey study. we sent the spanish version of the questionnaire on patient safety culture (ahrq) to the nursing staff of a polyvalent icu of 42 beds in a tertiary hospital. the questionnaire was sent to 179 nurses, receiving correctly answered 88 surveys (response rate of 49.16%). on a scale of 0 to 10, 6.97 points was obtained to estimate the safety climate for staff respondents. the item best scored was teamwork in the unit (65.9%). detected as a fortress, 'communication between nurses at shift changes' (76.1% positive responses). the worst rating was obtained in the section on human resources, followed by management support in the fi eld of patient safety. conclusion the perception of safety culture in an icu by nursing staff is far from optimal levels. the team work dimension was identifi ed as the most valued by workers, with the transmission of information on shift changes the most valued item. methods to compare our number of admissions, related activity and case-mix indicators 1 year before and after the geographical change was done. we analyzed our whole number of patients admitted to the icu. we used the chi-square test for categorical variables and one-way analysis of variance for quantitative data. minitab and statbas statistical programs were used. we plotted activity data using the barber-johnson 1 diagram. results a total of 2,774 cases (63% males; mean age 61 years) were admitted to our icu during the period (1 year before and after the transfer). no diff erences between both groups were founded in demographic data, knaus score and nyha status. regarding their origin, we found more patients admitted from other hospital centers (20 vs. 29%; p <0.001). apache ii score increased from 17.24 to 19.08% (p <0.001) and a slight increase change in saps 3 score was also found (52.29 to 53.75; p <0.01 there are several defi nitions of level 1 (l1) care, all refer to a group at risk of clinical deterioration on the ward [1] [2] [3] . there is evidence that ward patients who become acutely unwell often receive suboptimal care [4] . a regional study commissioned by norfolk, suff olk & cambridgeshire critical care network (nscccn) found that a majority of ward patients may be of l1 dependency and death rates appear to be correlated with l1 status. we aim to examine the relationship between the ward distribution of illness acuity, staffi ng and patient outcome. methods data were collected as part of nscccn's observational prevalence study in 2010. ward surveys included acuity of illness, staffi ng levels and skill mix. secondary data were obtained from the patient administration system. emergency, oncology, paediatric and maternity units were excluded. results complete datasets were obtained from 1,402 patients in 22 wards in our university hospital over two seasons. this constitutes 98.3% of inpatients from those wards. the mean ward occupancy rate was 94% (10th to 90th percentile: 85% to 100%). at least one l1 acuity criterion was scored by 898 (64%) patients, with 25% from geriatrics followed by orthopaedics (17%) and general surgery (10%). each ward had an average of eight qualifi ed nursing staff (range: 4 to 12) equating to an average staff :patient ratio (spr) of 0.253. there was no correlation between ward occupancy and nursing staff (pearson correlation, corr: 0.55), nor between prevalence of l1 criteria and staffi ng (corr: 0.34). the admission rate to intensive care was noted to be higher if the patients were nursed in a ward with lower than average spr compared with higher spr (2.7% vs. 1.2%, p = 0.058 fisher's exact), but this was not statistically signifi cant. senior nursing (band 6) staff were part of the skill mix on only nine of 44 ward surveys. conclusion better outcome with improved spr may be unsurprising, although if proven conclusively would signifi cantly inform workforce planning. lack of correlation between staffi ng levels and occupancy or acuity is also interesting given that we know l1 criteria are associated with worse outcome. introduction prolonged shifts, workload, stress, and diff erent confl icts are associated with burnout, loss of psychological wellbeing, and probably with an inadequate sleep quality (isq). this relevant disturbance leads to deterioration of the work performance, may impair quality of care provided to patients and increases the incidence of serious adverse events. the objective was to determine the prevalence of isq and sleepiness among uruguayan icu workers, and to evaluate risk factors associated with isq. methods a survey was conducted in six uruguayan icus. the sleep quality was evaluated on the basis of the pittsburgh score (ps), and the sleepiness was identifi ed by the epworth scale. isq was defi ned as ps greater than 5 points and sleepiness by an epworth scale higher than 6 points. icu's, patient's, and clinician's characteristics were assessed for their association with the prevalence of isq. all variables with p <0.2 in univariate analysis were included in a model of ordinal regression. p <0.05 was considered statistically signifi cant. results the survey was completed by 129 icu workers. the global prevalence of isq in icu was 67.4%. isq was observed in 45% of physicians and 82% of nurses and nurses assistant (p <0.001). sleep medication was used by 13.3% of the icu team. univariate analysis showed that isq was signifi cantly associated with sex (73% vs. 43%, p = 0.03 in women and men, respectively), marital status (84% vs. 61%, p = 0.01 in single and couple workers, respectively), more than 60 hours working in the last week (76% vs. 61%, p = 0.07) and less than 6 sleeping hours (95% vs. 54%, p <0.0001). multivariable analysis demonstrated that a sleep duration less than 6 hours was independently associated with isq (or = 24.5; 95% ci = 5.2 to 115.8; p <0.0001). furthermore, pathologic sleepiness was present in 59.3% of icu workers. sleepiness was independently associated with use of sleep medication (or = 5.9; 95% ci = 1.2 to 28.5; p = 0.025). conclusion the prevalence of isq and sleepiness is very high among icu workers. those disturbances are independently associated with a sleep duration less than 6 hours, and sleep medication use, respectively. these results highlights that strategies to decrease isq and sleepiness in icu clinicians are urgently needed to improve work performance, improve quality of care provided and prevent adverse events. introduction work-related stress is a potential problem among doctors and is associated with anxiety, depression, reduced job satisfaction, days off work, errors and near misses [1] . to compare stress levels between diff erent groups of doctors and identify causes of stress, we conducted a survey at university hospital lewisham using the uk health and safety executive's management standards (hsems). hsems is a validated tool developed to identify work conditions that warrant interventions to reduce stress levels across organisations [2] . methods we conducted an anonymous survey of doctors working in anaesthetics, intensive care, general medicine and accident and emergency (a&e) departments over 6 weeks using the hsems question naire. we also surveyed awareness of the trust's stress management services and whether staff had a designated supervisor or mentor. results were analysed using the hsems analysis tool, which rates stressors with a score from 1 to 5 (5 represents the lowest amount of stress). we compared the trust's results against hsems national standards. results seventy-two doctors completed the survey. lowest stress levels were found in doctors working in intensive care (n = 12, mean 3.63, sd 0.39). this was followed by medicine (n = 26, mean 3.55, sd 0.47), anaesthetics (n = 27, mean 3.40, sd 0.44), and a&e (n = 7, mean 3.11, sd 0.65), which had the highest stress levels. there was no signifi cant diff erence in stress levels between diff erent grades of doctors. when compared with hsems targets, staff relationships and peer support exceeded national standards. however, management of organisational change and demands at work need improvement. the majority of doctors (82%) had no idea what stress management services were provided by the trust. seventy-nine per cent of doctors had an allocated supervisor or mentor, 91% of those felt able to approach their supervisor. conclusion these survey results provide reassurance that stress levels in intensive care compare well, despite critically unwell patients and higher mortality rates. we identifi ed areas that need improvement within the trust and will present these results to all relevant departments. with the support of hospital management we will initiate hsems-validated measures to reduce stress. introduction although recent reports show an improvement in outcomes for pediatric hematology patients requiring intensive care [1, 2] , respiratory failure remains one of the major risks of pediatric mortality. this study was conducted to assess our hypothesis that mortality associated with respiratory failure is higher than that for other organ failures in pediatric hematology patients admitted to our icu. methods a retrospective study analyzed children with hematological disorders admitted to our icu between april 2005 and june 2012. all of the included children required emergency admission and invasive mechanical ventilation. those who did not need intubation, or required intubation only for therapeutic intervention and died within 24 hours of icu admission were excluded. the survival group was defi ned as patients who were discharged from the icu, and the nonsurvival group was defi ned as those who died in the icu or within 7 days after discharge from the icu. the pelod score and pim-ii were applied as morbidity scoring systems results twenty-seven patients, including 18 males and nine females, with a median age of 6.1 years (range, 0.2 to 16.6 years) were analyzed. sixteen patients had leukemia, fi ve had hemophagocytic syndrome, six had solid tumors. the average predicted mortality rate was 31.3% in pim-ii. the survival group included 15 patients (56%) and the nonsurvival group included 12 patients (44%). when the survival group was compared with the nonsurvival group, there were no signifi cant diff erences in the systolic blood pressure (101.3 ± 13.9 mmhg vs. 92.8 ± 25.4 mmhg; p = 0.15), the proportion of patients requiring continuous renal replacement therapy (33.3% vs. 50.0%; p = 0.30), and pelod score (15.5 ± 10.4 vs. 21.8 ± 15.4; p = 0.22). in the nonsurvival group, the pim-ii was higher than that in the survival group (27.9 ± 10.4 vs. 35.7 ± 9.0; p = 0.06); the pao 2 /fio 2 (272.5 ± 136.7 vs. 153.3 ± 123.3; p = 0.03) and oxygenation index (6.7 ± 8.1 vs. 14.1 ± 9.5; p = 0.04) were signifi cantly worse in the nonsurvival group than in the survival group. conclusion the data show that respiratory failure is more strongly associated with mortality than other organ failures in pediatric hematology patients requiring intensive care. these results also suggest that mechanical ventilation intervention in patients with respiratory failure must occur earlier to improve the outcomes for these patients. introduction critically ill patients with haematological malignancies (hm) have high hospital mortality [1] . severity of illness scores may underestimate mortality in such patients [2] . methods data collection was conducted at three hospitals from 2008 to 2011. patients with any active hm condition were matched with two control patients at two hospitals and with one control at christie hospital. control patients had the same apache ii (within 2 points) and admission diagnosis, but no hm. readmissions and planned surgical cases were excluded. results a total of 163 patients with hm were compared with 237 control patients. seventy-four admissions with hm were identifi ed at two hospitals, and each was matched with two control patients. eightynine admissions with hm from christie hospital were identifi ed. these were matched with 89 controls. patients with hm spent signifi cantly longer in hospital before icu admission (table 1) . unit and hospital mortality rates were not statistically diff erent between patients with hm and without hm ( table 2) . conclusion unit mortality of critically ill patients with hm was similar to those without hm. hospital mortality in patients with hm was higher than those without hm, although not statistically signifi cant. severity of illness at presentation to critical care is the main determinant of outcome in patients with hm. group when requiring emergency admission to the icu in a tertiary cancer centre. methods a retrospective review of medical notes between 2004 and 2012. results a total of 249 patients were admitted, of whom 54 had more than one admission. there were 310 episodes in total. leukaemia n = 85; lymphoma n = 90; myeloma n = 36. we compared the characteristics of those who survived icu admission with those who failed to survive to discharge from icu. the two populations were similar (age 51 vs. 57; males 59% vs. 57%). those who survived had a lower apache ii score on admission (19 vs. 23; p <0.001), lower mean organ failure scores (1 vs. 2; p <0.05), lower requirements of inotropes (26% vs. 50%; p = 0.001), ventilation (31% vs. 64%; p = 0.001) and fi ltration (11% vs. 26%; p = 0.004). there was no diff erence in the prevalence of sepsis at the time of admission (64% vs. 70%). both groups included patients with prior bone marrow transplant (38% vs. 40%). of note, icu and 6-month survival were 27% and 50%, respectively. these values are lower than those reported in the literature to date. conclusion icu and 6-month mortalities were 27% and 50%, respectively. patients with haematological malignancy stand to benefi t from intensive care, and should be off ered admission based on clinical need. introduction many evidence-based interventions are not delivered to patients [1] . this may not be due to a clinician's intentional decisions. the aim of this project was to compare the use of starch before and after removing it as an option from an e-prescribing template. methods our e-prescribing software enables users to prescribe intravenous fl uids from a series of menus. one of these is a template that has several fl uids available to use as a bolus when instructed by a clinician. we removed starch as an option from the template in april 2009. starch could still be prescribed elsewhere on the prescribing system. data on the use of starch from november 2008 to november 2012 were analysed as the mean volume of starch infused per patient per month. the mean of each set of parameters was then compared using a student's t test. results the mean volume of starch per patient administered before and after electronic prescription options were altered was 480 ml and 21 ml, respectively (p = 0.004). see figure 1 . conclusion despite clinicians intending to reduce the use of starch it was still regularly administered on our icu. the removal of a default prescribing option dramatically reduced the volume of starch used whilst not restricting the ability to make a conscious choice to prescribe it. adjusting default options has potential to infl uence clinical decisions and ensure more reliable, evidence-based care. introduction early detection of sepsis is important for a suffi cient treatment to reduce mortality. we hypothesized that using modifi ed systemic infl ammatory response syndrome criteria over 1 hour using an electronic software program facilitates the clinical diagnosis of sepsis. methods after irb approval and informed consent we enrolled in this prospective, observational, single-center study 1,119 consecutive patients (age 68.6 ± 16.4, female/male 476/649) admitted over a 6-month period to a surgical icu. a total 149 of them met modifi ed systemic infl ammatory response criteria. patients were monitored by an electronic software program using live data from the laboratory and bedside monitors to detect modifi ed systemic infl ammatory response syndrome criteria persisting over 1 hour. the physicians were blinded to the software program alerts that notifi ed in real time when modifi ed systemic infl ammatory response syndrome criteria were detected and persisted over 1 hour, but did not provide treatment recommendations. results there was a total of 149 modifi ed systemic infl ammatory response syndrome criteria alerts. seventy-four were confi rmed as true sepsis cases by physicians. the overall incidence of sepsis was 7%. patients were categorized into length of stay <24 hours, 24 to 96 hours and >96 hours. the overall sensitivity of our system for detecting sepsis was 68% and the specifi city was 91%. the positive predictive value is 34% and the negative predictive value is 98%. conclusion real-time alerts using an automated, electronic monitoring of modifi ed systemic infl ammatory response syndrome criteria facilitate the clinical diagnosis of sepsis. beds. intentional rounds or proactive patient rounds were recognised by the royal college of physicians and the royal college of nursing [1] as structured, evidence-based processes for nurses to carry out regular checks with individual patients at set intervals. the senior nursing team decided to adapt this initiative to the intensive care setting in order to address clinical challenges and provide guidance for shift leaders to focus on key elements of care. methods our intentional rounds, performed once per shift (twice daily), include two components. first, pressure area care -this component involves the shift leader checking whether key elements of pressure sore prevention have been performed. these include completion of the waterlow risk assessment tool [2] , noting the frequency of repositioning, use of lateral positioning and pressure-relieving pads. second, renal replacement therapy rates -this element was identifi ed as an area for focus after we established that our haemofi ltration fl uid use per hour of therapy was twice that of a near identical clinical setting. this pattern continued even after adopting similar therapy guidelines. the shift leader was guided to check whether therapy rates had been adjusted in line with latest biochemical results. the incidence of pressure ulcers in the 4 months since the initiative began has averaged 2.25 per month compared with 7.8 per month prior to commencement of intentional rounding. added to the rounding tool at the end of september 2012, rrt rates in the preceding 4 months averaged 31.5 ml/kg/hour over 24 hours, an 11.9% reduction from the previous average of 35.75 ml/kg/hour. if the pattern of rrt was to continue, this could equate to a cost saving of uk£40,000 per annum. conclusion the use of a modifi ed targeted intentional rounding tool by the nursing shift leader can help ensure that best practice guidelines are adhered to. this strategy can improve patient outcomes and provide potentially signifi cant fi scal benefi ts. references introduction handovers are often associated with poor communi cation. icu patients with multiple complex problems are ideal to study naturally occurring handovers. however, few studies have been conducted in the icu. methods we conducted questionnaires of physicians and nurses involved and observed handovers in real time of medical icu patients over 1 month. we interviewed 580 of 672 physicians and nurses involved (86.3%) and observed 90 real-time handovers (45 patients, 26.8%) of 168 patients. mean duration of handover was 391.3 (± 263.6) seconds, 78.5% were face to face and 1.26 (± 1.75) distractions per handover were noted, person-to-person calling being the commonest mode of distraction (46.7%). nurses received training during induction in signifi cantly higher numbers, covered allied specialties more and reviewed the patients early (all p <0.05). perception of the relative importance of diff erent components of the handover varied signifi cantly between donors, recipients, physicians and nurses. both physicians and nurses seldom (39.7%) reviewed the available electronic past medical records of the patient before handover, which in addition to training in handover and overall confi dence level in the management following handover are signifi cantly associated with better satisfaction in univariate analysis; only the confi dence level in patient management remained signifi cant after multivariate analysis. however, agreement between donor and recipient on overall satisfaction was poor (p >0.05). nursing handovers were signifi cantly longer than physicians' (572.08 ± 214.68 vs. 168.6 ± 97.27 seconds, p <0.001) but are also associated with higher distractions particularly during evening shifts. conclusion a higher percentage of nurses received handover training; nursing handovers are longer and more inclusive of other components of patient management; perceived importance of components of handover varies among healthcare professionals; distractions are common during handovers and associated with longer duration, by nurses and in the evening shifts; and higher confi dence level in patient's management following the handover is associated with better satisfaction. using telemedicine to provide acute burn and critical care consultation on pediatric and adult burn patients in lviv, ukraine, as well as in triage and transport of critically ill patients from lviv to a tertiary-care facility in the usa for further management. methods using a new telemedicine learning center established at city hospital #8 in lviv, ukraine, consultations regarding acutely injured burn victims occurred between physicians in ukraine and physicians at shriners hospital and massachusetts general hospital in boston. after the initial presentation, each patient was reviewed on a daily basis by physicians in boston. skype, an internet-based communication tool, was used in communication with the burn center in lviv. radiographic images were scanned and digitalized using an electronic scanner, and jpeg image compression was used to facilitate the transmission of radiographic images and patient charts. informed consent and hippa guidelines were followed in transmitting any patient-related information. results since 2011 we have provided consultation on 14 patients in lviv, ukraine, ranging in age from 15 months to 63 years. each patient had an average of six consultations. we present two of these cases as examples of the capabilities of our telemedicine program. the fi rst case involved a 15-month-old female with 40% tbsa from scald injury, where telemedicine was instrumental in the primary assessment as well as to arrange a direct assessment from a nearby burn surgeon. the second case resulted from a house fi re with multiple casualties, where physicians in boston were able to utilize telemedicine to guide the initial resuscitation and airway management of three critically burned children, as well as to arrange for transport of one of the victims, an 11-year-old male with 87% tbsa, from ukraine to the usa for acute management. multiple diffi culties were overcome in implementing the system between the two countries including: time zone diff erences, language barrier, and diff erent approaches to patient care. conclusion we have established a telemedicine program linking physicians in boston, ma, usa with city hospital #8 in lviv, ukraine to improve care in pediatric and adult burn patients. our program has provided consultation on 14 patients since 2011, and it highlights the capabilities of telemedicine for acute consultation as well as triage and transport of critically ill patients to tertiary-care facilities. introduction during the last few years the frequency of end-oflife decisions (eold) signifi cantly increased in icus. the method of nurse involvement in making eold is diff erent worldwide [1, 2] . the purpose of this study was to analyze opinions of nurses about therapy restriction. we have examined with a multicenter study the opinions of the medical stuff about end-of-life care in hungarian icus. methods we performed a questionnaire evaluation among physicians and nurses of icus about infl uencing factors of therapy restriction, the method of the decision-making process, and the frequency of diff erent eold. the questionnaire, containing 21 questions, was delivered electronically to hungarian icus, and then we analyzed the responses anonymously. the retrieved 302 answers (191 physicians, 102 nurses) were analysed using a nonparametric student's test. results a total 71% of the nurse responders work in university clinics, 2% in regional centrum, 24% in municipal hospital, 3% in other icus. the nurses found both human (2.72/5 vs. 1.98/5) and material (2.81/5 vs. 2.12/5) resources more restrictive factors during patient admission than physicians (p = 0.025, p = 0.0024). nurses working in municipal hospital were more strongly infl uenced by lack of material and human resources (3.34/5, 3.3/5) than nurses working in university clinics (2.2/5, 2.43/5), p = 0.01, p = 0.025. younger nurses (working between 6 and 10 years) were more interested in the patient's or surrogate's wishes than older nurses (working more than 10 years). religion did not infl uence patient admission and forego therapy; however, religious nurses compared with atheists and nonpracticing believers preferred to prolong therapy against the patient's will (p = 0.04). nurses felt that physicians slightly involved them in the end-of-life decision-making process (2.1/5 vs. 2.4/5 p = 0.0001). conclusion we found that the workplace, level of medical attendance, godliness, work experience, and position in medical staff strongly infl uenced making eold. while limitation of the therapy should be team work, nurses felt their opinions were hardly taken into consideration, although nurses seemed to be more realistic in the decision-making process. introduction more than one in fi ve people admitted to an icu will die there. research has highlighted concerns about support for patients and families and decision-making in this context [1, 2] . here, we describe the development and evaluation of a tool to improve palliative care in a 32-bed general icu in a central london teaching hospital. methods medical research council guidance for complex interventions phase 0 to i comprised literature review, theoretical modelling, observation and qualitative interviews and focus groups with staff and families exploring concerns and views of interventions identifi ed in the literature review. phase ii comprised intervention development, implementation and evaluation of tool feasibility and eff ects using staff survey, observation, audit of records and relative survey. results phase i: 47 staff and 24 family members were interviewed. the short time between decisions for treatment withdrawal and death, plus concerns for support management, communication and decision-making, highlighted a need to ensure excellent psychosocial assessment for all. phase ii: as part of integrated care guidelines, we developed the king's psychosocial assessment and care tool (k-pace). k-pace is used for all patients entering the icu, completed within 24 hours of admission. it contains psychosocial assessment of the family and patient needs, and identifi es key individuals for contact. educational training was supported by k-pace and was implemented in two waves. post-implementation survey of 95 icu staff found that most (80%) were aware of k-pace. eighty-two per cent of nurses but only 17% of doctors had completed the tool. in total, 158/213 (74%) family members responded to the survey (additionally three patients responded). there were high levels of satisfaction for symptom control and psychosocial care but concerns continued regarding explanation of treatment and care. conclusion k-pace is a feasible tool to improve the palliative care of patients and their families in the icu. further refi nement is needed and planned, with consideration of roll-out into the wider medical centre. be concerned involving the family's will. especially, stopping or withdrawing therapy is a quite diffi cult operation in japan because of legal issues. our hypothesis is that some diff erence exists in thoughts between physicians and nurses for terminal patients in the icu. the aim of this study is to know their real thoughts. methods a questionnaire survey was performed on physicians and nurses in our medico-surgical icu. the questionnaire consists of 11 questions with fi ve optional answers related to the thoughts of participants about treatment of hopeless or brain death patients. concretely, the questions were; whether to withhold therapy or not, whether to accept to withdraw therapy or not and with family's will, whether to accept to immediately stop therapy and with family's will, whether to positively or not donate organs from a brain death patient, necessity of icu care for brain death patients, and feeling guilty and stress for stopping or withdrawing therapy. the optional answer has fi ve gradations from 'yes' to 'no' for all questions. the participants were asked to answer the questionnaire by expressing themselves without regarding legal issues or the consensus. it was guaranteed to be anonymous for them in the data analysis. the answers were compared between physicians and nurses. the mann-whitney u test was used for statistical analysis. p <0.05 was considered statistically signifi cant. results there were in total 52 participants (response rate 98.1%) with 20 physicians and 32 nurses. withdrawing therapy was signifi cantly accepted in nurses than in physicians (83% vs. 55%, p = 0.039), when the family well understood. withholding therapy should not be operated for brain death patients for physicians (65%), while it seemed a diffi cult judgement for nurses (23%, p = 0.021). icu care for brain death patients is less necessary for physicians than nurses (80% vs. 53%, p = 0.016). there were no signifi cant diff erences in other questions between physician and nurses such as feeling guilty or stress for stopping or withdrawing therapy. conclusion some of end-of-life thoughts in the icu showed diff erences between physicians and nurses. introduction optimal patient evaluations of icu rehabilitation therapy remain unclear. methods one hundred icu patients with acute respiratory failure were randomized to receive early rehabilitation (er) or usual-care (uc). cohort 1 (n = 50) received er as one physical therapy (pt) session/day versus uc; cohort 2 (n = 50) received er as 2 pt/day with the second session resistance training, versus uc. uc was without er. blood was drawn for cytokines through day 7. cohort 2 underwent strength and physical functional assessments using the short physical performance battery (sppb), a valid and reliable measure of physical function consisting of walking speed, balance, and repeated chair stands. it is a well-studied composite measure in older persons, but has not been used in icu survivors. small changes of 0.5 to 0.6 points in the sppb have been shown to be clinically meaningful. conclusion in this pilot study, early icu rehabilitation was safe, and was associated with numerically although not statistically shorter hospital stay, greater strength and improved functional scores. particularly, the sppb demonstrated discriminatory ability in groups of icu survivors with low physical function. future early icu rehabilitation studies should consider icu survivor assessments using the sppb due to its ease, reproducibility and discriminatory ability following icu and hospital discharge. of the demographic variables such as sex, age, education, race and length of stay had an eff ect on perceived quality of care. conclusion the cqi 'r-icu' turned out to be a valid, reliable, sensitive and feasible instrument. large-scale implementation is recommended. actual incidence of global left ventricular hypokinesia in adult septic shock sepsis and the heart cardiovascular biomarkers in the icu plasma endothelin-1 levels in septic patients the role of endothelium and endogenous vasoactive substances in sepsis nicotinic acetylcholine receptor α7 subunit is an essential regulator of infl ammation cholinergic agonists inhibit hmgb1 release and improve survival in experimental sepsis thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome infl ammation, stress, and diabetes procalcitonin increase in early identifi cation of critically ill patients at high risk of mortality post-operative hypoalbuminaemia and procalcitonin elevation for prediction of outcome in cardiopulmonary bypass surgery enhanced oxygen delivery by perfl ubron emulsion during acute hemodilution iv perfl ubron emulsion versus autologous transfusion in severe normovolemic anemia: eff ects on left ventricular perfusion and function effi cacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial nosocomial infections in a cohort of extracorporeal life support patients the epidemiology and outcome of medical emergency team call patients treated with non invasive ventilation early prehospital use of non invasive ventilation improves acute respiratory failure in acute exacerbation of chronic obstructive pulmonary disease bts guidelines for the management of community acquired pneumonia in adults: update smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia the smart-cop score performs well for pneumonia risk stratifi cation in australia's tropical northern territory: a prospective cohort study application and comparison of scoring indices to predict outcomes in patients with healthcare associated pneumonia eff ects of continuous positive airway pressure in acute asthma noninvasive positive pressure ventilation in status asthmaticus eff ect of nasal continuous positive airway pressure on methacholine-induced bronchoconstriction the royal college of anaesthetists [www.rcoa.ac.uk/nap4] 2. diffi cult airway society equipment list cochrane handbook for systematic reviews of interventions. version 5.1.0. the cochrane collaboration proceedings book of 40th congress of the society of critical care medicine early goal-directed therapy in the treatment of severe sepsis and septic shock oxygen transport in cardiogenic and septic shock evidence based of the use of the pulmonary artery catheter: impact data and complications the eff ectiveness of right heart catheterization in the initial care of critically ill patients statistical methods for assessing agreement between two methods of clinical measurement use of central venous oxygen saturation to guide therapy comparison of central-venous to mixed-venous oxygen saturation during changes in oxygen supply/demand systematic review and meta-analysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients intraoperative fl uid optimization using stroke volume variation in high risk surgical patients: results of prospective randomized study accidental catheter removal in critically ill patients: a prospective and observational study national patient safety agency: reducing harm caused by the misplacement of nasogastric feeding tubes. npsa/2011/psa002. nhs national patient safety agency: reducing the harm caused by misplaced nasogastric feeding tubes. npsa/psa001./psa002. npsa epidemiology of severe sepsis in the usa: analysis of incidence, outcome, and associated costs of care post-injury multiple organ failure: the role of gut probiotics in the intensive care unit measures of crowding in the emergency department: a systematic review measuring and forecasting emergency department crowding in real time promoting global research excellence in severe sepsis (progress): lessons from an international sepsis registry interhospital transfer of critically ill patients: demographic and outcomes comparison with nontransferred intensive care unit patients outcomes of patients admitted to tertiary intensive care units after interhospital transfer: comparison with patients admitted from emergency departments outcome of critically ill patients undergoing interhospital transfer brain tissue oxygen monitoring and hyperoxic treatment in patients with traumatic brain injury association between early hyperoxia and worse outcomes after traumatic brain injury both hypoxemia and extreme hyperoxemia may be detrimental in patients with severe traumatic brain injury focused assessment with sonography in trauma (fast): should its role be reconsidered? it's higher than you think: chest drains and the 5th ics tube thoracostomy: complications and its management bts guidelines for the insertion of a chest drain american college of surgeons committee on trauma: advanced trauma life support for doctors, course manual. chicago: american college of surgeons american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care heart rate response to hemodialysis-induced changes in potassium and calcium levels survival in cancer patients undergoing in-hospital cardiopulmonary resuscitation: a meta-analysis acute intrathoracic gastric herniation as a rare cause of cardiac arrest dw hoelen references 1. kern kb: optimal treatment of patients surviving out-of-hospital cardiac arrest immediate coronary angiography in survivors of outof-hospital cardiac arrest immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest hypothermia for neuroprotection in adults after cardiopulmonary resuscitation investigation and early management of head injury. london: national collaborating centre for acute care updates in the management of intracranial pressure in traumatic brain injury guidelines for the management of severe traumatic brain injury bundled care for septic shock early prognosis in traumatic brain injury: from prophecies to predictions one-year extended glasgow outcome scale and hospital mortality predictors in patients with severe traumatic brain injury in brazil r turon 1 , fr ferreira 1 , d prado 1 bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors prophylactic anticoagulation with enoxaparin: is the subcoutaneous route appropriate in the critically ill? s26-s30. p370 massive blood transfusion for obstetric haemorrhage s simmons graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial the rule regulating ph changes during crystalloid infusion in vivo conditioning of acid-base equilibrium by crystalloid solutions: an experimental study on pigs mixing of medicines prior to administration in clinical practice: medical and non-medical prescribing procedural sedation goes utstein: the quebec guidelines barriers to propofol use in emergency medicine international sedation task force: adverse event reporting tool to standardize the reporting and tracking of adverse events during procedural sedation: a consensus document from the world siva international sedation task force mediators infl amm 2012 acute kidney injury in an infant after cardiopulmonary bypass predictive power of serum cistatin c red cell distribution width improves the simplifi ed acute physiology score for risk prediction in unselected critically ill patients red blood cell distribution width is an independent predictor of mortality in acute kidney injury patients treated with continuous renal replacement therapy incidence and prognosis of intraabdominal hypertension in a mixed population of critically ill patients: a multiplecenter epidemiological study eff ect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients acute renal failure in critically ill patients: a multinational, multicenter study impact of etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome cirrhotics admitted to intensive care unit: the impact of acute renal failure on mortality hyponatraemia as a risk factor for hospital mortality albumin-adjusted calcium is not suitable for diagnosis of hyper-and hypocalcemia in the critically ill derivation and internal validation of an equation for albumin-adjusted calcium conclusion succinate ameliorates (but does not return to normal) references 1. uk prospective diabetes study group p460 root cause analysis of hypoglycemic events in critically ill patients a mcdonald offi ce of national statistics population data sccm/esicm/accp/ats/sis international sepsis defi nitions conference the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome the logistic organ dysfunction system: a new way to assess organ dysfunction in the intensive care unit visualizing multiple organ failure: a method for analyzing temporal and dynamic relations between failing systems and interventions modelling gene expression data using dynamic bayesian networks disaster medicine compendium team japan critical care university of toronto, canada; 5 intensive care national audit & research centre oswaldo cruz foundation, rio de janeiro, brazil; 9 peking union medical college hospital standards for consultant staffi ng of intensive care units. ics & ibticm standards eff ectiveness of an educational program to reduce ventilatorassociated pneumonia in a tertiary care center in thailand: a 4-year study multi-departmental system analysis is needed for evaluation of severe sepsis care: a multi-centre study audit and feedback: eff ects on professional practice and health care outcomes surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock levels of critical care for adult patients acutely ill patients in hospital. nice guideline 50. nice an acute problem? ncepod hse management standards and stress-related work outcomes references 1. centre for maternal and child enquiries: saving mothers' lives: reviewing maternal deaths to make motherhood safer: 2006-08. the eighth report on confi dential enquiries into maternal deaths in the united kingdom 4% in non-infected patients, p = 0.223) and 40.3% were under haart (64.3% in patients admitted without infection, p = 0.016). mean cd4 count at admission: 219.62 ± 353.93 cells/mm 3 (vs. 370.22 ± 362.56, p = 0.048) 001) and 19.4% renal replacement (9.5% in no septic patients, p = 0.173). mean icu and hospital los was 10 ± 27.93 days (p = 0.016). icu mortality: 33.9% (19% in nonseptic patients, p = 0.098) conclusion sepsis is a common reason for admission to the icu in hiv patients and is accompanied by high mortality. pneumonia is the most frequent source of infection. septic patients are less frequently under haart and have a worse inmune status (lower cd4 count and higher viral load). despite a higher apache ii, and a higher need for hemodynamic and respiratory support, there is no statistically signifi cant diff erence in icu and hospital mortality between septic and nonseptic patients p515 survival of critically ill patients with haematological malignancies compared with patients without haematological malignancy r pugh 1 the outcome of haematological malignancy in scottish intensive care units intensive care unit admission in patients with haematological disease: incidence, outcome and prognostic factors intensive care management of patients with haematological malignancy comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel mm-comorbidity score icu and 6-month outcome of oncology patients in the intensive care unit assessing the quality of interdisciplinary rounds in the intensive care unit uni-and interdisciplinary eff ects on round and handover content in intensive care units perspective: physician leadership in quality rcn: ward rounds in medicine. principles for best practice. london: royal college of physicians, royal college of nursing the importance of accurate risk assessment and appropriate intervention in tissue viability handover in the emergency department: defi ciencies and adverse eff ects communicating in the 'gray zone': perceptions about emergency physician hospitalist handoff s and patient safety a national survey of end-of-life care for critically ill patients nurse involvement in end-of-life decision making: the ethicus study p528 alternative to improve palliative care for all patients and families in critical care units: development and preliminary evaluation following mrc guidance of the king's psychosocial, assessment and care tool i higginson, c rumble half the families of icu patients experience inadequate communication with physicians confl icts between physicians' practices and patients' wishes improving the quality of end-of-life care in the pediatric intensive care unit: parents priorities and recommendations on speaking less and listening more during end-of-life conferences evaluating end of life in ten brazilian pediatric and adults intensive care units parents' perspectives on physician-parent communication near the time of a child's death in the pediatric intensive care unit 001) and sepsis (p = 0.010) were signifi cantly diff erent between responders and nonresponders. responders had a lower mean gcs (7 ± 3 vs. 9 ± 3), lower amount of edema and were less likely to have had sepsis. in a multiple regression analysis, sepsis, edema, bmi and age explained 51% of the variance conclusion in patients with a better neurological condition, sepsis and/ or leg edema it was more diffi cult to obtain an adequate quadriceps contraction with nmes. nmes is safe to apply on the icu. references 1. dh and modernisation agency: the national outreach report. london: nhs modernisation agency pilot study of early rehabilitation strategies in acute respiratory failure d files physical rehabilitation following critical illness long term outcome from critical illness cg83 critical illness rehabilitation: guideline public health resource unit: critical appraisal skills programme. 10 questions to help you make sense of qualitative research quality measurement at intensive care units: which indicators should we use? handboek cqi ontwikkeling: richtlijnen en voorschriften voor de ontwikkeling van een cqi meetinstrument using the commissioning for quality and innovation (cquin) payment framework -guidance on national goals for refi nement, scoring, and validation of the family satisfaction in the intensive care unit (fs-icu) survey our data showed no benefi t with the use of a potent statin acutely in patients with sepsis or septic shock with regards to improvement in endothelial function. references conclusion the use of the lps-selective adsorption (particularly pmx-f) in patients with severe sepsis leads to improvement of systemic infl ammation and organ dysfunction. references s37 on these data we will continue to the next phase of this project and test pfc in the prevention of ards alone, and in combination with hs. references conclusion pp seems safe in obese patients and may improve oxygenation more than in nonobese patients. obese patients could be a subgroup of ards patients who may benefi t most from pp. references long-term functional outcome in adults with severe tbi: a meta-analysis m asselin 1 , y lachance 1 , g lalonde 1 introduction two previous classifi cations of acute kidney injury (aki) that are known as rifle criteria and akin criteria have shown that aki is associated with increased morbidity and mortality. diff erences in predicting ability for prognosis, however, have been reported. in 2012, kidney disease improving global outcomes (kdigo) created the new aki criteria, combining rifle and akin criteria. however, such a combination might cause inconsistency among each defi nition in the criteria. we have investigated all of the defi nitions in the new kdigo criteria in detail. methods this is a retrospective historical cohort study including adult patients admitted to the icu (jikei university, tokyo, japan) between january 2010 and october 2011. patients undergoing chronic dialysis were excluded. kdigo criteria were applied to all patients to diagnose aki. hospital mortality of patients with aki diagnosed by the 10 defi nitions in the criteria was compared. results a total of 2,399 patients were evaluated. aki occurred in 26.6% with standard defi nition of kdigo; 18.0% with creatinine criteria alone; 15.5% with urine output alone. by multivariable analysis, each aki stage was associated with hospital mortality: 5.6%, odds ratio 2.95, for stage 1; 10.1%, odds ratio 5.52, for stage 2; 30.2%, odds ratio 21.30, for stage 3. crude hospital mortality stratifi ed by the 10 defi nitions showed increasing trends with stage progression. mortality of the three defi nitions in stage 1 was from 4.2% to 8.8%. stage 2 had two defi nitions and their mortality was 12.1% and 12.9%. stage 3 had fi ve defi nitions and their mortality was from 20.5% to 55.6%. conclusion aki defi ned by the new kdigo criteria was associated with increased hospital mortality. in addition, defi nitions in the kdigo criteria seem to be appropriate because of clear relations between mortality and stage progression. introduction to evaluate whether urinary neutrophil gelatinaseassociated lipocalin (ungal) detects acute kidney injury (aki) earlier than the estimated glomerular fi ltration rate (egfr) in cardiac surgery patients. methods two-hundred and seventy-four adult patients undergoing cardiac surgery were consecutively included from february to december 2011. exclusion criteria were absence of diuresis due to end-stage renal disease or chronic renal failure and a previous cardiac catheterism with i.v. contrast use the week before surgery. four serial blood and urine samples immediately before (pre) and after (post) surgery, and 1 day (1d) and 2 days (2d) after surgery were obtained. ungal was measured in an architect 6200 (abbott diagnostics). akin criteria were used to diagnose aki. the study was approved by the local ethics committee and all patients gave informed consent. delta ungal was defi ned as the diff erence between the pre and the posts concentrations. results one-hundred and eighty-one patients (66.1%) were men; mean age was 68.2 ± 12.2 years. valve replacement was performed in 123, coronary artery bypass graft (cabg) in 81, valve surgery + cabg in 48, cardiac transplant in fi ve, aorta aneurism surgery in nine, and other procedures in eight patients. icu and hospital stays were 6.7 ± 8.1 and 15.7 ± 13.9 days, respectively. renal replacement therapy (rrt) was required in 16 patients (5.8%) within 48 hours of icu stay and in 28 patients (10.2%) within 4 weeks. mortality at 28 days was 2.9%. eighty-six patients (31.4%) were diagnosed with aki within 48 hours of surgery. area under the roc curve of post ungal for aki diagnosis was 0.72 (0.66 to 0.79) (p <0.0001) at an optimal cutoff value of 180 μg/l, introduction acute renal failure (arf) is a common complication in patients admitted to the icu. sepsis is also a well-known risk factor for the development of arf. the combination of arf and severe sepsis was reported to carry a mortality up to 70% whereas the mortality of arf alone is 40 to 45%. the aim of the study is to evaluate the role of renal perfusion scanning in detecting the prognosis and outcome of patients with acute renal failure due to sepsis. methods forty patients with acute renal failure due to sepsis, aged between 15 and 74 years, were enrolled in the study. they were monitored for their icu prognosis and outcome after doing renal perfusion scanning. all patients were subjected to routine icu and laboratory investigations including apache ii and sofa score. results thirty patients had normal renal scan and 10 patients had abnormal renal scan. the mortality percentage was higher among abnormal renal scan cases (three out of 10, 30%) compared with cases with normal renal scan (seven out of 30, 23.3%) with nonsignifi cant p value: 0.6. the median length of stay/day in icu was longer among nonsurvivors than survivors 15.5 ± 10, 11.5 ± 8, p value: 0.058 (approaching signifi cance). apache ii score was higher in nonsurvivors than survivors 23.9± 3.2, 19.6± 4.2, p value: 0.0001. the percentage of mortality among cases that needed mechanical ventilation was higher (nine out of 16, 56.3%) compared with mortality cases that did not need mechanical ventilation (one out of 24, 4.2% with p value: 0.0001). conclusion arf may exert an independent adverse eff ect on outcome in septic and septic shock patients. it is also a risk factor for mortality. tc-99m dmsa scanning is useful for detecting renal dysfunction and help to predict the outcome and prognosis. reference introduction acute kidney injury (aki) complicates over 50% of icu admissions. episodes of aki are a major risk factor for development or progression of chronic kidney disease (ckd); however, methods of estimated glomerular fi ltration rate (egfr) may be poorly calibrated to survivors of critical illness who may have reduced muscle mass. we hypothesized that egfr may underestimate rates and severity of ckd in icu survivors. methods a retrospective observational study of renal function in all patients admitted to a london teaching hospital icu for ≥5 days and surviving to hospital discharge in 2011. we excluded cases with current or new diagnosis of end-stage renal disease or renal transplant. we assessed aki in icu by kdigo 1 criteria and hospital discharge egfr by the ckd-epi equation. for comparison we assumed a normal gfr in a healthy individual as 120 ml/minute/1.73 m 2 at age 20 decreasing by 0.8 per year over age 20. results we identifi ed 282 patients, 180 of whom had aki. median age was 50 and 68% were male. median hospital discharge serum creatinine was 57 μmol/l (range 16 to 654), median egfr was signifi cantly higher than predicted normal gfr for age at 115 versus predicted 95 (p <0.001, median diff erence 16). in patients who had not had aki discharge the egfr was 119 versus normal predicted 98 (p <0.001, median diff erence 19), suggesting that egfr could be overestimating true gfr in our population by at least a factor of 1.23 ( figure 1 ). applying this correction factor to egfrs of patients who had recovered from aki resulted in 44% more diagnoses of ckd (egfr <60) at hospital discharge (36 vs. 25). conclusion egfr may overestimate renal function in survivors of critical illness confounding identifi cation of ckd in this at-risk population. prospective studies with measurement of actual gfr are required to assess the burden of ckd in survivors of critical illness. to analyze whether variables related to cardiopulmonary bypass (cpb) infl uence acute kidney injury (aki) occurrence and urinary neutrophil gelatinase-associated lipocalin (ungal) in cardiac surgery patients. methods a total of 274 adult cardiac surgery patients were consecutively included from february to december 2011. exclusion criteria were absence of diuresis due to end-stage renal disease or chronic renal failure and cardiac catheterism with i.v. contrast in the week before surgery. cpb, when performed, was used as standard cpb (scpb) or minicpb. we obtained four serial blood and urine samples, immediately before (pre) and after (post) surgery, and 1 day (1d) and 2 days (2d) after surgery. ungal was measured by architect 6200 (abbott diagnostics). akin criteria were used to diagnose aki. the study was approved by the local ethics committee and all patients gave informed consent. results one hundred and eighty-one patients (66.1%) were men; mean age was 68.2 ± 12.2 years. icu and hospital stays were 6.7 ± 8.1 and 15.7 ± 13.9 days, respectively. twenty-eight-day mortality was 2.9%. eighty-six patients (31.4%) were diagnosed with aki within 48 hours after surgery. in total, 219 patients required cpb (195 scpb, 24 minicpb) and 55 did not (no-cpb). seven no-cpb patients (12.7%) developed aki and their median ungal post was 330 (42.6 to 489.9) μg/l compared with 13.6 (6.9 to 38. 3 introduction neutrophil gelatinase-associated lipocalin (ngal), measured early after cardiac surgery, has been demonstrated to predict postoperative acute kidney injury (aki). fluid overload potentially masks a subsequent acute renal function loss through dilution of serum creatinine and maintenance of urine output just above akidefi ning criteria. methods we investigated the early postoperative value of ngal versus that of simultaneously measured serum creatinine to predict subsequent fl uid overload. we studied 100 adult cardiac surgery patients in the control arm of a rct (nct00672334). severe postoperative fl uid overload was defi ned as positive fl uid balance >10% of preoperative body weight within 48 hours after surgery. results severe postoperative fl uid overload was present in 5% of patients with a mean positive fl uid balance of 15.8 ± 9.5 l. at icu admission, urine ngal predicted severe fl uid overload (auc-roc 0.82 (95% ci = 0.70 to 0.94)) ( figure 1 ) and mortality (auc 0.88 (0.78 to 0.97)). serum creatinine measured at the same time did not predict severe fl uid overload (auc 0.52 (0.26 to 0.79)) or mortality (auc 0.61 (0.16 to 0.99)). conclusion early ngal-guided adjustments to fl uid management may reduce organ edema after cardiac surgery. findings should be validated in larger cohorts. survivors of acute kidney injury requiring renal replacement therapy rarely receive follow-up: identifi cation of an unmet need cj kirwan, r taylor introduction acute kidney injury (aki) occurs in more than 50% of icu admissions, requiring renal replacement therapy (rrt) in around 10% of cases. there is now increasing evidence that aki is a risk factor for the development and progression of chronic kidney disease (ckd); however, when aki occurs as a complication of critical illness appropriate follow-up may be neglected. accordingly, we reviewed the follow-up of renal function in all patients who received rrt on our icu and survived to hospital discharge. methods a retrospective audit of patients who received rrt in a central london adult critical care unit during 2011. results of 921 patients admitted, 203 received rrt with 109 surviving to hospital discharge. we excluded 52 patients who had end-stage renal disease, renal transplant or known glomerular disease. of the remaining 57 aki patients, median age was 60 (range: 18 to 77) and 37 (65%) were male. median discharge creatinine was 74.5 μmol/l (27 to 662). forty-two (74%) were off ered follow-up, but in only six cases (11%) was this to nephrology services. twenty-eight attended follow-up (fi ve to nephrology) at a median time of 6 weeks; however, creatinine was measured at in only 14 and in six of these it had risen (by median 16.5 μmol/l). in addition, 14 patients had creatinine measured 3 to 6 months post discharge and in eight it had risen (by median 31.5 μmol/l). conclusion follow-up of patients who received rrt for aki in the icu was poor and they were rarely referred to nephrologists. where renal function was measured after discharge, there was evidence of progressive renal dysfunction; however, renal function was often not assessed. we propose an algorithm for clinicians to guide follow-up. see figure 1 . introduction hyperglycemia and hypoglycemia have been linked to worse outcomes in critically ill patients. while there is controversy as to the optimal tightness of glucose control in critically ill patients, there is agreement that an upper limit to safe glucose levels exists and that avoiding hypoglycemic episodes should be prioritized. our algorithm can assist clinicians in maintaining blood glucose ([gbl]) within a desired target range while avoiding hypoglycemia. methods our model predictive control (mpc) algorithm uses insulin and glucose as control inputs and a linearized model of glucoseinsulin-fatty acid interactions. to allow the controller model to learn from data, a moving horizon estimation (mhe) technique tailored the tissue sensitivity to insulin to individual responses. patient data ([gbl] measurements, insulin and nutritional infusion rates) were from the hidenic database at the university of pittsburgh medical center. [gbl] measurements, typically hourly, were interpolated to impute a measurement every 5 minutes. the model captured patient [gbl] via nonlinear least squares by adjusting insulin sensitivity (si) and endogenous glucose production (egp0). the resulting virtual patient (vp) is used to evaluate the performance of the mpc-mhe algorithm. results mpc controller performance on one vp is shown in figure 1 . across a population of 10 vps, the average [gbl] under mpc is 6.31 mmol/l, the average minimum is 4.62 mmol/l, the population individual minimum is 3.49 mmol/l and the average absolute average residual error is 0.83 mmol/l from a 5.6 mmol/l target. with standard intervention, the 10 vps have an average [gbl] of 9.32 mmol/l, an average minimum [gbl] of 3.77 mmol/l, and a population minimum [gbl] of 2.78 mmol/l. algorithm performance deteriorates signifi cantly if the imputed sampling time exceeds 30 minutes, underlining the importance of dynamic variations in insulin sensitivity in this population. conclusion the mpc-mhe algorithm achieves targeted glucose control in response to changing patient dynamics and multiple measured disturbances for a pilot population of 10 vps. furthermore, the mhe scheme updates patient parameters in real time in response to changing patient dynamics. introduction blood glucose (bg) control reduces morbidity and length of stay, and is standard practice in patients undergoing cardiac surgery [1] . however, maintaining bg in the target range, while avoiding hypoglycemia, is challenging. continuous glucose monitoring (cgm) is a promising technology that may help address these challenges. we investigated the performance and safety of medtronic sentrino®, a newly developed cgm for critically ill adults, in the cardiac icu. methods adult patients with actual or planned cardiac icu admission at a single tertiary center were approached for participation and signed consent. other inclusion criteria were treatment with i.v. insulin (target bg <140 mg/dl) and life expectancy >96 hours. after initiation of i.v. insulin, sentrino® subcutaneous glucose sensors were inserted into patients' anterior thighs with planned study participation of 72 to 96 hours. reference bg was collected according to icu protocol, obtained from central venous catheter and analyzed with bedside blood gas analyzer (bga; i-stat®, abbott, usa). sensor glucose (sg) results were displayed, and its predictive alerts and alarms fully enabled. additional reference bgs were obtained during alarms and calibration. all treatment decisions were based on bga data, not on sg values. results a total of 21 patients were enrolled; all successfully completed the study. mean age was 65 years, 38% were women, 67% had diabetes. types of surgery were cabg (38%), valve replacement (29%), combined cabg and valve (19%) and cardiac transplant (14%). sg was displayed 95% of the time during the study, and 864 paired bg-sg points were used for analysis. overall mean absolute relative diff erence (mard) was 12.2%. no diff erences in cgm system accuracy were seen within subgroups of low versus high society of thoracic surgeons (sts) score (mard 12.1% and 10.6% for sts >8% vs. ≤8%, respectively) or hemodynamic status (mard 12.0% and 12.4% for compromised vs. stable hemodynamics). consensus grid analysis showed >99% of sg values within a/b zones, and 0% in d/e zones. no device or study-related adverse events were reported. in total, 80% and 100% of clinicians found sentrino® easy to use after one and two patients, respectively. conclusion the sentrino® cgm system demonstrated good analytic and clinically relevant accuracy, excellent reliability and safety in critically ill cardiac patients; and was easy to use and integrate in the cardiac icu. future studies are needed to determine whether cgm can improve bg control and reduce hypoglycemia in this patient group. introduction a large rct showed that tight glucose control (tgc), targeting age-adjusted normal fasting blood glucose levels with insulin infusion, decreased morbidity and mortality in critically children [1] . however, the incidence of hypoglycemia increased substantially in the tgc group. we aimed to assess the eff ect of tgc on the three domains of blood glucose dynamics (hyperglycemia, hypoglycemia and blood glucose variability) and their independent association with mortality in the pediatric icu. methods this is a preplanned substudy of a published rct in one 10-bed pediatric icu. seven hundred patients (age 1 to 16 years), admitted to the picu between october 2004 and december 2007, were randomized to either tgc (50 to 80 mg/dl in infants, 70 to 100 mg/dl in children) or to the usual care tolerating hyperglycemia up to 215 mg/ dl (uc). patients with at least two arterial blood glucose measurements were included (uc n = 349; tgc n = 348). results mean blood glucose levels were lowered from 143 ± 34 mg/dl in the uc group to 104 ± 24 mg/dl (p <0.0001). the median number of samples per patient did not diff er between uc (21 (13 to 48)) and tgc (22 (15 to 49)). tgc lowered the hyperglycemic index, a marker of introduction hiv infection is a major public health problem in the world. the use of prophylaxis against opportunist infection and the introduction of haart in 1996 increased life expectancies. the therapeutic use of icu resources for hiv patients has been controversial, questioning the admission of these patients especially in advanced stages of the disease, given the poor prognosis. the aim of this study was to determine the experience of the past 15 years in relation to the income of these patients in an icu. methods a retrospective case series consisting of patients with diagnosis of hiv infection (known or unknown) admitted between january 1995 and december 2009. we collected demographic and epidemiological data, process of acquisition of the disease, infection status: known or unknown patient infected, whether or not receiving antiretroviral therapy and whether it was eff ective (undetectable viral load at the time of admission), apache ii, cause of admission, need for mechanical ventilation (mv), pathology related or unrelated to hiv infection and icu mortality. results during this period 12,607 patients were admitted to the icu, 188 (1.5%) hiv-positive. mean apache ii score 17.6, median age 39 years, 73% men and 90% spanish nationality. principal risk behavior: addiction drugs injection (67%). seventeen percent of patients did not know who was infected with hiv at the time of admission to the icu. fifty-three percent were not receiving haart. of the 88 patients treated, 93% were receiving haart (eff ective in 88% of cases). sixty percent of the patients came from the emergency department of the hospital. main admission diagnoses: acute respiratory failure caused by infection (streptococcus pneumoniae and pneumocystis jirovecii), neurological disorders (coma for illicit drugs and psychotropic) and septic shock. seventy percent required mv. of patients whose hiv infection was not known, 93.5% were admitted for related pathology. in patients of known infection, the pathology associated with hiv was 30%. average length of stay 9 was days. icu mortality was 35%. most frequent causes of death: septic shock and multiple organ failure. conclusion depending on the patient and the cause of admission, icu admission may represent an excellent opportunity as a screening method to determine hiv status. given the greater effi cacy of haart at present, most patients with medical or surgical conditions unrelated to hiv infection will be eligible to join the icu. people with hiv can and should benefi t from using reasonable and individualized care in an icu. references conclusion neither immune status-related variables nor comorbidity or infection focus are mortality predictors. poor nutritional status, delayed icu admission, shock or renal failure increase the icu relative mortality risk. tachycardia, hypotension, hypercapnia, acidosis, and oliguria in the fi rst icu 24 hours increase signifi cantly icu mortality. mechanical ventilation is not a mortality predictor. introduction patients with lung cancer commonly require the icu for a variety of acute illnesses related to the underlying malignancy, treatment, or comorbid conditions. icu admission of patients with nonresectable lung cancer has been criticized based on the high mortality rate in this population. however, recent advances in critical care may have changed this scenario. the aim of this study was to identify factors associated with hospital mortality in this group of patients. methods a retrospective study was conducted in consecutive medical and surgical patients with lung cancer admitted to a university hospital icu in são paulo, between 2007 and 2012. a univariate analysis was performed to identify associated variables with hospital mortality. selected variables were included in the multivariate model. results from 597 patients included in the study, 477 were medical admissions (79.8%) and 120 were surgical admissions (20.2%). four hundred and twenty (70%) patients had metastasis, 222 patients (37%) required the icu because of respiratory failure and 121 (20%) because of septic shock. the icu and hospital mortality rates were 53.9% and 64%, respectively. in the univariate analysis, variables associated with hospital mortality were diagnosis of nonsmall-cell lung cancer, higher charlson morbidity index, medical admission, active neoplasm, vasopressor need at admission to and at 24 hours of icu, acute renal failure at admission, non-invasive ventilation or mechanical ventilation need at admission to and at 24 hours of icu and a higher admission arterial lactate. by multivariate analysis, risk factors of hospital mortality were diagnosis of nonsmall-cell lung cancer (or = 3.32; 95% ci, 2.08 to 5.29, p <0.001), medical admission (or = 2.89; 95% ci, 1.75 to 4.77, p <0.001), acute renal failure at admission (or = 4.09; 95% ci, 1.49 to 11.21, p <0.001), non-invasive ventilation at 24 hours of icu (or = 2.50; 95% ci, 1.48 to 4.23, p = 0.001) and mechanical ventilation at 24 hours of icu (or = 3.68; 95% ci, 1.87 to 7.26, p <0.001). conclusion hospital survival in patients with lung cancer requiring icu admission was 36%. our results provide evidence that icu management may be appropriate in patients with nonresectable lung cancer and appoint risk factors for mortality, helping to better triage cancer patients who will benefi t from icu care. introduction because the prognosis of older patients with cancer may be poor compared with younger patients, it remains controversial whether they benefi t from icu treatment. the objective of this study was to identify factors associated with hospital mortality in older patients with cancer requiring the icu.methods a retrospective study was conducted in consecutive medical and surgical older patients with cancer admitted to a university hospital icu in são paulo, between 2007 and 2012. univariate and multivariate analysis were performed to identify associated and independent factors related to hospital mortality. results from 8,976 patients with cancer requiring icu at the period, 600 patients were 80 years old or higher. most patients were male (53%), had solid neoplasm (86%), were from medical admission (54%) and 37% had metastatic disease. the mean age was 84 years (± 3). the icu and hospital mortality rates were 30% and 44%, respectively. in the univariate analysis, variables associated with hospital mortality were diagnosis of lung cancer, medical admission, active neoplasm, vasopressor need at 24 hours of icu, acute renal failure at admission, mechanical ventilation need at admission to and at 24 hours of icu and a higher admission arterial lactate. by multivariate analysis, risk factors of hospital mortality were diagnosis of lung cancer (or = 2.32; 95% ci, 1.08 to 3.29, p <0.001), medical admission (or = 6.473; 95% ci, 2.76 to 15.15, p <0.001), acute renal failure at admission (or = 3.09; 95% ci, 1.49 to 9.21, p <0.001), mechanical ventilation at 24 hours of icu (or = 5.68; 95% ci, 2.87 to 7.26, p <0.001) and lactate levels at admission (or = 1.02; 95% ci, 1.006 to 1.051, p <0.001). conclusion hospital survival in older patients with cancer requiring icu admission is acceptable. our results provide evidence that icu management may be appropriate in older patients with cancer and appoint risk factors for mortality, helping to better triage cancer patients who will benefi t from icu care. introduction readmission to the icu within 48 hours is an indicator of quality of intensive care and is associated with an increase in mortality. during the last years several groups have published data based on multivariate logistic regression analysis to describe characteristics of patients who needed readmission to the icu. older age, comorbid conditions and severity of illness (apache score) have been among the strongest predictors for readmission. in our icu most patients are in the groups formerly identifi ed as risk groups, which means that stratifi cation and prediction of readmission is diffi cult. because of the unusual high severity of acute and pre-existing illnesses we could not fi nd a data match on comparable patient groups. to investigate whether we could reduce our rate of readmission we therefore decided to perform a qualitative investigation to identify risk factors related to readmission. after identifi cation of the risk factors we will take actions to optimize care and perform ongoing control of the implemented actions to secure that they decreases the rate of readmission. methods retrospective data on patients readmitted to the icu within 48 hours during an 8-month period (november 2011 to june 2012) were drawn from the critical information system (cis) at icu zit, bispebjerg hospital, denmark. zit is a multidisciplinary unit with 10 beds and 500 to 600 admissions/year and a median saps ii score of 47. a group of consultants, junior doctors and nurses from the icu and the ward each read the patient fi les with focus on pattern recognition and suggested trigger points to focus on. data on trigger points were then drawn from the cis system and re-evaluated. finally, fi ve key points were identifi ed and serves as basis for future actions. results in a qualitative analysis, readmissions to the icu are related to the following fi ve key points -discharge outside day hours, lack of infection control, stay in icu <2 days, lung physiotherapy ordinated but not eff ectuated, and several minor organ dysfunctions (atrial fi brillation and acute kidney injury). age, diagnosis, saps ii score or ventilator treatment during intensive care was not diff erent in patients with successful discharge and patients readmitted in this group of patients. conclusion it is possible and suitable to identify key points for future eff orts in a given subgroup of patients using a systematic qualitative approach. conclusion the latest audit follows introduction of a referral system directly to the icu consultant and may account for the reduction in numbers of referrals attended by junior doctors. ed/medicine persist as the main source of referral to the icu. discussion with the referring team consultant may reduce inappropriate referrals. icu staffi ng should not be reduced. [1, 2] . this study aims to evaluate the impact of the time elapsed from request until admission to the icu on mortality and icu length of stay (los). methods a retrospective cohort study performed on patients in the icu of hospital regional de samambaia over a period of 4 years, from january 2008 to december 2011. the patients were allocated into two groups: patients who waited longer than 6 hours, long waiting period the management of emergency medical admissions has been a subject of recent clinical incidents. there was a high percentage of patients that were referred to the icu by staff in training, and 21% of referrals were made by junior doctors. consultant physicians had no knowledge of the case in 57% of referrals. methods a prospective study of 21 cases of referrals and admissions to the icu was conducted at the glasgow victoria infi rmary hospital from 8 to 21 september 2012. a questionnaire was produced relating to the referrals, admissions, seniority involvement, cause of referral, and time of patient review by the icu consultant after icu admission. they were distributed to specialist registrars and the icu consultants. all data were electronically recorded into an excel database. questionnaires that were not completely fi lled were further investigated using patient clinical notes and contact with medical staff . information that may identify a patient or clinician was removed from the questionnaire for confi dentiality purposes. results twenty-one complete questionnaires were collected. fiftyseven percent (12/21) of cases involved admission to the icu. nine percent of the cases involved contacting either a specialist registrar or icu consultant intensivist for assistance in practical procedures. of the patients admitted to the icu, 33% (4/12) were from medical wards, 33% were admitted from a&e. consultants were the most common professionals who referred patients to critical care (48%; 10/21). fourteen percent of cases (3/21) involved the referral of patients into icu by a junior doctor, but only one of the referrals was accepted by the icu intensivist. consultants referred or were aware of the referral in 71% (15/21) of cases. of admissions, 58% (7/12) were accepted by the icu consultant and the remaining by the specialist registrars. all accepted were acknowledged by the icu consultant. after admission all of the patients were reviewed by the icu consultant and the time of review after admission was on average 1 hour 23 minutes (25 minutes to 3 hours 45 minutes). conclusion there is still an issue with junior doctors referring patients to the icu without the acknowledgement of consultant physicians, resulting in unnecessary admissions and decreased time that icu trainees spend in the icu. there are more appropriate icu admissions when there is involvement with seniority. contact with icu staff to perform practical procedures outside the icu and not about admissions should be explored further. reference introduction the requirements for the intensivist in handling medical technology are constantly growing. it appears necessary to acquire technological competences particularly within the fi elds of medical technology and physics. in the master's degree program 'masteronline physico-technical medicine' , such technical authority is conveyed. to cope with the intensive vocational situation of the physician, this study course follows the blended-learning concept; that is, it is conceived as an online study course with small portions of intermittent presence phases. within the fi rst year, technical basic skills such as 'measurement technique' , 'informatics' , and 'advanced physics' are covered. subsequently, two of various advanced courses in diff erent fi elds of medical technology ('technology in intensive care medicine' , 'technology in surgery' , 'technical cardiology' , 'radiology' , and other) are selected. methods in a survey, we evaluated the study course. therefore, a questionnaire was distributed among all students including the topics course contents, learning materials, time management, supervision, and overall impression. the students were asked to score their agreement to the statements 'content is well structured' , 'content extent is appropriate' and 'content is relevant for medical purposes' on a scale ranging from 1 (fully disagree) to 5 (fully agree). results the students participated actively in this study course with highest motivation and large commitment. the students' workload was in the targeted range of about 10 hours/week. content structure was scored with 4.3 ± 0.1, content extent with 4.1 ± 0.2 and medical relevance with 4.3 ± 0.2. conclusion the blended-learning concept fulfi lls the requirements for occupation-accompanying continued medical education, since it off ers the possibility to study self-employed accessing text documents, lecture recordings, and electronic lectures and to convert in concentrated presence phases this knowledge into practical exercises. the fi rst-hour protocol determines the patient-specifi c resources for the start of an icu stay [1] . staff resources are decided through triage. task charts direct the start of intensive care. our primary goal is to improve patient care. methods a triage method (red, yellow, green) is used to manage icu resources according to the severity of illness. for example, one doctor and one nurse would admit a stable (green) patient coming from the operating room for postoperative icu care. a patient in septic shock with multiple organ disorder (red), on the other hand, would be admitted by a team of two doctors and three nurses. each staff member has a task chart in a checking-list format. also, an admission chart is used to improve data collection. the use of the protocol started as a pilot study in early 2012. simulation education for staff members started in august 2012 and has included video recordings and debriefi ng of each simulated icu admission. primary goal-directed therapy goals have been mean arterial pressure (map >65 mmhg), spo 2 >94%, timing of the laboratory tests, start of antibiotics, and blood glucose level 6 to 8 mmol/l. quality indicators have been followed from the data provided by the finnish intensive care consortium. questionnaires for the staff members have been used to evaluate opinions about the fi rsthour protocol. results according to the questionnaire replies, 80% (n = 64/80) of our nurses estimate that the fi rst-hour protocol has improved the starting process of our patients' intensive care. twenty percent (n = 16/80) of the nurses considered that the protocol has no eff ect, and none thought it to be adverse for patient care. corresponding numbers for our icu doctors were 87% (benefi cial n = 13/15), 13% (no eff ect n = 2/15) and 0% (adverse). furthermore, 82.5% (n = 66/80) of the nurses replied that education of new nurse staff members has improved because of the fi rst-hour protocol. a total of 17.5% (n = 14/80) thought there has been no eff ect, and none considered the protocol harmful for education. for icu doctors the protocol did not bring either clear educational advantages or disadvantages. the variable life-adjusted display curves (the finnish intensive care consortium) have shown improvement in our patient care after the implementation of the fi rst-hour protocol. however, we cannot determine whether it is a signifi cant factor in our intensive care results. conclusion the fi rst-hour protocol has helped us in resource management, start of the patients' intensive care and education of nursing staff . introduction demand for critical care services is increasing yet a comprehensive understanding of how critical care nurses -the largest group of icu direct care providers -impact outcomes remains unclear. the purpose of this study was to determine how critical care nurse education (hospital proportion of bachelor's prepared icu nurses) and icu work environment infl uenced 30-day mortality of mechanically ventilated older adults. methods a multi-state cross-sectional nurse survey was linked to hospital administrative data and medicare claims (2006 to 2008). the fi nal sample included 55,159 mechanically ventilated older adults in 303 hospitals. logistic regression modeling was employed to jointly assess the relationship of critical care nurse education, work environment and staffi ng on 30-day mortality while adjusting for hospital and patient characteristics and accounting for clustering. results a 10% increase in the proportion of icu nurses with a bachelor's degree or higher was associated with 2% lower odds of death while controlling for patient and hospital characteristics. patients cared for in better work environments experienced 11% lower odds of riskadjusted death than those cared for in poorer icu work environments. conclusion patients cared for in hospitals with a greater proportion of bachelor's prepared icu nurses and in better icu work environments experienced signifi cantly lower odds of death. as the demand for critical care services increases, attention to the education level of icu nurses and icu work environment may be warranted to optimize currently available resources and potentially yield better outcomes. introduction information about big hospital geographical transfer is scarce in the medical literature. on 20 february 2011 our hospital (in fact, a big university complex) was transferred from their previous location in the north-center of our city towards a new southern peripheral, geographical location. this transfer has been done without any changes in assisted population or nursing/medical staff . the only change was a slight increase in bed number (21 to 24). our aim is to analyze changes in activity indexes (length of stay, occupancy rate, and so forth) and case mix (origin, previous quality of life and nyha score, main diagnostic groups, severity scores, in-icu and in-hospital mortality). introduction south-east london (sel) presents unique challenges to healthcare providers due to its diverse demographic. the high levels of poverty, immigration and psychiatric illness impact delivery of obstetric care. these were identifi ed as risk factors for poor outcome in the latest cmace report [1] . the intensive care national audit and research centre (icnarc) produced data on obstetric critical care admissions in 2007 [2] . we reviewed the obstetric critical care admissions in three sel hospitals and compared this with the national average determined in the icnarc and cmace data. methods all critical care admissions in three high-risk obstetric units in sel (1 august 2009 to 31 july 2011) were screened for patients who were currently or recently pregnant. we compared local results with national data by icnarc and cmace. there were 68 obstetric critical care admissions in the sel hospitals within the audited time frame. the mean age was 30.05 in icnarc data compared with 33.93 in sel. average apache ii scores were lower in sel compared with the icnarc data, but length of stay was greater in sel (2.72 days) compared with icnarc (1.5 days). haemorrhage was the most common reason for admission in sel, whilst sepsis was the leading cause of death according to the latest cmace report (figure 1 ). conclusion data from national audits may guide protocol, but services must be tailored to local circumstances. sel has unique population characteristics and obstetric critical care admissions diff er signifi cantly from national statistics; in particular, haemorrhage is over-represented in our region. critical care services were generally required for a short period of time; during this period, routine postpartum care may be omitted as treatment priorities diff er. dedicated critical care services on the labour ward may be a way to combine postnatal care with transient high-dependency requirements. this may enhance patient experience and prove cost-eff ective. introduction adverse drug events (ades) are associated with a substantial increase in morbidity and mortality in any setting. because patients in icus were critically ill with complex diseases and varied organ dysfunction, the incidence of ades on such patients is much more crucial than the counterparts. we thus assessed the nature of ades and their infl uence in icus. methods we conducted a prospective cohort study at icus at three large tertiary-care hospitals in japan. trained research nurses reviewed all medical charts, incident reports and reconciliations from the pharmacy to identify suspected ades as well as the background of patients. ades are any injuries that result from the use of a drug. after suspected ades are collected by research nurses, physician reviewers independently evaluated them and classifi ed them as ades or rule violations. we used the validated methodology [1] . results we included 459 patients with 3,231 patient-days. the median age was 70 years and the median length of stay was 3 days. in total, 70 patients (15%) had at least one ade during their stay in the icu. the median icu stay in patients who had ades was 14 days while 2 days in patients who had no ades (p <0.0001). the median length of the ade onset days since admission was 3 days. regarding the mortality, 73 patients (16%) were dead during their icu stay: 12 deaths (17%) in patients who had ades and three of 12 deaths were caused by an ade, and 61 deaths (16%) in counterparts (p = 0.8). there were no signifi cant diff erences of patients' characteristics between patients with ades and without ades (table 1) . conclusion ades were associated with longer stay and caused a part of death in icu (4%) although they did not increase the mortality. because the characteristics of patients were not associated with ades, early detection and intervention for ades could be important to improve the morbidity and reduce the death caused by ades in icus. introduction in hungary, despite the high level of social support, the number of organ recoveries from deceased donors has not changed signifi cantly. the donation activity shows a positive relationship with the level of education of staff in icus as well as with their attitude towards transplantation. the aim of this cross-sectional study is to estimate the attitude and knowledge of intensive care specialists and nurses as regard donation and transplantation. methods the self-completed questionnaire that consisted of 20 items was completed at the congress of hungarian society of anesthesiology and intensive therapy in 2011. besides the epidemiological data, the intensive care specialists (n = 179) and nurses (n = 103) were asked about donation activity, participation in an organ donation course, selfreported knowledge of joining eurotransplant, donor management, legislation, and transplantation. the data were analyzed by spss 17.0. results a total of 53.6% of physicians and 16.7% of nurses attended an earlier organ donation course (p <0.01). the average age of those who participated in training was signifi cantly higher among doctors (p <0.01). fifty-nine percent of doctors and 65.1% of nurses did not even want to participate in such training. donation activity was higher among staff who joined training (p <0.01). independently from accepting the presumed consent legislation (91.1%), 66% of physicians agreed with the hospital practice that requests the adult donor's relatives to consent to organ recovery. this standpoint did not depend on donation activity, participation in an organ donation course, opinion about legislation and the nature of staff . a total 95.4% of participants consented to their organ retrieval after death. the staff who participated in an organ donation course had more knowledge regarding the law and ethics of donation (p <0.01), donor management (p <0.01), living and deceased donor transplantation (p <0.01) and joining eurotransplant (p <0.01). older professionals had more information about all fi elds (p <0.01). nurses had less knowledge concerning donor management (p <0.01), law and ethics (p <0.01) and deceased donor transplantation (p <0.01) than doctors. conclusion education about organ donation needs to be part of specialist training of intensive care staff , and refresher courses every fi fth year as well. the course should include knowledge regarding brain death, donor management and communication with family. this is the fi rst step to improve the number of transplantations. in the uk, three people die each day awaiting trans plantation, due to the unavailability of donor organs. traditionally, donor identifi cation has been restricted to the icu. however, following the uk organ donation taskforce report in 2008 [1] , a number of emergency departments (eds) have been working with specialist nurses for organ donation (sn:od) to identify potential donors and approach their families for consent in the ed. we present our initial experience after the introduction of a sn:od to an irish teaching hospital's ed. methods we conducted a retrospective review of deaths in our ed during a 28-month period. for those who died in the ed, case notes were reviewed to identify those suitable for organ donation. referral and donation rates were compared in two cohorts, pre and post introduction of a sn:od. fisher's exact test was used to assess diff erences between groups. results ninety-one deaths occurred in the study period. following introduction of the sn:od, referrals increased from zero to eight. of the eight referred, three received consent and were transferred to the icu, two of whom became successful donors. the number of missed potential donors fell from six to one (p = 0.009). conclusion introduction of a sn:od and a clinical pathway has led to the identifi cation of previously missed potential organ donors in the ed. several patients have subsequently been admitted to critical care solely to facilitate organ donation. reference introduction admission to hospital overnight has been shown to increase mortality and decrease hospital length of stay [1] . the objective of this study was to determine whether this relationship is valid in patients admitted to our icu, and whether length of stay was aff ected. methods a retrospective data collection identifi ed 5,827 patients admitted to a fi ve-bed icu from april 1994 to november 2012. data regarding patient age, sex, apache ii score and icu admission date and time were collected along with the length of stay in the unit and hospital. defi nitions of day and night were set to local icu standards of 9:00 am to 8:00 pm. patients were then separated into two groups and analysed using analyse-it software for excel. results crude icu and hospital mortality rates in patients admitted during the day and overnight were examined. there was no signifi cant diff erence in unit mortality (day 22.3% vs. night 22.7%, or = 1.02, 95% ci = 0.91 to 1.16, p = 0.718) or hospital mortality (day 30.7% vs. night 29.1%, or = 0.93, 95% ci = 0.83 to 1.04, p = 0.203). the mean unit length of stay showed no diff erence in patients admitted during daytime compared with those admitted overnight (4.27 days vs. 4.09 days, p = 0.162). the mean hospital length of stay was decreased in patients admitted during daytime compared with patients admitted overnight (19.3 days vs. 21.7 days, p = 0.004). the average age of patients was less in those admitted out of hours (night 56.5 years vs. day 59.2 years, p = <.0001). there was no signifi cant diff erence in apache ii scores of patients between the groups (day 19 vs. night 19, p = 0.580). conclusion there is no signifi cant diff erence between the mortality of patients admitted overnight and patients admitted during the day to our unit. the hospital length of stay is increased in patients who are admitted overnight to intensive care; however, icu length of stay is not aff ected. adjustment for other confounders such as current bed occupancy and staffi ng ratios during the entire patient stay may help to understand the diff erences seen in the hospital length of stay. introduction interdisciplinary rounds (idrs) in the icu are increasingly recommended to support quality improvement and to reduce confl icts, but uncertainty exists about assessing the quality of idrs. we developed, tested, and applied a scoring instrument to assess the quality of idrs in icus. methods a literature search was performed to identify criteria for instruments about assessing team processes in the icu. then, 10 videotaped patient presentations led by diff erent intensivists were analyzed by delphi rounds. appropriate and inappropriate behaviors were highlighted. the idr-assessment scale was developed and statistically tested. the inter-rater reliability was evaluated by rating nine randomly selected videotaped patient presentations by three raters. finally, the scale was applied to 98 videotaped patient presentations during 22 idrs in three icus for adults in two hospitals in groningen. results the idr-assessment scale had 19 quality indicators, subdivided into two domains: patient plan of care, and process. the domain patient plan of care refl ects the technical performance from the initial identifi cation of a goal to the evaluative phase. the domain process refl ects the team processes that are important to ensure that the appropriate plan of care is agreed, understood, and executed as planned by all care providers. indicators were essential or supportive. the inter-rater reliability of nine videotaped patient presentations among three raters was satisfactory (κ = 0.85). the overall item score correlations between three raters were excellent (r = 0.80 to 0.94). internal consistency in 98 videotaped patient presentations was acceptable (α = 0.78). application to 22 idrs led by 14 diff erent intensivists in three icus in two hospitals demonstrated that indicators could be unambiguously rated. the staff and management of all three icus that were rated had considered their idrs to be adequately performed, and they were surprised by these study results. conclusion this study showed that the quality of idrs can be reliably assessed for patient plan of care and process. the idr-assessment scale had satisfactory inter-rater reliability, excellent overall item score correlations, and acceptable internal consistency. our instrument may provide feedback for icu professionals and managers to develop adjustments in quality of care. testing the idr-assessment scale in other icus may be required to establish general applicability. the development of patient-centered care by interdisciplinary teams in the icu has focused attention on leadership behavior. the purpose of this intervention study was to measure the eff ect of leadership training on the quality of performed interdisciplinary rounds (idrs) in the icu.methods in this nonrandomized intervention study, participants included nine intensive care medicine fellow trainees (intervention group) and 10 experienced intensivists (control group). participants in the intervention and control groups previously were untrained in leading idrs in the icus. after each participant led an idr that was videotaped, the fellow trainees participated in a 1-day leadership training, which was consistent with principles of adult learning and behavioral modeling. after training, each fellow trainee led another idr that was videotaped. quality of the performed idrs was measured by review of videotapes of the 19 idrs lead by 19 intensivists, including 198 patient discussions subdivided into four icus, and assessment with the idr-assessment scale. results comparison of the intervention versus control groups shows that the intervention group has more yes scores on the idr-assessment scale than the control group. this diff erence was signifi cant in 12 of the, in total, 19 quality indicators. conclusion quality of leadership will be reliably trained and measured in the context of idrs in icus. training in a simulation environment, with real-life idr scenarios including confl icting situations, and workplacebased feedback in the preparation and feedback phases, appears to be eff ective to train leadership behaviour. results over a 6-month period, 131 teleconsultations (114 patients) were done. mean age was 50.1 years, 57.1% was male and mean apache ii score was 24.3. a total of 64.8% originated from the icu and 35.2% from the ed. main consultation diagnoses were sepsis (31.3%); stroke (29.8%); survival from cardiac arrest (6.1%); trauma (6.1%); and acute myocardial infarction (5.3%). tm improved diagnosis in 14.5% and infl uenced the clinical management in 85.5% of the consultations. invasive procedures were indicated in 61.1%. life-saving procedures were tm related in seven patients (6.1%): stroke thrombolysis (n = 6) and limb amputation (n = 1). seven patients (6.1%) were transferred and submitted to surgical procedures (heart surgery (n = 2), neurosurgery (n = 4) and liver transplantation (n = 1)). the majority of the patients remained at hmmd and were discharged. conclusion a tm program is feasible to be implemented in a community hospital. the major benefi t is expertise medical transfer from the tertiary hospital to the community setting, improving diagnosis and management of critical care patients, and avoiding routine transfer to a major urban center. introduction the purpose of our study was to assess the attitudes of slovenian intensivists towards end-of-life (eol) decision-making and to analyze the decision-making process in their clinical practice. methods a cross-sectional survey among slovenian intensivists and intensive care medicine residents from 35 diff erent icus was performed using a questionnaire containing 43 questions about views on eol decision-making. fisher's exact test and the fisher-freeman-halton test were applied to cross-tabulated data; signifi cance level was set at p ≤0.001 due to the large number of tested hypotheses. the response rate was 72.1% (267 questionnaires were returned out of 370 distributed), which represented roughly the same percentage of all slovenian intensivists. termination of futile treatment was assessed as ethically acceptable (p <0.001). the statement that there is no ethical distinction between withholding and withdrawing of treatment could not be confi rmed (the answers 'there is a diff erence' and 'undecided' were less frequent, but not statistically signifi cant; p = 0.216). a do-not-resuscitate order (dnr) was used more often than other withholding treatment limitations (p <0.001). a dnr was used most frequently in internal medicine icus (p <0.001; compared with paediatric and surgical icus). withdrawal of inotropes or antibiotics was used more often than withdrawal of mechanical ventilation or extubation (66.7% vs. 12.0%; p <0.001). withdrawal of mechanical ventilation or extubation was more often used in the paediatric icus (21.7%) as compared with the internal medicine icus (19.6%) and the surgical icus (3%) (p <0.001). over two-thirds (70.6%) of intensivists were against termination of hydration, which would be more often used in the internal medicine icus (p <0.001). thirty-one percent of intensivists used written dnr orders. conclusion termination of futile treatment was found to be ethically acceptable for slovenian intensivists, although they were not convinced that withholding and withdrawing of treatment were ethically equal. a dnr would be used most often. withdrawal of inotropes or antibiotics would be used more often than withdrawal of mechanical ventilation or extubation. termination of artifi cial hydration would be rarely used in practice. of 457 consultant attendees from the uk, 149 completed the survey (33%). for 58% of consultants there was no formal institutional protocol for withdrawal of futile therapy. when deciding to withdraw therapy, 57% of consultants routinely seek and document a second opinion. regarding donation after cardiac death (dcd), 93% of consultants were happy to delay withdrawal to facilitate successful donation, 85% have already done so in their practice and 14% routinely withdraw therapy in theatres rather than on the icu. even if it would impact on the care of other patients, 48% would delay withdrawal of therapy to facilitate dcd. for patients accepted for dcd, 36% think that some intensivists withdraw more aggressively (in essence, hasten death) in the hope of improving the likelihood of a successful organ donation and 29% have felt pressurised to withdraw therapy more quickly than their usual practice. furthermore, 45% experienced pressure to refer a patient for dcd when it they felt it was not appropriate. conclusion this survey confi rms variation in the practice and attitudes to withdrawal of futile therapy amongst uk consultant intensivists. formal protocols were frequently unavailable to guide withdrawal and second opinions were often not sought. nearly one-half of the intensivists delay withdrawal to facilitate donation, even if this may impact on the care of other patients. many intensivists have felt pressure to refer for donation when they feel this is inappropriate and there is a perception that some intensivists may withdraw care more aggressively in those who are accepted for dcd to improve the likelihood of a successful donation. this survey may help inform debate in this ethically challenging area. reference the research shows that the diffi culty of communi cation is a factor that impacts negatively on the grieving process. moreover, it stresses the importance for parents to rediscuss the moment of their child's death with health professionals. references methods a randomised controlled trial was undertaken in adult survivors of icu admission. they were allocated to receive an 8-week in-hospital supervised aerobic programme consisting of two cycle ergometry and one unsupervised session per week (exercise group) or no exercise (control group). primary outcomes were the anaerobic threshold (in ml o 2 /kg mass/minute), physical function and mental health scores (sf-36 questionnaire), measured at weeks 9 and 26. participants were then allocated to focus groups where the interpretation of experiences was compared with outcomes from the pix study. results fifty-nine patients were recruited to the study. the anaerobic threshold increased at week 9 in the exercise group by a clinically and statistically signifi cant amount of 2 ml o 2 /kg mass/minute (90% ci, 1 to 3 ml/kg/minute). there was further improvement in fi tness levels in both groups by week 26 (although no signifi cant diff erence between groups). no signifi cant diff erence in hrqol measures between groups was demonstrated; however, the exercise group did show an improvement in their mental health scores. the focus groups centred on feelings of isolation, abandonment, vulnerability, dependency and reduced physical activity post hospital discharge. many reported a lack of social inclusion as they did not have the energy or confi dence to venture outside. however, those in the exercise group felt that the rehabilitation programme was motivating, built up confi dence, improved fi tness, helped social interaction and gave them a sense of achievement.conclusion the 8-week exercise intervention resulted in statistically signifi cant improvements in fi tness at 9 weeks while focus group participants highlighted the positive eff ects of the exercise intervention leading to enhanced energy levels, motivation and achievement. psychological benefi ts of the exercise programme are apparent from the focus group, emphasising the important link between physical and mental health. introduction survivors of critical illness often have a prolonged stay on the icu. these patients may suff er from icu-acquired weakness. it has been shown that reduction in muscle mass and muscle strength occurs early after admission to the icu. however, in the very early stage on the icu, patients are often sedated and not able to participate in any active mobilizations. therefore the use of neuromuscular electrical stimulation (nmes) is becoming a treatment of interest in the icu. the aim was to study the feasibility and safety of nmes in a surgical and medical icu of a large, tertiary referral university hospital. methods fifty patients with an expected prolonged stay on the icu of 5 more days (judged on day 3) with no trauma or neurological disease were included. they then received daily a nmes session (duo 500; gymna, belgium) for 25 minutes on the quadriceps bilaterally during their entire stay on the icu. the main outcome was the ability to produce a contraction of the quadriceps through nmes. the muscle contraction was quantifi ed on a 5-point scale: 1 (no contraction palpable and visible) up to 5 (contraction very well palpable and visible). patients were classifi ed as responders when an adequate muscle bulk was obtained in ≥75% of the sessions. the potential factors associated with the feasibility were: gender, age, body mass index (bmi), diagnosis of sepsis, barthel index prior to admission to the hospital, apache ii score, glasgow coma scale (gcs), fi ve questions for adequacy, stimulus intensity and leg edema. a multiple regression analysis was performed to identify the factors determining whether or not a contraction could be expected in a patient. safety of nmes was assessed through heart rate, blood pressure, oxygen saturation and respiratory rate. results in 48% of the patients we were able to achieve adequate muscle contractions in more than 75% of the sessions. gcs (p = 0.047), edemaintroduction trauma is the most common cause of morbidity in young people. it has a high social impact both because of the high cost of the acute treatments and because of the physical and psychological consequences that it may cause. a prospective, observational, singlecenter study on quality of life 12 to 24 months after trauma was carried out. the aim of the study is to evaluate life quality after trauma and to identify the most important needs of the patients, in order to improve the level of care after an icu stay and to implement a faster and more eff ective reintegration into the active and productive society. the aim was to analyse the outcomes and patient satisfaction of a recently implemented icu follow-up clinic. these clinics are national institute for clinical excellence recommended [1] . methods a retrospective analysis of prospective collected data from january to december 2012. the clinic is run monthly by an icu consultant and a critical care outreach sister. criteria to be invited to the clinic are mechanical ventilation ≥3 days. patients fi lled an anonymous satisfaction survey after the clinic. results our attendance rate is 50% (26 patients), which is similar to other series reported in the literature. those patients who attended the clinic required a longer length of mechanical ventilation (5.3 days vs. 7.1) and a longer length of stay in the icu (7.6 vs. 13) and in hospital (14 vs. 28). we identifi ed a wide range of physical and nonphysical morbidities on these patients (figure 1 ). we referred them to the appropriate specialities. patients were very satisfi ed with this new service ( figure 2 ). this study aims to quantify the acute exercise response to early passive and active activities in order to inform exercise prescription when designing rehabilitation programmes for the critically ill. critical care survival is often associated with a poor functional outcome [1] , with recent investigations presenting the case for early rehabilitation in order to optimise functional recovery [2] . there, remains, however, a scarcity of research investigating the immediate response to exercise and subsequent exercise prescription, in the acute phase following critical illness. methods this study is a prospective randomised controlled trial with a repeated-measures crossover design. eligible participants, requiring mechanical ventilation for 4 or more days, completed two exercise activities routinely used in early critical care rehabilitation, a passive chair transfer (pct) and active sitting on the edge of the bed (soeob). the oxygen consumption and cardiovascular parameters were measured to quantify and compare the exercise response between the two activities. introduction the aim of this study was to investigate the eff ect of a 6-week exercise programme on outcomes in post-icu patients. with improvements in intensive care medicine, increasing numbers of patients are surviving catastrophic illness [1] . severe weakness is common in patients with prolonged critical illness and results in considerable morbidity, mortality and healthcare costs [2] . the nice83 guidelines rehabilitation in critical care recommend follow-up for post-icu patients and that further research is needed in this fi eld [3] . methods patients who have been discharged home from hospital following an icu stay of 48 hours or more were recruited to the study. patients were only excluded if they were not considered safe for exercise. baseline measurements were completed prior to stratifi ed (age, gender, apache ii score) random allocation to either the exercise or control group. outcome measures included cardiopulmonary fi tness (6-minute walk test), balance (berg balance scale), grip strength (jamar grip dynamometer) and hospital anxiety and depression (had score). the exercise group completed a 6-week supervised exercise programme, twice a week for up to 1 hour. in the seventh week, all patients repeated the baseline measurements. an unpaired student's t test was used to compare any diff erences between the control and exercise groups. results at baseline measurements, there were no statistical diff erences in age, gender, length of stays or apache ii scores between the two groups. results indicate that the exercise group (n = 10) had signifi cantly greater improvements in cardiopulmonary fi tness (p <0.001) and balance (p <0.05) compared with the control group (n = 10). greater improvements were also evident in anxiety, depression and grip strength in the exercise group, although not statistically signifi cant. conclusion this pilot study highlights that a 6-week supervised exercise programme can signifi cantly improve cardiopulmonary fi tness and balance in post-icu patients. further recruitment to the study and 6-month/1-year follow-up is needed. references introduction intensive care patients suff er psychological and physiological distress that may have debilitating and long-lasting eff ects [1] [2] [3] . healthcare professionals are in a position to help avoid or alleviate this stress [4] . to action this it is important to identify the main stressors from the patient's perspective. a systematic review was performed to provide a list of what patients consider stressors in intensive care. these were then ranked in order to provide an identifi cation tool that can be used to shape appropriate care. methods a systematic review was performed using medline, cinahl, psych info and academic search complete. grey literature was included and searches were not restricted to type of intensive care or country. criteria were used to fi lter those articles that identifi ed the patients' views of their stressor, not the patient experience. eligible articles were critiqued using the critical appraisal skills programme for qualitative studies [5] and brought together using a narrative synthesis.all of the reviewed studies used a questionnaire as a means to identify what elements on the intensive care patients found stressful. a list of the top-10 stressors could then be expressed for each study and compared. from this information, a set of guidelines for best practice were devised. introduction this study describes the development and validation of the consumer quality index relatives in icus (cqi 'r-icu'), which aims to measure the satisfaction of relatives and to identify aspect of care that need improvement in the icu in a reliable and valid way.according to the quality standards of the dutch society of intensive care, every icu needs to record the satisfaction of relatives [1] . at this moment there is insuffi cient insight into the quality of care off ered to relatives on the icu because an evidence-based dutch measurement instrument is missing. methods the cqi 'r-icu' has been developed based on a scientifi c and standardised method [2] . a mixed design method is used, consisting of qualitative and quantitative survey studies. factor analyses are carried out to determine the underlying structure of the newly developed questionnaire. multiple regression analysis is used to explore the relationship between demographic variables and the perceived quality of care. results in six hospitals the cqi 'r-icu' is sent to relatives after receiving informed consent (n = 441), 55.1% of the respondents are the patient's partner. respondents seem to be most satisfi ed with the presence of a professional at fi rst entrance to the icu. the highest need for improvement scores relate to information about meals, parking and other disciplines (for example, social worker, spiritual worker or psychologist). factor analysis shows that quality of care is determined by four clusters of items: support, communication, general information and organisation. the reliability of the cqi 'r-icu' is suffi ciently high, only communication and support are signifi cant predictors of total quality judgement of relatives (adj. r 2 = 0.74). in addition, there is a signifi cant diff erence in mean total quality judgement between the six hospitals as well as between the four wards within erasmus mc. none we are conducting a cluster randomized trial with two parallel arms to evaluate strategies to improve family satisfaction with the care that themselves and their critically ill relatives receive in the icus of nonacademic brazilian public hospitals. here we report the results of the baseline phase of this trial. methods in this baseline phase, we interviewed the family member most closely involved with the care of critically ill patients who stayed in the icu for at least 72 hours. we applied a form with 24 questions divided into four domains: overall icu experience, communication, decision-making, and questions related to end-of-life care for patients who died in the icu. each question scored from 0 (very poor) to 100 (excellent). the form was adapted from the family satisfaction with care in the icu (fs-icu 24). as many questions assessed the quality of intensivist care or communication, the interview was applied by a psychologist or a nurse. results families of 564 patients were interviewed. a total 45/564 (8.3%) died in the icu. most respondents were satisfi ed with overall icu experience (mean ± sd score 85.5 ± 11.9). however, family satisfaction with communication (67.8 ± 18.0) and decision-making (69.5 ± 21.1) resulted in somewhat lower scores. most families of patients who died in the icu (38/45 (82.6%)) considered that their relative's life was neither extended nor shortened unnecessarily. also, most of the families believed that their relative did not suff er or suff ered little in the icu (37/46 (80.4%)) and felt supported by the healthcare team (40/46 (87.0%)). conclusion most families were satisfi ed with the care themselves and their critically ill relatives received in the icu. also, most relatives of patients who died in the icu felt that end-of-life care was adequate. although we believe there is much room for improvement in communication, decision-making and support critically ill patients and their families, as their baseline satisfaction with patient care is quite high, it may be hard to demonstrate substantial improvement after interventions. key: cord-005497-w81ysjf9 authors: nan title: 40th international symposium on intensive care & emergency medicine: brussels, belgium. 24-27 march 2020 date: 2020-03-24 journal: crit care doi: 10.1186/s13054-020-2772-3 sha: doc_id: 5497 cord_uid: w81ysjf9 nan ventriculostomy-related infection (vri) is a serious complication in patients with hemorrhagic stroke. in such patients, diagnosis of vris is complicated by blood contamination of csf following ventricular hemorrhage. we aimed to evaluate the diagnostic potential of white blood cells count (wbc), c-reactive protein (crp), and procalcitonin (pct) to identify vris in patients with hemorrhagic stroke during the time of external ventricular drain (edv) in situ. this retrospective study was conducted at the neurosurgical-icu, university hospital of zurich. a total of 347 patients with hemorrhagic stroke and an external ventricular drain (evd) were admitted over a 6 years period at the icu. of those, 14 patients with vris ("vri"), defined by positive csf bacterial culture and increased wbc in csf (>250/ul), and 115 patients without vris and with serial csf sampling ("no-vri") were analyzed. patients with csfcontamination or suspected vri (negative csf cultures but antibiotic treatments) were excluded. wbc, crp, and pct were measured daily. csf was sampled routinely twice a week or by t>38°c. for the analysis, mean peak values of wbc, crp, pct during the time of evd in situ were compared between groups (t test). data are expressed as mean with ci 95%. results: between groups, wbc and crp were similar (wbc: 15.13 g/l and 14.55 g/ l, p=0.68 and crp: 115.93 mg/l and 129.44 mg/l, p=0.56 in the group vri and no-vri, respectively) ( figure 1, panel a and b ). in the group vri, pct was low and significantly lower than in the group no-vri (0.16 ug/l and 2.61ug/l, p=0.03 in the group vri and no-vri, respectively) (panel c). wbc in csf were similar between groups (710.14/ul and 675.16/ul p=0.93 in the group vri and no-vri, respectively). in this study, serum-inflammatory markers were not able to screen patients with vris. their routine measurement should be carefully evaluated. introduction: central nervous system (cns) infections constitute a potentially lifethreatening neurological emergency. patients admitted to the intensive care unit (icu) usually present with a severe disease and organ failure, leading to high mortality and morbidity. we have performed a retrospective analysis during a 5-year period of patients admitted to a polyvalent icu. clinical, demographic and outcome data were collected to evaluate its clinical impact on the outcome of patients with cns infections. we identified 30 patients with the diagnosis of meningitis, meningoencephalitis and ventriculitis, where the median age was 57,6 years (range 24-80). upon clinical presentation, their most frequent signs were fever (70%), meningeal signs (40%), seizures (30%), and a glasgow coma scale score <8 (66%). all needed ventilation support and 66% needed cardiovascular support. a definitive microbiological diagnosis was achieved on 22 patients and antibiotic therapy was adjusted on 18 of them. most common microorganisms were streptococcus pneumoniae (n=7), listeria (n=5) and pseudomonas aeruginosa (n=4) (figure 1 ). other gram negative microorganisms were detected and lead to more adverse outcomes. meningitis was the cause of admission on 26 patients and on a minority (n=4) meningitis was considered to be a secondary diagnosis on patients admitted for other causes (traumatic brain injury, subarachnoid or intraparenchymal hemorrhage, postoperatively of neurosurgical tumor). patients that eventually died had at least one risk factor (age>65, immunocompromised due to diabetes, corticotherapy, hiv or heart transplantation). patients admitted to the icu were not so aged, but had some comorbidities and risk factors leading to more uncommon microorganisms, increasing the risk of adverse outcomes. this lead to an increase of mortality: 23% in the icu and an overall of 43%. study of selenium levels in unresponsive wakefullness (uws) patients with systemic inflammatory response syndrome (sirs) e kondratyeva 1 , s kondratyev 2 , n dryagina 2 the objective of this study was to evaluate the pharmacokinetics (pk) of levetiracetam (lev) in critically ill patients with normal and augmented renal clearance (arc), and determine if the recommended dosage regimen provides concentrations in the therapeutic range (12-46 mg/l) [1] . a prospective observational study was conducted in a tertiary hospital. six blood samples were taken during a dose interval at steady state and lev was quantified by hplc. a population pk study was carried out. statistical analysis was conducted to evaluate the differences in pk between patients with and without arc. the suitability of drug concentrations was also assessed. results: seventeen patients were included, 13 with normal creatinine clearance (crcl) (80-129 ml/min) and 4 with crcl≥130 ml/min (arc). ten patients received 500mg q12h, one 1000mg q12h and two 1500mg q12h. the data were best fitted to a two-compartment model. figure 1 shows lev concentrations during the dosing interval. mean clearance (cl) was 4 l/h and mean volume of distribution of central compartment (v) was 44 l. interindividual variability was 38 and 61% for cl and v, respectively. no differences were identified between both groups (p>0.05) in pk parameters. no correlation was found between lev cl and crcl. trough levels were below the minimum concentration (c min ) 12 mg/l of the therapeutic range in all patients except 1. furthermore, between 3-5 h 50% of samples were below the c min . conclusions: administered doses were not able to maintain lev concentrations in the recommended therapeutic range. other dosage strategies, such the extension of infusion time with higher doses, could be evaluated in order to obtain a more favourable profile. no correlation between lev cl and crcl was found. the mechanical properties of muscles such as tone, elasticity, and stiffness are often affected in chronic critical ill (cci) patients. a hand-held device known as the myotonpro demonstrated acceptable relative and absolute reliability in a ward setting for patients with acute stroke [1] . the technology works on the principle of applying multiple short impulses over the muscle bulk via the testing probe. the aim of our study is to assess the feasibility of objective measurement of muscle tone in cci patients with neurological dynamics and serum biomarkers. the study included 23 cci patients with neurological disorders (stroke, traumatic brain injury, neurosurgical intervention for brain tumors) with more than a 3-weeks stay in icu. dynamic measurements of the muscle properties were taken on the deltoideus, brachioradialis, quadriceps femoris, gastrocnemius using the myo-tonpro. to identify the leading factor in impaired muscle tone also were measured neurological (s100, nse), inflammatory (il-6), bacterial load (pct) biomarkers using elecsys immunoassay and the serum level of microbial metabolites using gc-ms (thermo scientific). results: all patients were divided into groups depending on positive and negative clinical dynamics. significant differences were obtained in parameters characterizing changes in muscle tone of lower limbs -f gastrocnemius (tone) -15.5 vs 18.5 hz, r quadriceps femoris (the mechanical stress relaxation time) -16.5 vs 13.6 ms (p < 0.01, respectively). some significant correlations between five parameters of muscle tone biomarkers and microbial metabolites were revealed. the results of a quantitative measurement of muscle tone objectively reflect the dynamics of neurological status, which in the future may be promising technique for the personalized approach cci in patients. introduction: changes in hormonal status in patients with unresponsive wakefulness syndrome (uws) remains poorly understood. methods: 275 patients in uws were examined at the period from 2007 to 2017. 152 patients (115 men) with tbi and 123 patients (63 men) after hypoxia. acth, cortisol, tsh, free t3 and t4, sth, prolactin and natriuretic peptide were studied in the period from 2 to 4 months uws. in men, the level of total testosterone, lh and fsh was additionally studied. the obtained data was compared with the uws outcome in 6-12 months (crs-r scale assessment). none of the studied hormones of the hypothalamic-pituitary-adrenal axis were a reliable criterion for predicting the outcome of uws. most often and consistently was revealed a tendency of disrupt the rhythm of cortisol secretion, with higher rates in the evening hours. the average value of sth was higher in men with the consequences of head injury who had recovered consciousness than in those who remained in uws. significant decrease in testosterone levels, regardless of age, was found in patients with a consequence of tbi. mean levels of lh were higher in patients with tbi and hypoxia who remained unconscious than in patients who later restored consciousness. the average level of fsh was higher in patients who had recovered consciousness . the increase of natriuretic peptide level was observed both in patients who remained in chronic uws and in those who restored consciousness. no certain endocrine background, characterising this category of patients was found. violations of some hormones secretion rhythms, in particular, cortisol can be considered usual for uws patients, especially in patients with tbi. therapeutic hypothermia has not been used before our research in chronically critically ill (cci) patients. temperature decrease in neuronal cells is a strong signal that triggers endogenic cytoprotection programs using early response genes expression. our goal is to determine influences of craniocerebral hypothermia (cch) on level of consciousness in cci patients. we examined 98 patients with different types of brain injuries. 54 males and 44 females, mean age 45.56 ±16.03. patients were divided into 2 groups: main group -47 patients (vegetative state (vs) -28, minimally conscious state (mcs) -19), comparison group -51 patient (vs -32, mcs -19), groups were equal on main parameters (severity, functional state, comorbidity). patients from main group received courses of cch, duration -180 minutes, scalp temperature 5-8°с, cerebral cortex cooling up to 32-34 o c, session end was without slow reheating period, and session's amount was set -until signs of consciousness recovery. cortex temperature check done noninvasively by using detection of brain tissue emi in shf-range. consciousness recovery in vs and mcs patients controlled using crs-r scale. results: cch sessions significantly increased level of consciousness in vs and mcs patient groups. in vs patients vegetative state increased until minimally conscious state and mcs +, and in mcs group until lucid consciousness (p <0.05) (figure 1 ). craniocerebral hypothermia is used in chronically critically ill patients for the first time. our research results demonstrated effectiveness of cch as an additive treatment tool in such patients. this let us optimistically determine the perspective of inclusion of cch method in chronically critically ill patient's rehabilitation to increase level of consciousness. despite the clinical benefit of endovascular treatment (evt) for large vessel occlusion (lvo) in ischemic stroke, space-occupying brain edema (be) represents a common complication during the course of disease. routinely, ct imaging is used for monitoring of these patients, notably in the critical care setting, yet novel and easy bed-side techniques with the potential to reliably predict be without repetitive imaging would be valuable for a time and cost effective patient care. we assessed the significance of automated pupillometry for the identification of be patients after lvo-evt. we enrolled 40 patients admitted to our neurocritical-care unit who received evt after anterior circulation large vessel occlusion. we monitored parameters of pupillary reactivity [light-reflex latency (lat; s), constriction and re-dilation velocities (cv, dv; mm/s), and percentage change of apertures (per-change; %)] using a portable pupilometer (neuroptics®) up to every 60 minutes during the first 72 hours of icu stay. be was defined as midline-shift ≥5mm on followup imaging within 3-5 days after evt. we assessed differences in pupillary reactivity between patients with and without be (u-test) and evaluated prognostic performance of pupillometry for development of be (roc analysis). in 32 patients (19 women, 74.3±12.0 years) without be, 1,224 assessments were compared to 207 assessments in 6 patients (3 women, 71.7±11.8 years) with be. on day 1, day 2, and day 3 after evt, patients with be had significantly lower cvs and dvs, and smaller perchanges than patients without be, whereas lat did not differ between both groups. roc-analyses revealed a significant negative association of cv, dv, and per-change with development of be. conclusions: automated pupillometry seems to identify patients at risk for be after evt. a prospective study should validate whether automated pupillometry harbors the potential to reduce unnecessary follow-up ct imaging. the aim of this preliminary analysis is to detect differences between the qualitative and quantitative evaluation of the pupillary function carried out by doctors and nurses of an intensive care unit (icu) of a tertiary level hospital. secondary purpose is to investigate new indications for the use of pupillometry in a population admitted in icu methods: the study has been conducted (currently in progress) at the intensive care unit and ecmo referral center at careggi teaching hospital (florence; italy). the enrolled patients are adult subjects (> 18 years) with alteration of consciousness defined by a glasgow coma scale (gcs) < 9, following a primary brain injury and/or the use of sedative drugs. the studied parameters, obtained with neurolight pupillometer ® (id-med, marseille, france) are analyzed, integrated and visual/qualitative evaluation of the pupil function shows a lower reliability if compared to automated pupillometry. the estimated error in the proper determination of photomotor reflex is 34.9% (p< 0.01). no significant difference is reported between quantitative and qualitative pupillometry in the detection of anisocoria. our preliminary results are compatible with previously reported data [1] [2] [3] , even if there was no difference in anisocoria determination. interestingly, a longer latency period among patients treated with opioids has been observed. other results are still in progress. introduction: due to the dynamic of critical care disease, a rapid bedside, noninvasive and highly sensitive and specific method is required for diagnosis. in this study we set out our experience with trancranial color-coded duplex ultrasound (dxt) [1] . the dxt study identifies cerebral arteries as well as hemorrhagic phenomenon, hydrocephalus, mass-occupying lesions and midline shift. this is the main difference between dxt and conventional transcranial doppler (dtc) which is a blind study and do not provide any image. descriptive, cross-sectional and observational study from december 2018 to june 2019. 21 patients were included. inclusion criteria: neurocritical patients. exclusion criteria: no acoustic window, presence of ultrasound artifacts. data collection was performed. it was used a lowfrequency transducer from 1.5-3.5 mhz with trancranial duplex preset ( figure) . the patterns were defined as normal, vasospasm, high resistance, hypermedia and cerebral circulatory arrest, depending on the cerebral flow velocity, lindegaard ratio (lr) and pulsatility index (ip). results: 12 men (57.1%) and 9 women (42.9%). average age 55.6(20-79). patients diseases: subarachnoid hemorrhage 6, traumatic brain injury 5, av malformation 4, stroke 2, hemorrhagic cerebrovascular accident 2 and mass occupying lesions 2. normal pattern: 10 patients (rel. freq 0.47). vasospasm: 5 patients (rel. freq 0.23). high resistance: 4 patients (rel. freq 0.19). hyperemia: 1 patient (real. freq 0.04). cerebral circulatory arrest: 1 patient (rel. freq 0.04) conclusions: dxt should be part of the routine of neuromonitoring, it allows real time images especially useful in unstable conditions. although it will be needed a large amount of patients to be statistical significant, dxt is useful considering a non invasive study, bedside and it allows early identification of different clinic conditions. introduction: embolization of the draining vein during endovascular treatment of arteriovenous malformation (avm) may result in venous outflow obstruction and hemorrhage. anaesthesiologist can use deliberate hypotension to reduce blood flow through avm which may be somehow helpful to prevent this scenario. adenosine-induced cardiac arrest may facilitate the embolization too. the goal of our study was to improve the results of endovascular treatment of avm using adenosine-induced cardiac arrest. methods: after obtaining informed consent 13 patients (8 male, 5 female) were selected for adenosine-induced cardiac arrest during endovascular avm embolization. main age was 40,8±6 years old. 9 of them were evaluated as iii class asa, 4 as iv. endovascular treatment in all cases was performed under general anaesthesia. propofol, fentanyl, rocuronium were used to induce anaesthesia, then all the patients were intubated and ventilated with parameters to keep etco2 32-35 mm hg. sevoflurane 2,1-2,6 vol% (12 cases) or desflurane 6 vol% (1 case) were used to maintain anaesthesia. hemodynamic monitoring consisted of ecg, pulsoximetry, non-invasive blood pressure measurement. onyx or/and squid were used as embolic agents. ct was performed to every patient just after procedure as well as neurological examination. results: adenosine dosage was 0.875-1.26 mg/kg. time of consequent cardiac arrest was 10-40 sec. there were 10 cases we administered adenosine for 1 time, in one case we had to administer it twice, in one fig. 1 (abstract p014) . circle of willis and pulsed-wave doppler mode of middle cerebral artery -3 times and 4 times in one more case as well. hemodynamic parameters recovered without any particular treatment in all the patients. embolization has been performed in all the cases uneventfully. postoperative ct showed no hemorrhage. nobody from investigated group had neurological deterioration in postoperative period. our study shows that adenosine-indused cardiac arrest is not very difficult to perform method and it can be useful during avm embolization. a major risk factor for stroke is atrial fibrillation (af). to treat af anticoagulation is needed. there are now several anticoagulants available. however, a lack of head to head data as well as the absence of accurate techniques makes it difficult to compare them and measure determine there efficacy. stroke is known to produce an abnormal clot microstructure which is a common factor in many thrombotic diseases. this pilot study aims to use a functional biomarker of clot microstructure (d f ) and clotting time (tgp) to investigate the therapeutic effects of different anticoagulants in stroke and af. we recruited 114 patients (59 af and 55 stroke & af). two samples of blood were taken: before anticoagulation (baseline) and post anticoagulation (6-10weeks) . patients were either given warfarin (31%) or axipaban (69%). d f and tgp were measured and compared before and after anticoagulation. results: warfarin increased t gp (267±56 secs to 332±78 secs (p<0.05)), and decreased d f (1.71±0.05 to 1.65±0.06 (p<0.05)). apixaban increased tgp (235±66 sec to 410±105 sec (p<0.05)) but did not change df (1.72±0.04 & 1.72±0.05). interestingly we found that in the apixaban group tgp significantly correlated (p=0.05) with blood drug concentration levels. in this study we show that d f and tgp can quantify and differentiate between the therapeutic effects of two different oral anticoagulants. showing that warfarin prolongs clotting and weakens the ability of the blood to form stable clots. conversely apixaban prolongs clotting time but does not affect the bloods ability to form stable clots. this shows the utility of the d f and tgp biomarkers in comparing two different treatment options, something no other current marker has proven able to do. where d f and tgp may prove useful tools in a personalized approach to anticoagulation treatment and monitoring in an acute setting. hospital mortality compared to the model with the original hairscore. patients with poor-grade aneurysm subarachnoid hemorrhage (asah) world federation of neurological surgeons (wfns) grades iv and v, have commonly been considered to have a poor prognosis (70-100% mortality). though early intervention and aggressive treatment in neuroicu has improved outcome in the past years, it is controversial because most of the patients left hospital severely disabled. the objective of this study was to investigate the clinical and social outcomes in intracranial aneurysm patients with poor-grade asah underwent different intervention therapies. a single center observational registry of 25 poor-grade asah consecutive patients, defined as wfns grades iv and v, treated at tertiary chilean referral center from december 2013 to march 2019 were enrolled in this study. the clinical data including patient characteristics on admission and during treatment course, treatment modality, aneurysm size and location, radiologic features, signs of cerebral herniation (dilated pupils), and functional neurologic outcome were collected. clinical outcomes were assessed via gose and and sociooccupational outcome, both at discharge and at 6 months. figure 1 ). 20% mortality is less than previously reported, and survivors had a favorable recovery, confirmed with neuro psychological test. poor-grade asah patients in our study shows a more positive outcome than previously considered. prognosis of subarachnoid hemorrhage (sah) is scarce, indeed almost half patients die or become severely disable after sah. outcome is related to the severity of the initial bleeding and delayed cerebral infarction (dci). infection and more precisely pneumonia have been associated with poor outcome in sah. however, the interaction between the two pathologic events remains unclear. therefore, we hypothesized that dci may be associated to pneumonia in sah patients. thus the aim of our study was to analyze the association between delayed cerebral infarction and pneumonia in patients with sah. in this retrospective, observational, monocentric cohort study, patients included in the analysis were admitted in neurosurgical intensive care unit or surgical intensive care unit in the university hospital of brest (france) for non-traumatic sah. primary outcome was diagnosis of dci on ct scan or mri 3 months after sah. multivariate analysis was used to identify factors independently associated with dci. a total of 224 patients were included in the analysis (female male ratio 141/83, median age 57 [47-65] years). multivariate analysis was adjusted on sedation, intracranial surgery, fisher classification of sah severity, pneumonia occurrence and non-pneumonia infectious event occurrence ( figure 1 ). pneumonia occurred in 66 patients (29.5%) and other causes of infections in 45 patients (20.1%). dci was found in 108 patients (48.2%). factors independently associated with dci were pneumonia (or 3.10 [1.41-7.06]; p=0.006) and non-pneumonia infectious events (or 2.50 [1.20-5.39 ]; p=0.016). interestingly severity table 1 (abstract p023). correlation of safety and efficacy markers of thrombolysis and thrombolysis time with distance from stroke centre results expressed as odds ratio with 95% confidence interval of initial bleeding evaluated by fisher scale was not independently associated with dci. dci is independently associated with the occurrence of pneumonia or other cause of sepsis. those results may highlight the need for rigorous approach for prevention protocol, early diagnosis and treatment of hospital acquired infectious diseases in sah patients. introduction: traumatic brain injury (tbi) can have devastating neurological, psychological and social sequelae. increased psychiatric morbidity after tbi has been shown in both adult and the pediatric population. also, critical illness as such is a risk factor for psychiatric problems in youth. our aim was to assess risk factors for later being prescribed psychiatric medication in survivors of intensive care unit (icu)-treated pediatric tbi. we used the finnish intensive care consortium (ficc) database to identify patients 5-17 years of age, treated for tbi in four icu in finland during the years 2003-2013. we examined electronic health records and ct scans and collected data on drug prescription after discharge. we used multivariable logistic regression models to find statistically significant risk factors for psychiatric drug reimbursement. we identified 248 patients of which 46 patients received psychiatric drug prescription (19%) during follow up. the median time to prescription was 14 months after tbi (interquartile range [iqr] 5-31 months). 33 patients received antidepressants, 9 received stimulants and 18 received antipsychotics. increasing age showed a positive association with all drug prescriptions except for stimulants, where an inverse relationship was observed (table 1) . using multivariable analyses, we could not find any admission or treatment related factors that significantly associated with being prescribed psychiatric medications. teenage survivors with moderate disability (glasgow outcome scale [gos] 4) showed high numbers of psychotropic drug utilization (45% received any medication, 36% received antidepressants, 24% received antipsychotics). our data suggests, that the risk of psychotropic drug prescription after tbi depends on factors other than those related to injury severity or treatment measures. the incidence of drug prescription is especially high in patients with moderate disability. the effects of 1-adamantylethyloxy-3-morpholino-2-propanol hydrochloride on the formation of steroid neurotoxicity in rats with brain injury a. semenenko 1 , s. semenenko 2 , a. solomonchuk 3 , n. semenenko 3 depending on the nature of the brain injury and the severity of the victims, mortality in traumatic brain injury (tbi) ranges from 5 to 65% [1] . one of the targets for pathogenetic influence on the course of tbi is the use of pharmacological agents that are able to counteract the negative effects of excess concentrations of glucocorticoids on brain. the therapeutic effect of new pharmacological derivative 1adamantylethyloxy-3-morpholino-2-propanol hydrochloride (ademol) in rats with tbi was evaluated for 8 days. the pseudoperated animals and control group received 0.9% nacl solution and the comparison group received amantadine sulfate. cortisol levels were used to determine the efficacy of the test drugs in tbi. in rats treated with ademol, the level of cortisol in the blood ranged from 179 to 188 ng/ml (p5-p95) and was 2.58-fold lower (p<0.05) compared to control pathology group on the 8 day of therapy. instead, the effect of amantadine sulfate on the level of cortisol in the blood was significantly less than that of ademol. the concentration of cortisol in rats with amantadine sulfate in the blood ranged from 271-280 ng/ml (p5-p95), was 1.73 times lower (p<0.05), compared with the control pathology group, and by 49.2% (p<0.05) exceeded the corresponding value in animals treated with ademol. therapeutic treatment of rats with severe tbi with a solution of ademol, preferably better than rats in the group with 0.9% nacl and amantadine sulfate protect the brain from the formation of steroid neurotoxicity by cortisol (p<0.05). although cerebrovascular pressure reactivity (prx) well correlate to patient's outcome [1] , it requires continuous monitoring and mobile average calculation for its determination. we therefore hypothesized that a simplified model of variation between mean arterial pressure (map) and intracranial pressure icp over the first three days of admission would have been able to predict patient outcome: we call this new parameter cerebrovascular pressure correlation index (cpc). we performed a retrospective observational study of all adult patients with severe tbi admitted to icu from january 2017 to april 2018 inclusive. all consecutive patients with a clinical need for icp monitoring were included for analysis. both for icp and map data were mean value over 2-hours registration, for a total of 12 observations/day, cpc was therefore calculated as the pearson correlation coefficient between icp values (x axis) and map values (y axis), obtaining one single value every 24 hours. variables included in the model (i.e. cpc, cpp, icp, systemic glucose, arterial lactate, paco 2 , icp, and internal body temperature) were collected for the first 3 days since trauma. for the main outcome only the minimum value of cpc fit the regression analysis (p = 0.004). the correspondent roc curve showed an auc of 0.80. the associated youden criterion was ≤0.26 (sensitivity = 0.90; specificity = 0.68). of all the variables considered for the secondary outcome only cpcmin fit the regression model (p =0.03). table 1 reports the median and iqr range for sg and nsg of all the variables considered in the model. this observational study suggests that cpc could be a simplified model of variation between map and intracranial pressure icp over the first three days of admission predicting patient outcome. introduction: impaired cerebrovascular reactivity (car) after traumatic brain injury (tbi) is a marker for disease severity and poor outcome. it is unclear how dynamic changes in body temperature and fever impact car and outcome. we calculated the pressure reactivity index (prx) using the center-tbi high-resolution intensive care unit cohort, as a moving correlation coefficient between intracranial pressure (icp) and mean arterial pressure (map). minute and hourly values of prx and temperature were averaged in patients with simultaneous recording of icp and abp. demographic data was based the core registry (v2.0). linear mixed models were calculated based on minute-by-minute data using r with lme4 v1.1-21 and ggeffects v0.9.0. generalized estimating equation models were used to analyze changes during effervescence (increase of temperature of >1°c within 3 hours). we assessed high frequency physiological data during 567 days of 102 patients admitted to the icu with predominantly a closed injury type (n=94/102). median age was 46 years (iqr 29-62), baseline gcs was 6 (iqr 3-9), and 27% had at least one unreactive pupil. the main measurement site for temperature was the urinary bladder 55/ 102(54%). half of the patients (49/102) developed fever(>1h with mean t ≥ 38.3°c) with a total of 834h fever and a median of 9h fever(iqr 4-24) per patient. of 110 effervescence episodes 30(27%) reached the febrile threshold of 38.3°c which was associated with an increase in prx from 0.09 (±sd 0.25) at baseline (2h before) to 0.26 (±sd 0.3) during the febrile peak (p=0.014) (figure 1-a) . linear mixed models showed a quadratic relationship between prx and temperature (p<0.001) with an increase in predicted prx with febrile and hypothermic temperatures ( figure 1b ). the association of increasing body temperature with worsening of car supports prevention of fever in severe tbi. prospective studies are needed to further differentiate between mechanisms involved (i.e. inflammation) and central autonomic dysregulation. fig. 1 (abstract p030) . the patients with a good 6-month outcome (gose>3) after severe traumatic brain injury showed an increase in root mean square of successive differences between normal heartbeats (rmssd) (compared to baseline 30 -minutes before tracheal succtioning) acute kidney injury (aki) is relatively common in patients with severe traumatic brain injury (stbi) and it can contribute to morbidity and mortality [1] . nephrocheck is a point-of-care urine test that flags two biomarkers that indicate if a critically ill patient is at risk for aki. we investigated the incidence of subclinical aki in patients with stbi. we performed a prospective observational study of all adult patients with severe tbi admitted to icu from january 2017 to april 2018 inclusive. all consecutive patients with a clinical need for icp monitoring were included for analysis. urine samples of severe tbi patients was collected at icu admission from 33 patients to measure nephrocheck (nc) test [igfbp7] x was performed using the nephrocheck® astute1 40 ™ meter. serum creatinine was collected at admission, during the first three days, at icu dismission and 60-days follow up to assess renal recovery. the diagnosis of aki was based on kdigo criteria. hemodynamics, electrolytes, peep, p/f, kind of fluid administered, fluid balance, % fluid overload, length of stay, the sequential organ failure assessment score, injury severity scores and mortality were collected. a total of 15 patients (45%) presented a median nc higher values at icu admission. one patient with positive nc value experienced aki at 24 hrs. the positive nc group had more plasma transfusion (p-value 0.03) and a lower median hematocrit at 24 hrs (p-value 0.013), but similar hospital length of stay (p=0.17) and mortality rate (p=0.80) conclusions: nc at icu admission identifies subclinical aki in tbi patients and it maight be used to predictclinical aki. hemodilution (but not fluid overload) seems to be associated with development of subclinical aki. higher nc at icu admission is not associated with worst longterm outcome in tbi patients. severe traumatic brain injury (tbi) is considered a serious public health problem in europe. partly because of the heterogeneity of tbi, considerable uncertainty may exist in the expected outcome of patients. the international mission for prognosis and analysis of clinical trials in tbi (impact) and the corticosteroid randomization after significant head injury (crash) prediction models are considered the most widely validated prognostic models [1, 2] . however, studies using these prediction models for benchmarking of outcomes have been scarce. we aimed to compare actual outcomes in a tbi cohort of critically ill tbi patients with predicted outcomes in a quality of care initiative in an academic hospital. in this retrospective cohort study, we included consecutively admitted tbi patients to the icu adults of erasmus mc, university medical center, rotterdam, the netherlands between january 2018 and february 2019. we included 87 patients with tbi. 14-day mortality was 25%, sixmonth mortality was 36% and six-month unfavourable outcome was 50%. the impact core+ct+lab model predicted 34% 6-month mortality (vs 35% actual, p=0.89) and 51% unfavourable outcome (vs 50% actual, p=0.9). the 14-day mortality prediction by crash prognosis calculator was 43% versus actual 14-day mortality of only 25% (p=0.01), whereas 6-month unfavourable outcome prediction by crash was 67% (vs. 50% actual, p=0.02) ( figure 1 ). the impact model, although developed more than a decade ago, seemed appropriate for benchmarking purposes in this single center cohort in the netherlands, while crash predictions were less applicable to our setting. introduction: out of hospital cardiac arrest (ohca) continues to be associated with significant mortality and morbidity. centralisation of care has considerably improved patient survival but has resulted in increased morbidity in the form of neurological deficit. accurate neurological prognostication remains challenging incorporating repeated clinical examination and ancillary investigations [1, 2] . data was collected retrospectively and analysed for 96 patients admitted post ohca from october 2018 to october 2019. patient arrest demographics were collected in conjunction with extensive inpatient investigation findings including ct, traditional pupil assessment, pupillometry and eeg. results: 50% of patients survived to hospital discharge. patients presenting in a shockable rhythm continue to have higher survival rates ( table 1) . 53% of patients who received immediate cpr survived to hospital discharge in comparison to 41% of patients who did not receive immediate cpr. 73% of patients underwent non-contrast ct head. 74% of patients had traditional pupillary examination performed on arrival. pupillometry was introduced in december 2018; 31 out of a possible 85 patients had pupillometry during their inpatient stay. eeg was undertaken in 11% of cases. our data shows receiving immediate cpr and presenting with a shockable rhythm remain positive prognostic factors. ct head as a stand-alone prognostic modality is unreliable with 14% of patients who survived to discharge, with intact neurology, had an admission ct head reported as hypoxic brain injury. a new neuroprognostic strategy is required in our unit that adds further certainty to likely clinical outcome. this includes increased use of tests such as eeg and pupillometry and the introduction of biomarkers such as neuron specific enolase, somatosensory evoked potential testing and magnetic resonance imaging. introduction: post-resuscitation care of patients following an out-of-hospital cardiac arrest (oohca) is set out by the uk resuscitation council [1] . this is in line with the european resuscitation council guideline [2] . the aim of this audit was to review compliancy to this guideline at the intensive care unit at the bristol royal infirmary . a retrospective audit was performed over a six-month period in adults who were admitted to the intensive care unit at the bri following an oohca whom later died during that admission (41 patients). the focus was on whether the neuroprognostication and end-of-life (eol) care received was as per the standards set by the uk resuscitation council. the main neuroloical examinations documented were pupillary reflex (100%), corneal reflex (75%) and motor response to pain (100%). 61.5% of patients received an ssep analysis >72 hours post-rosc, 81.5% underwent an eeg and 66.7% had >2 serum neuron-specific enolase measurements recorded. all patients (100%) underwent a ct head during their admission. 5.6% of patients were referred to palliative care during their admission. 22% of patients were prescribed all eol medications. most common prescriptions included alfentanil (90.2%) and midazolam (58.5%). finally, 100% of appropriate patients were referred to be potential organ donors. the audit reflected our local practice and that some parameters were not being maintained as set by uk resuscitation guideline. multiple introduction: the prognostication of neurological outcome in comatose out-ofhospital cardiac arrest (ohca) patients is an integral part of post cardiac arrest care. biochemical biomarkers released from cerebral cells after hypoxic-ischemic injury represent potential tools to increase accuracy in predicting outcome after ohca. currently, only neuronspecific enolase (nse) is recommended in european prognostication guidelines. in this study, we present the release dynamics of gfap and uch-l1 after ohca and evaluate their prognostic performance for long-term neurological outcome in ohca patients. serum gfap and uch-l1 were collected at 24, 48 and 72 h after ohca. the primary outcome was neurological function at 6-month follow-up assessed by cerebral performance category scale (cpc), dichotomized into good (cpc 1-2) and poor (cpc [3] [4] [5] . outcome prognostic performance was investigated with receiver operating characteristics (roc) by calculating the area under the receiver operating curve (auroc) and compared to nse. results: 717 of 819 included patients had at least one serum gfap or uch-l1 value at 24, 48 or 72 h after ohca. gfap and uch-l1 levels were significantly elevated in patients with poor outcome. gfap and uch-l1 discriminated excellently between good and poor neurological outcome at all time-points (auroc gfap 0.88-0.89; uch-l1 0.86-0.87) and overall predictive performance measured by auroc of gfap and uch-l1 was superior to nse (auroc 0.76-0.85) ( figure 1 ). however, the roc at the highest specificities of uch-l1 and gfap overlap those of nse and comparing the sensitivities for uch-l1 and gfap with those of nse for the highest specificities (>95%) revealed higher sensitivities for nse than for uch-l1 and gfap at 48 and 72 h. gfap and uch-l1 predict poor neurological outcome in patients after ohca excellently and with a higher overall accuracy than nse, but both biomarkers perform inferior to nse at specificities over 95% at 48 and 72 h limiting their clinical use to guide decisions on prognosis. blood pressure after cardiac arrest and severity of hypoxicischemic encephalopathy c endisch 1 , s preuß 2 , c storm 3 introduction: blood pressure management in post cardiac arrest (ca) patients ensures sufficient cerebral perfusion to avoid secondary brain injury. in local chain-of-survival improvements affect p-ohca survival [1] [2] [3] [4] [5] . also initial rhythm in p-ohca is an important predictor of survival [1, 4] . little is known about the relationship between initial rhythm in p-ohca and long-term outcome [6] [7] [8] . our aim was to establish the relation between shockable rhythm and favorable long-term outcome in pohca. all children aged 1 day-18 years who experienced non-traumatic ohca between 2002-2017 and were admitted to the sophia children's hospital in rotterdam were included. long-term outcome was determined using a pediatric cerebral performance category score at the longest available follow-up interval. the primary outcome measure was survival with favorable neurologic outcome, defined as pcpc 1-2 or no difference between pre-and postarrest pcpc. the association between shockable rhythm and the primary outcome measure was calculated in a multivariable regression model, adjusted for the pre-defined variables. from the 329 patients included in the 16 year study period 126 (38%) patients survived to hospital discharge of which 99 patients (30%) had favorable neurologic outcome (median follow-up duration of 24 months). the rate of favorable neurologic outcome rose from 17% in 2002 to 52% in 2017 (p < 0.001 for trend) (fig. 1) the odds of favorable neurologic outcome at the longest follow-up duration were significantly higher after a shockable initial and unknown rhythm. secondly, trend analysis showed an increase in aed defibrillation and shorter cpr duration. this was followed, finally, by a rise in rosc, survival to hospital discharge and favorable neurologic outcome rate. low socioeconomic status is associated with worse outcome after cardiac arrest. this study aims to investigate if patients´socioeconomic status impacts the chance to receive early coronary angiography after cardiac arrest. in this nationwide retrospective cohort study, 4011 patients admitted alive after out-of-hospital cardiac arrest (ohca) and registered in the swedish registry for cardiopulmonary resuscitation were included. individual data on income and educational level, prehospital parameters, coronary angiography results and comorbidity were linked from other national registers. in the unadjusted model there was a strong correlation between income level and rate of early coronary angiography where 35% of patients in the highest income quartile received early angiography compared to 15% in the lowest income quartile. when adjusting for confounders (educational level, sex, age, comorbidity and hospital type) there were still higher chance of receiving early coronary angiography with increasing income, or 1.31 (ci 1.01-1.68) and 1.67 (ci 1.29-2.16) for the two highest income quartiles respectively compared to the lowest income quartile. when adding potential mediators to the model (initial rhythm, location, response time, bystander cardiopulmonary resuscitation and if the arrest was witnessed) no difference in early angiography related to income level where found. the main mediator was initial rhythm (figure 1 ). higher income is strongly related to the rate of early coronary angiography after ohca. this finding is consistent when adjusting for known confounders. however, the association between income and early angiography seems to be mediated by initial rhythm. patients with low income more often presents with non-shockable rhythms which lowers the likelihood to undergo early coronary angiography. a. the total amount of mortality as a stacked bar: in light-red the number of patients who deceased at scene, in green the number of patients deceased during admission, in red patients who died after discharge. the grey line is the total number of inclusions. b. the rate of bystander aed use, rate of initial shockable rhythm, rate of less than 15 minutes of cpr and rate of favorable neurologic outcome over time. p for trend significant for bystander aed use, less than 15 minutes of cpr and favorable neurologic outcome. trend analysis performed using binary logistic regression for dichotomous data (and a kruskal-wallis test for non-normally distributed continuous data) effect of simulation teaching of cardiopulmonary resuscitation for nursing v spatenkova 1 introduction: simulation teaching is a modern type of critical care (cc) education. the aim of this study was to assess the effect of simulation teaching of cc on a comparison of final examination in different model levels of cardiopulmonary resuscitation (cpr) after the first (cc1) and third, final cc3. the success rate of cpr was tested in prospective study (2017) (2018) on two groups with a total of 66 students in cc1 and cc3 at the faculty of health studies. three semester of undergraduate nursing simulation education (lectures and training) used the laerdal simman 3g. quality of cpr was evaluated according to 4 parameters: compression depth, compression rate, chest release and time of correct frequency. we tested if cpr quality differed between the two groups. for the compression depth and compression rate parameters, first the conformity of variance was verified and then two-sample t-test. as the chest release and time of correct frequency are recorded as percentages, the wilcoxon rank-sum test was conducted for these parameters. to ensure good resuscitation, all recorded parameters must be properly performed during resuscitation. thus, pivot tables were used to generate statistics and test if the number of correctly performed resuscitation parameters for cc1 and cc3 differ. the compression depth parameter was statistically significantly higher for the cc3 than for the cc1 (p=0.016). there were no differences in compression rate (p=0.210), chest release (p=0.514) and time of correct frequency (p=0.586). it was also tested how many of the parameters were performed correctly by students at cpr. the chi-square test shows the relative frequency of cpr success is higher for the cc3 group than for the cc1 group. at least 3 out of 4 parameters were correctly performed by 13% of cc1 students compared to 28% of cc3 students. the study showed a significant improvement of cpr in the final cc3 and supported the three semester simulation education. changes in blood gases during intraoperative cardiac arrest jj wang, r borgstedt, s rehberg, g jansen protestant hospital of the bethel foundation, anaesthesiology, intensive care and emergency medicine, transfusion medicine and pain therapy, bielefeld, germany critical care 2020, 24(suppl 1):p049 introduction: blood gas analysis (bga) is a common approach for monitoring the homeostasis during surgery. while it is well known that cardiac arrest (ca) leads to circulatory collapse and disturbances in homeostasis, little is known about changes of blood gas during peri-operative ca. we retrospectively analysed patients ≥18 years who suffered from peri-operative ca during non-cardiac surgery from 01/2014 to 12/ 2018. peri-operative ca was defined as need for cardiac compression during anaesthesia care. collected data included ph, paco2, pao2, return of spontaneous circulation (rosc) and 30-day mortality after ca. within the study period, we observed 56 peri-operative ca (m=35, f= 21; age 69±16) during 62742 anaesthesia procedures (rosc occurred in 38 patients (68%). 30 days after ca, the mortality was 45% (n=17), 23% (n=13) were discharged, and 14% (n=8) still in hospital. 87% (n= 49) of ca patients had an invasive blood pressure monitoring, 52% (n=29) had bga before and 66% (n=37) during peri-operative ca. prior to ca, the average values were: ph 7.3±0.1, paco2 39±8 and pao2 225±107. during ca, the average values were ph 7.2±0.2, paco2 50±17 and pao2 215±138. table 1 shows the distributions of blood gas before and during ca. there were no statistical differences between the groups (ph: p=0.4; paco2: p=0.19; pao2: p=0.21). hypercapnia and respiratory acidosis is common in peri-operative ca. these data suggests inadequate ventilation during peri-operative resuscitation. further studies should focus on its impact on the outcome. ]. comparing cases with and without rosc, there were significant more diagnostics done in the group without rosc but more therapeutic consequences seen in the rosc-group (table 1) . icu-ca is frequent. diagnostics to detect reversible causes of ca were used rarely in icu-ca (44%), even in patients without rosc. notably, diagnostics often had therapeutic consequences particularly in rosc. further studies are required to define standardized diagnostic algorithms during icu-ca. continuous monitoring of cardiac patients on general ward were improved short term survival of in-hospital cardiac arrest uj go 1 introduction: the importance of early detection in the in-hospital cardiac arrest (ihca) is emphasized. previous studies have reported that clinical outcomes are improved if ihca is witnessed, or if a patient admitted to a monitored location [1, 2] . this study aimed to evaluate the association between continuous monitoring and survival of ihca on general ward. a retrospective cohort study of ihca in patients admitted to ward at an academic tertiary care hospital between january 2009 and december 2018 was performed. the primary outcome was return of spontaneous circulation (rosc). the secondary outcomes were 72hour survival and survival to hospital discharge. (table 1) . cardiac patients with continuous monitoring on general ward showed improving rosc and 72-hour survival but not survival to hospital discharge in ihca. in-hospital cardiac arrest is associated with poor outcomes. although steroids are frequently used in patients with septic shock, it is unclear whether they are beneficial during cardiac arrest and after return of spontaneous circulation (rosc). of 369 cardiac arrest patients evaluated, 100 were enrolled. advanced life support was conducted according to the2015 resuscitation guidelines. forty-six patients were randomly assigned to receive methylprednisolone 40 mg during resuscitation, and 54 to receive saline (placebo). after resuscitation, steroid-treated patients received hydrocortisone 240 mg daily for up to 7 days, followed by tapering . there was no significant difference between the two groups in scvo 2 andall the secondary outcomes (p>0.05 for all comparisons). the present study found no significant physiologic benefit of corticosteroid administration during and after resuscitation in hospitalized patients with cardiac arrest. the experiences of ems providers taking part in a large randomized trial of airway management during out of hospital cardiac arrest, and the impact on their views and practice. results of a survey and telephone interviews m thomas 1 introduction: the aim is to explore ems experiences of participating in a large trial of airway management during out-of-hospital cardiac arrest (air-ways-2), specifically to explore: 1. any changes in views and practice as a result of trial participation. 2. experiences of trial training. 3 . experiences of enrolling critically unwell patients without consent. 4. barriers and facilitators for out-of-hospital trial participation. an online questionnaire was distributed to 1523 ems providers who participated in the trial. in-depth telephone interviews explored the responses to the online questionnaire. quantitative data were collated and presented using simple descriptive statistics. qualitative data collected during the online survey were analysed using content analysis. an interpretive phenomenological analysis approach was used for analysis of qualitative interview data results: responses to the online questionnaire were received from 33% of airways-2 study paramedics and 19 study paramedics were interviewed. paramedics described barriers and facilitators to trial participation and changes in their views and practice. the results are presented in five distinct themes: research process; changes in views and practice regardingairway management; engagement with research; professional identity; professional competence. conclusions: participation in the airways-2 trial was enjoyable and ems providers valued the training and study support. there was enhanced confidence in airway management as a result of taking part in the trial. study paramedics expressed preference for the method of airway management to which they had been randomized. there was support for the stepwise approach to airway management, but also concern regarding the potential to lose tracheal intubation from 'standard' paramedic practice. causes of medical care-associated cardiac arrest on the intensive care unit s entz 1 introduction: cardiac arrest on intensive care unit (icuca) following therapeutic interventions is of imminent importance, because the interventions are comparatively predictable and precautions can potentially be taken. this study investigates medical care associated complications that led to icuca. intensive care database was screened for patients ≥18 years who experienced icuca in a tertiary hospital with five icu (two medical, two surgical, one interdisciplinary, with a sum of 71 icu beds) in germany from 2016-2018. icuca was defined as receiving chest compression and/or defibrillation after admission on icu and classified as "medical care associated" if it was preceded by a therapeutic intervention (i.e. induced by medication, bedding procedures, iatrogenic injuries, procedure associated). subgroups included patients with recurrence of spontaneous circulation (rosc) vs. no-rosc and patients with vs. without vasopressor therapy before intervention. there were 125 icuca in 114 patients of totally 14,264 icu patients. medical care associated complications leading to icuca were detected in 28 cases (22%) [incidence 19.6/10,000(ci95 12.3 -26.9)]. icuca following therapeutic interventions occurred because of circulatory insufficiency [n=20(70%)], respiratory failure [n=5(17%)] and airway associated problems [n=3(10%)]. nine of the 28 patients (32%) with care-associated icuca died. table 1 demonstrates therapeutic interventions followed by icuca. care-associated complications were common reasons for icuca. most of events were induced by circulatory insufficiency due to induction of anaesthesia and bedding procedures. further investigations should focus on preventive strategies, such as vasopressor infusion before therapeutic interventions. in-hospital cardiac arrest (ihca) is a lethal event. however, ihca has received less attention than out-of-hospital cardiac arrest (ohca). there have been some studies on ihca; however, there is a lack of information on the evidence and clinical features of ihca compared with information for ohca. we therefore conducted this study to clarify important aspects of the epidemiology and prognosis of ihca in patients with code blue activation. we carried out a retrospective observational study of patients with code blue events in our hospital during the period from january 2010 to october 2019. we obtained information on the characteristics of patients including age and gender, ihca characteristics including the time of cardiac arrest, event being witnessed, presence of bystander cardiopulmonary resuscitation (cpr), initial shockable rhythm, vital signs 1 h or 6 h before cardiac arrest, survival to hospital discharge (shd), and the cardiac arrest survival postresuscitation in-hospital (caspri) score. the primary endpoint was shd. we performed univariate and multivariate logistic regression analyses. a total of 293 code blue events were activated during the study period. finally, 81 patients were included in this study. overall, the shd rate was 28.4%. the median time of cpr was 14 min (interquartile range, 6-28 min). the rate of initial shockable rhythm was 19.8%. there were significant differences in cpr duration, shockable rhythm, and caspri score between the shd group and non-shd group by univariate-logistic regression analysis. caspri score was found to be the most effective predictive factor for shd (or=0.98, p=0.006) by multivariate-logistic regression analysis. our results demonstrated that caspri score is associated with shd in cpa patients with in-hospital code blue events. caspri score in ihca patients would be a simple and useful adjunctive tool for management of post-cardiac arrest syndrome (pcas). peri-operative cardiac arrest in prematurityincidence and causes at a tertiary care hospital between 2008-2018 g jansen, j popp, e lang, r borgstedt, b schmidt, s rehberg protestand hospital of the bethel foundation, anaesthesiology, intensive care and emergency medicine, bielefeld, germany critical care 2020, 24(suppl 1):p058 the peri-operative care of premature pediatric patients requires special expertise and is therefore reserved for specialized centers. although premature birth is described as a risk factor for peri-operative complications and cardiac arrest (poca) there are no data on its incidence and causality in this particular population [1] . the present study investigates the incidence and causality of pediatric poca at a tertiary care hospital and level i perinatal center in germany. in the anesthesia database of the study center, all anaesthesiological procedures in patients <16 years of age were examined for poca in preterm infants (gestational age <40th week of gestational age) between 2008 and 2018. the peri-operative period was defined between the beginning of anesthesiological care up to 60 minutes after anesthesia and/or sedation. we defined cardiac arrest as the necessity of chest compressions. the perioperative phase and the cause of the poca, gestational age and birth weight were recorded. between 2008 and 2018, 308 (1.3%) of the 22,650 pediatric anesthesiological procedures were performed on 301 premature infants. in total, 10 poca occurred in 9 of these patients (f=6, m=3; average gestional age 208±27 days; average birth weight 1510±747g (incidence 3.2%, ci 96 1.3-5.2%). the time of occurrence and the causes of poca are shown in table 1 . poca in premature babies is rare and has an incidence of 1.3%, which is significantly higher than the non-premature babies. the main causes are problems or complications associated with the respiratory tract and its management, as well as massive hemorrhage. introduction: peri-operative cardiac arrest (poca) in children's anesthesia care is a dreaded event. depending on the country and population, studies describe incidences between 2.9-20.6 per 10,000 children's anesthetics. there are no data on the current incidence of pediatric poca in germany. the present study investigates the incidence of poca at a tertiary hospital and level i perinatal center in germany. in the anesthesia database of the study center, all anaesthesiological procedures in patients <16 years were examined for poca. the peri-operative period was defined between the beginning of anesthesia care up to 60 minutes after anesthesia or sedation. cardiac arrest was defined as the necessity of chest compressions. age, weight, asa status, cause of death and survival after 30 days were recorded. results: 18 poca (median weight was 2525g [q1 7151;q75(14748)]) were observed in 22,650 anaesthesiological procedures (incidence 7.9±4.2 per 10,000 [ci95 4.3-11.6]). table 1 shows the distribution of the individual age groups, incidences and mortalities of poca. peri-operative 30-day mortality was 3 per 10,000 [ci 95 [1] [2] [3] [4] [5] . three children died intraoperatively as a result of hemorrhagic shock, one on the picu as a result of malignant hyperthermia. 30 days after poca, 4 more children had died on the icu due to their underlying disease. poca is a rare event. risk factors are an age <28 days and an asa status ≥ iii. the main cause of peri-operative death in patients <16 years of age is massive hemorrhage, the 30-day mortality is determined by the underlying disease. in-hospital cardiac arrest -predicting adverse outcomes t partington, j borkowski, j gross northwick park hospital, anaesthesia/critical care, london, united kingdom critical care 2020, 24(suppl 1):p060 introduction: cardiac arrest occurs in 1.2 per 1000 hospital admissions in the uk. return of spontaneous circulation (rosc) is achieved in approximately half of resuscitation attempts, but rate of survival to hospital discharge is substantially lower [1] . in our centre, post-arrest care accounts for 6.4% of icu admissions. premorbid social function is purported to affect outcomes, but comorbidity scores are more often used for risk stratification. using a novel social function score alongside an existing comorbidity scale, we aimed to identify trends to inform management of patients at risk of deterioration. a six-month prospective observational study was conducted in a major uk hospital from october 2017 to april 2018. for all adult inpatient cardiac arrests, medical notes were reviewed and data collected on the following domains: patient demographics comorbidities and functional status admission details post-arrest events statistical analysis was performed using student's unpaired t-test. results: 54 cardiac arrests occurred. 85% were in medical patients, with the majority male (63%) and aged over 75 (63%). 89% were emergency admissions, with mean duration of hospital stay pre-arrest 9 days. in 17 cases (31%) sustained rosc was achieved. however, seven of these (41%) were not subsequently admitted to the icu. only six patients (11%) survived to hospital discharge. pre-admission function and comorbidity were worse in patients who did not survive to discharge ( fig. 1 ), but these were not statistically significant in view of small survivor group size. in an increasingly frail inpatient population, a substantial proportion of patients in whom circulation is restored after cardiac arrest are subsequently considered unsuitable for icu admission. given our understanding of inferior outcomes in patients with poor physiological reserve, we encourage early discussion regarding the appropriateness of cpr in selected patients, guided by social function and comorbidity. references: 1. national cardiac arrest audit 2017/18 introduction: there are studies that determine events related to poor outcome in cardiac arrest [1] . in our study, following parametres were determined ohca patients; age median years, asian/europe/syrian, bystander cpr, bystander aed, ems defibrillation, initial cardiac rhythm, prehospital rosc, corneal and pupillary light reflex and day survival. we determineted poor prognostic sign with post-cardiac arrest patients. in this study, we identified the causes of poor outcome in patients with ohca. this was a single-centre, retrospective study. we determined incidence and epidemiological factors including: demographics, initial cardiac rhythm. our study population were non-traumatic ohca. our icu, all ohca patient were evaluated wtih echo, and fluid, inotrope and vazopressor were added according to cardiac performance. results: during our study, 5970 patients who were admitted to intensive care unit between 2012-2019 were screened. 133 of these patients were out-of-hospital arrest and 41 of them were in-hospital arrest. development of cerebral oedema during treatment in hospital remains a poor prognostic sign. the evaluation of initial cardiac ritm is useful to predict neurological outcome in post-cardiac arrest patients. survival after ohca remains low. the evaluation of initial cardiac ritm is useful to predict mortality and neurological outcome in postcardiac arrest patients. basic life support (bls) education and training for school children is active in japan. however, the bls action by schoolchildren may be limited by school rules. this study aimed to analyse the time factors for basic life support performance and outcome in classmatewitnessed out-of-hospital cardiac arrest (ohca) and to investigate how schoolchildren act when they detect ohca. methods: nation-wide database for 1,068 school children cases with ohca and local extended database for 5,478 ems-unwitnessed ohca, both of which were prospectively collected during the period of 2011-2016, were retrospectively analysed. proportion of schoolchildren-detected ohca was low in classmate cases (16.8%, 179/889) in nationwide database and extremely low in all ems-unwitnessed ohcas (1.6%, 88/5,478) in local database. nationwide database analyses revealed that both emergency call and bystander cpr were delayed when a classmate witnessed the ohca case: median, 1 vs. 0 min and 3 vs. 2 min, respectively. classmate-witnessed cases were associated with higher incidences of shockable initial rhythm, aed use and traumatic causes. the rate of neurologically favourable outcome was 19.6% and 12.3%, respectively in classmate-witnessed and other cases: adjusted or; 99% ci, 1.24; 0.63-2.47. of 88 cases detected by schoolchildren in our prefecture, 8 (34%) cases had presumed cardiac aertiology and 12(13.8%) cases were caused by suicide attempts (hanging and fall). school children placed emergency 119 calls as the first action only in 32 (36.4%) cases. emergency calls were largely delayed when school children dialled other numbers or left the scene to seek adult help. school children were rarely involved in bystander cpr (21%) and aed placement (1%). school children are rarely involved in entire bls. emergency calls and bystander cpr are delayed when schoolchildren act to seek help. because schoolchildren detect suicide-related ohcas, psychological care to schoolchildren involved in bls may be necessary. prognostic value of neutrophil/lymphocyte and platelet/ lymphocyte predicting cardiopulmonary resuscitation with spontaneous circulation recovery c li the affiliated suzhou hospital of nanjing medical university, suzhou, china critical care 2020, 24(suppl 1):p063 to investigate the predictive value of peripheral blood neutrophil-tolymphocyte ratio (nlr) and platelet-to-lymphocyte ratio (plr) on inhospital mortality in patients with spontaneous circulation recovery after cardiac arrest. a retrospective analysis was made of 30 patients who recovered from cardiac arrest in our hospital from april 2012 to november 2018 and were admitted to the intensive care unit for more than 24 hours. they were divided into survival group and death group according to the outcome of discharge.the dynamic changes and differences of nlr and plr in 24 hours and 48-72 hours after admission to icu between the two groups were analyzed and compared. multivariate analysis and roc curve were used to explore the predictive value of nlr and plr for in-patient mortality. compared with the survival group, plr in the dead group was significantly lower within 24 hours of admission to the intensive care department (p < 0.05), while nlr in 48-72 hours was significantly higher (p < 0.05). the nlr of surviving group was significantly lower than that of 24 hours (p < 0.05), while the nlr and plr of death group were not significantly different (p < 0.05) from that of 24 hours (p < 0.05). multivariate logistic regression analysis and roc curve showed that nlr of 48-72 h in icu was an independent risk factor for predicting in-patient mortality, and had high sensitivity and specificity in predicting death outcomes. neutrophil to lymphocyte ratio, platelet to lymphocyte ratio can help to judge the outcome of patients with cardiac arrest and recovery of autonomic circulation after cardiopulmonary resuscitation. [2, 3] patients with sofa score > 12 (vs sofa score ≤ 12) had a higher free iron level (35.5 μmol/l vs 16 μmol/l, p = 0.0333) ( figure 1 ). we found a positive correlation between free iron level at h0 and changes of sofa score between h0 and h48 (r= 0.56 ic95[0.08;0.76]). out-of-hospital cardiac arrest is associated with a significant change of plasma free iron level. free iron level at admission is associated with short term outcome. further research is warranted to better determine the significance of such changes. the optimal level of arterial oxygen in the post-resuscitation period is unknown. recent studies show conflicting results in regard to hyperoxia and its association with survival after out-of-hospital cardiac arrest (ohca) [1] . the aim of this trial is to study the association between early hyperoxia after ohca with return of spontaneous circulation (rosc) and 30-day survival. observational study using data from three swedish national registers (i.e. intensive care, cardiac arrest and national patient registries after a successful resuscitation, a systemic inflammatory response occurs, and the c-reactive protein (crp) level represents the degree of inflammation [1] [2] [3] . this study examined the association between increased inflammation and early-onset pneumonia (eop) in patients treated with extracorporeal cardiopulmonary resuscitation (ecpr) after out-of-hospital cardiac arrest (ohca). this retrospective study included data of patients with ohca treated with ecpr admitted to st. luke's international hospital between april 2006 and april 2019. the exclusion criteria were as follows: age < 18 years, therapeutic hypothermia withdrawal due to death or circulatory failure, or sepsis as a suspected cause of cardiac arrest. patients were diagnosed with eop according to clinical signs and symptoms acquired after a hospitalization period of >48 h and within 7 days of admission. the crp levels were measured daily from admission to day 3. we studied 55 patients with a median age of 55 years (interquartile range: 42-65 years). furthermore, 52 (95%) patients were males, and the median time interval from collapse to adequate flow was 51 (42-63) min. all patients received prophylactic antibiotics, and 18 (33%) of them had favorable neurological outcomes (cpc, 1-2). eop occurred in 32 (58%) patients, with a significantly higher crp level on day 3 than that in those without eop (13. 9 categorizing reasons for death after ecpr is important for comparing outcomes to other studies, assessing benefits of interventions, and better define this heterogeneous patient collective. a categorizing for death after cardiac arrest in both in-hospital (ihca) and outof-hospital (ohca) arrests has been proposed in non-ecpr patients by witten et al. here, we adopt this categorization to ecpr patients. single-center, retrospective, cohort study of patients without rosc after ihca or ohca and ecpr between 2010 and 2017. patients with survival below 24 hours were excluded. patients were allocated to one of five predefined reasons for death. results: 231 va-ecmo patients were included (age 58.6±14.3, 29.9% female, 58% ecpr, 30 day survival 42.9%). reasons for death for patients with va-ecmo for shock (survival 53%) and ecpr (36%) were: neurological withdrawal of care (10% vs 25%), comorbid withdrawal of care (18% vs 4%), refractory hemodynamic shock (16% vs 33%), respiratory failure (3% vs 2%), and withdrawal due to presumed patient will (0% vs 1%) ( figure 1 ). the differences in reasons for death among the two groups were significant (p <0.001), driven by withdrawal due to neuroprognostication, comorbidity and hemodynamic instability. categorizing death after va-ecmo into five categories is feasible. there are significant difference between patients with va-ecmo for shock and ecpr. interestingly, only a quarter of patients after ecpr died due to brain damage. introduction: scarcity of potential dead brain donors and the persistent mismatch between supply and demand of organs for transplantation has led the transplant community to reconsider donation after circulatory death (dcd) as a strategy to increase the donor pool. normothermic regional perfusion (nrp) by extracorporeal membrane oxygenation (ecmo) may be the most effective method for preserving abdominal organs in dcd, especially in liver transplantation [1, 2] . a pitfall of this method is its complexity and the unavailability of this resource in some hospitals, especially in regional hospitals, where potential dcd donors may exist. aim of this study is to report the use of mobile ecmo team in controlled dcd. from june 2018 to november 2019 our group has worked as a mobile ecmo team for cdcd outside our center. portable equipment included cannulation material and the ecmo device. the transplant team consisted of 1 transplant coordinator (anesthesiologist-intensivist, ecmo operator and organ extraction supervisor), 1 cardiac surgeon (cannulation), 1 interventional radiologist (cannulation) and one cardiovascular perfusionist (ecmo operator). twenty-five cdcd donations were performed. characteristics of donors and organs retrieved are summarized in figure 1 . from 25 cdcd, 17 livers, 4 lungs, 45 kidneys were obtained. the evolution of grafts and receptors was favorable at day 30 post-transplant. mobile ecmo teams may enable cdcd in hospitals without these resources, thereby increasing the pool of donors and optimizing graft outcomes. what is the useful coagulation and fibrinolysis marker for predicting extracorporeal membrane oxygenation circuit exchange due to intra-circuit thrombus? y izutani, k hoshino, s morimoto, k muranishi, j maruyama, y irie, y kawano, h ishikura fukuoka university hospital, emergency and critical care center, fukuoka-shi, japan critical care 2020, 24(suppl 1):p071 a thrombus formation is one of the most frequent and adverse complications during extracorporeal membrane oxygenation (ecmo) support. previous studies have reported that increased d-dimer is a useful predictor of thrombus formation within the ecmo circuit. the purpose of this study was to identify coagulation/fibrinolysis markers for predicting the replacement of ecmo circuit due to intra-circuit thrombus during ecmo support. fourteen patients who underwent veno-venous ecmo for acute respiratory failure between january 2014 and december 2018 were enrolled. these patients received a total of 125 days of ecmo support. of these, 9 days (times) on which the ecmo circuits were replaced was regarded as the replacement group, while the remaining 116 days were considered as the non-replacement group. the several coagulation/fibrinolysis markers were routinely measured every day during ecmo support. we compared with the levels of these markers between two group to identify the most relevant marker for ecmo circuit replacement due to thrombus. the mean duration of ecmo support was 9±11 days, and the mean number of ecmo circuit replacement was 0.6±1.0 times per patient. ddimer, thrombin-antithrombin complex (tat), plasmin-α2 plasmin inhibitor complex (pic), and soluble fibrin (sf) were significantly higher in the replacement group rather than in the non-replacement group (p < 0.01, respectively). according to a multivariate analysis, sf was the only independent predictor of ecmo circuit replacement due to thrombus. the odds ratio (95% confidence intervals) for sf (10 μg/ml) was 1.2 (1.1-1.3). the area under the curve and optimal cut-off value were 0.94 and 85 ng/ml for sf, respectively (sensitivity, 100%; specificity, 85%). from these results, we concluded that sf may be the useful marker rather than d-dimer for predicting the replacement of ecmo circuit due to intra-circuit thrombosis. inhomogeneity of lung elastance in patients who underwent venovenous extra corporeal membrane oxygenation (v-v ecmo)-a computed tomography scan study rd di mussi 1 , ri iannuzziello 2 , fm murgolo 2 , fd de carlo 2 , e caricola 2 , na barrett 3 , lc camporota 3 , sg grasso 2 1 università degli studi di bari "aldo moro", department of emergencies and organ transplant, bari, italy; 2 università degli studi di bari "aldo moro", bari, italy; 3 department of adult critical care, guy´s and st thomas´nhs foundation trust, king´s health partners, london, uk critical care 2020, 24(suppl 1):p072 in patients with acute respiratory distress syndrome (ards), nonaerated, poorly aerated, and normally aerated regions coexist to variable degrees in lung parenchyma. the recruitment maneuvers aim to reopen collapsed lung tissue. in a theoretical point view, this strategy may also prevent the normal aerated lung tissue hyperinflation [1] . the objective of our study was to evaluate lung characteristics in terms of hounsfield units (hu), volume and elastance before and after a recruitment maneuver. in 37 patients with severe ards who underwent v-v ecmo, computed tomography scans (ct-scans) at 5 cmh 2 o of continuous positive airway pressure (cpap) and 45 cmh 2 o were performed. the same ct image was selected at the two different levels of pressure. the distribution of lung opacities, in terms of hu, was classified using the "ucla" colour coding table (osirix image processing software, geneva, switzerland). correspondent lung regions of about 1020 voxels were selected. the quantitative analysis, in terms of volume air (vair) was performed with maluna software (version 3.17; maluna, goettingen, germany). elastance was calculated as the pressure(cmh 2 o)/ vair (ml) ratio. results: see figure 1 . lung inhomogeneity occurs also after recruiting maneuvers. our data confirm that the elastance of recruited lung regions is higher than the elastance of the normal aerated lung regions at low positive end-expiratory pressure (peep) (baby lung). on the contrary the "baby lung" frequently develops hyperinflation. the unpredictable pattern of distribution of volume after recruitment maneuverers may explain the controversial role of peep during the ards treatment. . formal recommendations on target, timing, and rate of at supplementation are lacking. we conceived this study to evaluate the effect of prolonged at supplementation in adult patients requiring veno-venous ecmo for respiratory failure on heparin dose, adequacy of anticoagulation and safety methods: before ecmo start patients were randomized to either receive at supplementation to maintain a functional at level between 80 and 120% (at supplementation group) or not (control group) for the entire ecmo course. anticoagulation was provided with unfractionated heparin following a standardized protocol [1] . the primary outcome was the dose of heparin required to maintain the ratio of activated partial thromboplastin time between 1.5 and 2. secondary outcomes were the adequacy of anticoagulation measured with anti-factor xa and the incidence of hemorrhagic and thrombotic complications and amount of blood products fig. 1 b) . conclusions: this retrospective analysis was not able to show a survival benefit for additive pp to ecmo support in general. early initiation of pp could be an important factor for improving survival in this setting and should be considered in a randomized controlled trial for further evaluation. cause-specific mortality during extracorporeal membrane oxygenation, a single center review of medical records m panigada, d tubiolo, p properzi, g grasselli, a pesenti fondazione irccs ca´granda ospedale maggiore policlinico, intensive care unit, milano, italy critical care 2020, 24(suppl 1):p075 introduction: mortality during extracorporeal membrane oxygenation (ecmo) settles around 35% and the occurrence of bleeding during ecmo is associated with a high mortality rate. however, cause-specific mortality is rarely reported, probably due to the difficulty of its classification. the purpose of the study was to evaluate the agreement between two expert icu physician in the classification of the cause of death of patients supported with ecmo for either respiratory or cardiac support. methods: two intensive care unit (icu) expert staff physicians independently reviewed the entire medical records of all ecmo patients who died before icu discharge from january 2011 to september 2019 at fondazione irccs ca' granda, milan. they were asked to choose the cause of patient's death among six categories. in case of disagreement, a third expert adjudicated the case. the two reviewers were also asked whether, in their opinion, bleeding during the last 24 hours contributed to death. elso definition of major bleeding [1] during the last 24 hours was also recorded for each patient. results: two-hundred and two patients were supported with ecmo of whom 70 (34.6%) died. most of these patients (n=53, 75.7%) died during ecmo. interrater agreement for cause-specific mortality between the two expert physicians was substantial (k 0.71, se 0.07, p<0.01) of the 14 discordant cases 6 were categorized as refractory respiratory failure and 4 as multiorgan failure and septic shock respectively. the distribution of cause-specific mortality is shown in figure 1 . major bleeding (elso) was present in 27 (38.6%) patients, only in 9 (33.3%) of them bleeding contributed to death according to the reviewers. patients treated with early pp while ecmo showed a superior survival to patients treated with late pp or without pp while ecmo. optimal cut off value for duration of ecmo initiation to first pp was calculated using roc-analysis (auc = 0.789) and the youden-index. highest sensitivity and specificity for beneficial survival were achieved for a beginning of pp in <0.71 days. (log rank=0.018). pp: prone positioning p076 non-invasive mechanical ventilation in veno-venous extracorporeal membrane oxygenation j rilinger, v zotzmann, x bemtgen, pm biever, d duerschmied, c bode, dl staudacher, t wengenmayer heart center freiburg university, department of cardiology and angiology i, freiburg, germany critical care 2020, 24(suppl 1):p076 introduction: veno-venous extracorporeal membrane oxygenation (ecmo) support can be combined with a variety of different non-invasive ways to deliver oxygen to the patient's lung. several positive effects might be linked to this so called "awake ecmo". so far there is little evidence about indications and outcome of this approach. we report retrospective registry data on all ards patients treated with ecmo support at a university hospital between 10/2010 and 04/ 2019. in a systematic review of medical records, we distinguished between patients with invasive mechanical ventilation (imv) from the initiation of ecmo therapy (imv group) and patients that received any kind of non-invasive oxygen supply (non-imv group). a total of 276 patients could be analysed. 16 (5.8%) patients received non-imv ecmo support. patients receiving non-imv ecmo therapy showed severe underlying pulmonary disease and immunosuppression (fig. 1) . these patients had higher rates of lung fibrosis, long-term oxygen therapy, pulmonary hypertension, renal insufficiency and immunosuppression (p<0.05). 12 of 16 patients (75%) required imv during the hospital stay in average 5.3±5.0 [0.8-17.1] days after ecmo initiation. reasons were hypoxia despite of ecmo, insufficient ecmo-flow, insufficient protective reflexes or patient agitation. patients with initially non-imv ecmo support showed a numerical but not significant lower icu and hospital survival (25.0% vs. 45.4%, p= 0.111). non-imv ecmo support was applied in patients with severe underlying pulmonary disease and/or immunosuppression. in a high proportion of patients the ventilation regime had to be switched from non-invasive to invasive. survival in this very selected cohort was low. in this retrospective analysis no evident benefit for a noninvasive ventilation strategy could be found. the high proportion of patients who switched from non-imv to imv therapy underlines the need for rigorous patient selection. intra-hospital transportation on extracorporeal membrane oxygenation (ecmo) -a single centre experience in ireland. z siddique, s o´brien, e carton, i conrick-martin mater misericordiae university hospital, department of critical care medicine, dublin, ireland critical care 2020, 24(suppl 1):p077 the objective of this study is to evaluate intra-hospital transportation of patients on extracorporeal membrane oxygenation (ecmo). it is a retrospective analysis of prospectively collected database, performed as part of ongoing quality improvement initiatives. the setting of this study is an 18-bed, combined surgical and medical adult intensive care unit (icu) located in a 570-bed hospital that serves as the national referral centre for cardiothoracic surgery, heart & lung transplantation and ecmo in ireland. we reviewed 33 months of data (from 2017 to 2019) regarding patients admitted to our critical care unit who required intra-hospital transfer for diagnostic and/or therapeutic interventions. we also compared the data to available local guidelines. results: 23 patients were transported on ecmo on a total of 28 occasions; the most common indication being ct brain (table 1) . ecmo cannulation sites were peripheral in 20 patients, 3 patients were centrally cannulated. median time from start of the transfer until the patient was returned to icu was 50 minutes (range: 35-195). the ecmo console was placed on a dedicated ecmo trolley apart from two occasions where it was placed on the patient's bed. number of staff required for transport was between 4 to 10; with an icu consultant as team leader. ecmo specialist nurses were always present on the transport team. 27 transfers were during normal working hours with 1 happening on a weekend. a total of 12 complications occurred during the transports, of underlying pulmonary disease or status of immunosuppression in ecmo patients without invasive mechanical ventilation which 1 was significant and 11 were not. the significant complication encountered was ventricular tachycardia in a v-a ecmo patient which required electrical defibrillation. no adverse events related to transport were seen following return to icu. in this single-centre study, we have demonstrated safe intra-hospital transport of ecmo patients. the use of local guidelines, appropriate personnel and performance during normal working hours is recommended. a novel approach for flow simulation in ecmo rotary blood pumps a supady 1 , c benk 2 , j cornelis 3 , c bode 1 , d duerschmied 1 1 heart center freiburg university, cardiology and angiogiology i, freiburg, germany; 2 heart center freiburg university, department of cardiovascular surgery, freiburg, germany; 3 fifty2 technology gmbh, 79108 freiburg, germany critical care 2020, 24(suppl 1):p078 introduction: extracorporeal membrane oxygenation (ecmo) is used increasingly in critically ill patients suffering from acute respiratory failure, cardiogenic shock or cardiac arrest. however, this therapy can have deleterious side effects such as bleeding or clotting complications and hemolysis. these complications are particularly caused by physical stress acting upon the blood components while passing through the ecmo system, especially within the rotary pump. we here present a novel approach to simulate blood flows through rotary blood pumps used in current ecmo systems in order to better understand the genesis of these complications. geometries of the xenios dp3 (xenios ag, heilbronn, germany) rotary pump were reconstructed by ct-scans and manual measurements using computer-aided design (cad). the computational fluid dynamics (cfd) simulation was performed using the software preon-lab (fifty2 technology gmbh, freiburg, germany), which implements a mesh-free lagrangian method requiring minimal preprocessing of the cad data. the geometries are introduced to the simulation model as tessellated surfaces. five operating points have been specified by the rotation of the centrifugal fan and the corresponding inflow and outflow of blood. the blood is approximatively modelled as a newtonian fluid with a density of 1040 kg/m 3 . preonlab allows detailed assessment of the blood flow while passing through the rotary pump including analysis of local flow rates, pressure gradients and shear stress acting upon the blood. dead zones in the fluid flow can be detected which gives reference points for optimizations of the pump design. for the first time, we demonstrate a novel approach for flow simulation in an ecmo rotary pump ( figure 1 ). this approach may help better understand hemodynamics within the extracorporeal system to define optimal operating points or re-design components aiming to limit hemolysis, coagulation disorders and bleeding in seriously ill patients. one-year experience of bedside percutaneous va-ecmo decannulation in a territory ecmo center in hong kong km fong, sy au, pw leung, kc shek, hj yuen, sk yung, hl wu, so so, wy ng, kh leung queen elizabeth hospital, intensive care unit, hong kong critical care 2020, 24(suppl 1):p079 when veno-arterial extra-corporeal membrane oxygenation (va-ecmo) support can be terminated, arteriotomy wounds of the patients of are traditionally closed by open repair in the operation theaters. lots of manpower are involved and timeslots in operating theaters are scarce. transport of the critically-ill is risky. successful va-ecmo decannulation using percutaneous device called proglide has been reported and our group had adopted and modified this approach [1] . methods: this is a retrospective study analyzing the one-year experience of bedside va-ecmo decannulation. our institution is a 23-bed tertiary ecmo referral center in hong kong. our first bedside decannulation was performed in november 2018, and since then, this practice had replaced the traditional open repair, unless contraindicated. data from november 2018 to october 2019 were analyzed. in the study period, 39 patients received va-ecmo. 28 survived to decannulation and 25 received bedside percutaneous decannulation. their median age was 59 (52-67). the default arterial catheter size was 17fr, with 15 fr in 3 cases and 19fr in one. five (20%) failed percutaneous closure and they were subsequently surgically repaired without extra corporeal life support (ecls) continues to be associated with high mortality rates. our ability to predict outcome prior to initiation ecls remains limited. here we take a single cell rnaseq approach in an effort to identify novel immune cell types that are associated with-and may contribute to-survival on ecls. whole genome transcriptomic profiles were generated from~40,000 peripheral blood monocytes obtained from 38 patients at the time of cannulation for veno-arterial ecls (va-ecls). within each subpopulation, differential gene expression analysis was performed to identify new markers associated with survival. findings were validated in a additional cohorts by flow cytometry. surviving patients had significantly higher proportions of cd8 + nkt cells (cd3 + /cd8 + /cd19 -/cd56 + ) that were cd52 + (p = 0.001, fdr < 0.05) ( figure 1 ). to validate this observation, we performed fc analysis of a second cohort of 20 patients. for each patient, we quantified the proportion of cd8 + nkt cells that were cd52 + . using the median proportion as the cutoff, we again found that a high proportion of cd52 + cells among cd8 + nkt cells was predictive of 48 hour survival (p=0.024). we noted that while high levels of cd52+ cells among the cd8+ nkt cells was protective in this cohort of va-ecls patients, this relationship did not hold for patients with sepsis. as only a few the va-ecls patients were septic, we analyzed a third cohort of septic ecls patients. we observed that high levels of cd52+ cells among the cd8+ nkt populations was not protective in this population. the proportion of cd8+ nkt cells that are positive for cd52 is predictive of survival among patients undergoing va-ecls for noninfection related indications. introduction: the use of calcium sensitizers has grown enormously in the last decade, probably due to their interesting pharmacodynamic properties. levosimendan (ls) is frequently administered in patients under mechanical circulatory support. we performed a retrospective evaluation of patients treated with ls prior to weaning from mechanical support. this evaluation was combined with a review of the literature. a query of our icu patient data management system revealed 22 patients receiving ls prior to or during vad/ecls support. outcome data were obtained from the patients medical records. of our 22 patients, 78% was successfully weaned off ecls. fourteen patients (63 %) died before being discharged of whom 5 while on ecls support. of the weaned patients, 9 died afterwards. 4 of the converted patients needed subsequent veno-venous ecls support for right ventricular support after the implantation. survival to discharge ratio for the whole group was 31 %. more detailed demographic results can be found in table 1 . a pubmed search using the terms "(ecmo or ecls) and ls and weaning" resulted in 7 publications which dealt specifically with weaning of ecls support. several weaning approaches are available, however poor outcome has remains a problem. some recent studies show a possible beneficial effect of ls infusion prior to weaning from ecls. however most of these studies are retrospective or observational at best. because ls is primarily reserved for the most severe cases, outcome interpretation is difficult. overall weaning success ranges from 82%-92% and variation is very dependant of inclusion criteria. the calcium sensitizer ls can be used when weaning off patients from ecls, certainly given its low incidence of complications. future, large randomized trials are however needed in order to confirm this strategy. cardiogenic shock is well described in newly diagnosed pheochromocytoma, and crisis may be precipitated by hemorrhage into tumour. v-a ecmo represents a rescue therapy in a subset of these patients refractory to medical management, facilitating cardiac recovery and subsequent definitive surgery. consent to publish: written informed consent for publication was obtained from the 2 patients. during a spontaneous breathing trial respiratory mechanics can worsen, and respiratory muscle effort can increase, leading to respiratory muscle fatigue, pump failure, hypercapnia and an unsuccessful weaning from mechanical ventilation. this case report discusses the possibility of applying extracorporeal co 2 removal (ecco 2 r) to reduce respiratory muscle effort in a liver transplant recipient who already failed three weaning attempts from mechanical ventilation. the ecco 2 r membrane lung was integrated into a conventional renal replacement therapy circuit and blood flow was increased from 150 to 300 ml/min. measurements of respiratory mechanics (including esophageal pressure, as shown in fig. 1 ) were used to assess the reduction of respiratory effort before and during the application of ecco 2 r. was delivered through a 13fr-double-lumen-cannula; 350 ml/min blood-flow with 10lt oxygen sweep-gas-flow and aptt 1.5-2 baseline were maintained (iv-heparin). in all cases respiratory and metabolic parameters improved without complications ( figure 1 ). ecco2r-crrt facilitated extubation (4 out 9 imv pts). in 4 out of 5 pts at risk of niv failure, it avoided imv. treatment mean duration was 73±31 hours, mean lenght of icu stay was 6±4 days. all patients survived to the treatment, nevertheless 2 patients died due to irreversible multiple mof. in our aecopd series prismalung®-prismaflex® facilitated weaning from imv and avoided intubation in patients at risk of niv failure without complications. these positive results may be related to minimal invasiveness of the low-flow device used and may constitute the rationale for a larger randomized controlled trial. consent: written informed consent for data publication has been obtained. extracorporeal the primary outcome findings from the supernova trial [1] demonstrated that the use of extracorporeal carbon dioxide reamoval (ecco 2 r) allows a reduction in tidal volume (tv) to ultraprotective levels (≈4 ml/kg predicted body weight or pbw) during mechanical ventilation in ards patients without significant increases in the arterial partial pressure of carbon dioxide (paco 2 ). unfortunately, it was not feasible to directly measure ecco 2 r rates during the trial. we used a mathematical model of whole-body oxygen (o 2 ) and carbon dioxide (co 2 ) transport and biochemistry [2] to calculate ecco 2 r rates that permit a fit to the data reported for hemolung (alung technologies) and ila (novalung)/cardiohelp (getinge) devices in the supernova trial [3] . the mathematical model was calibrated under baseline conditions where patients were mechanically ventilated at a tv of 6 ml/kg pbw in the absence of an ecco 2 r device; the o 2 consumption rate, co 2 production rate and pulmonary shunt fraction were adjusted to match the measured baseline arterial partial pressure of o 2 and paco 2 . assuming all baseline parameters were fixed, tv was then reduced to 4.1 ml/kg pbw and the mathematical model predicted the ecco 2 r rate to the change in the paco 2 level. model predictions for the devices are shown in table 1 . these predictions suggest that ecco 2 r rates for ila/cardiohelp devices were approximately twice those for hemolung devices during the supernova trial. these results may be useful to evaluate the expected performance of novel ecco 2 r devices. efficiency and safety of a system crrt plus ecco2r to allow ultraprotective ventilation protocol in patients with acute renal failure f maldarelli 1 despite renal function replacement techniques (crrt), a patient who develops acute renal failure(aki) in intensive care unit (icu) has a mortality rate of 5-80%. this risk is partly due to the adverse effect of aki on other organs than the kidney. respiratory complications are frequently associated with the development of aki. new machines combining crrt with a carbon dioxide removal membrane (ecco2r) allows the setting up of an ultra-protective ventilation (4 ml/kg of predicted boby weight (pbw)) to reduce any lung damage from mechanical ventilation (mv). the reduction in tidal volume (vt) is associated with a decrease in lung damage partly triggered by aki. we evaluated the efficacy of a combined system crrt+ecco 2 r to reduce the vt to ultraprotective values in patients with acute respiratory failure and aki. ards is a syndrome with high morbidity and mortality. an emerging treatment option is ecco2r, but the benefit its remains unclear. we assess different degrees of ecco2r and varying dead space (ds) on ventilator settings in order to minimize mechanical power. we calculated mechanical power as (1) power=rr*{δ〖vt〗^2*[1/2*el+rr*(1+i:e)/(60*i:e)*r]+ δvt*peep} (el: system elastance, r: airway resistance, peep: positive end expiratory pressure, i:e: inspiratory to expiratory ratio). we calculated the combination of respiratory rate (rr) and tidal volume (vt) ("optimal rr" and *optimal vt*) leading to minimal applied power for a stable carbon dioxide elimination of 300 ml/min (vco2) for two scenarios: 1) variation of physiological ds from 10 to 40 % of vt at a fixed rate of eccor2. 2) variation of ecco2r of either 80, 120, 160 or 200 ml/min at a fixed physiological ds of 20%. the alveolar ventilation (va) necessary to eliminate the vco2 was calculated as (2) va= (-vco2*σ_co2*r*t*(1+k_c ))/(vco2/q-p_vco2*σ_co2*r*t*((1+k_c ))/760) σco2: co2 solubility in blood, r: gas constant, t: temperature. pvco2: venous partial pressure, kc: function of ph (12.5 for a ph of 7.2), q: blood flow [5 l/min]). increasing ds from 10 to 40% increases the minimal mechanical power from 5.9 to 10.8 j/min, primarily caused by an increase of optimal vt (495 -672 ml). optimal rr was only slightly increased (6.4 -7.5 /min, figure 1 panel a). for varying ecco2r removal, necessary ventilation ranges from 1.6 to 3.6 l/min. this predicts a minimal power between 5.6 and 10.4 j/min with an unchanged optimal vt (540 -543 ml) and an increasing optimal rr (5.4 to 12.3 /min ( figure 1 panel b)). in order to minimize mechanical power, increasing shunt or co2 production should be met with increases in rr while increases in ds should be met with increases in vt. our results indicate that during ecco2r, mechanical power and thus risk for lung injury can be minimized with higher vt compared to conservative ventilation strategies. validity of empirical estimates of physiological dead space in acute respiratory distress syndrome jd dianti, eg goligher, as slutsky university of toronto, interdepartmental division of critical care medicine, toronto, canada critical care 2020, 24(suppl 1):p091 increased physiological dead space fraction (v d /v t ) is a hallmark of the acute respiratory distress syndrome (ards) and has been shown to predict ards mortality. v d /v t is also important in estimating the reduction in tidal volume (v t ) and driving pressure (δp) with extracorporeal co 2 removal (ecco 2 r). v d /v t can be measured with volumetric capnography but empirical formulae using the patient's age, weight, height, gender and paco 2 have been proposed to estimate v d /v t based on estimates of co 2 production (v co2 ). the accuracy of this approach in critically ill patients, however, is not clear. secondary analysis of a previously published trial [1] in which v d /v t and v co2 were measured in ards patients. estimated dead space fraction (v d,est /v t ) was calculated using standard formulae. agreement between methods was evaluated by bland-altman analysis. the predicted change in δp with ecco 2 r was evaluated using both measured and estimated alveolar dead space fraction (v dalv /v t ). results: vd,est/vt was higher than measured vd/vt, with a low correlation between the 2 (r2= 0.21). vco2 was underestimated by the predicted approach (table 1) , accounting for 57% of the error in estimating vd/vt. the expected reduction in δp with ecco2r using vdalv/ vt was in reasonable agreement with the expected reduction using introduction: acute respiratory distress syndrome (ards) is a common condition in critically ill patient. however neuromuscular blockers (nmb) result controvertial in early treatment of ards [1] . we ought to search systematically and realize a meta-analysis on the matter. an electronic search of randomized clinical trials in adult patient treated with early neuromuscular blockers compared without neuromuscular blockers in ards. the primary objective of the analysis was the mortality at 21 to 28 days. secondary endpoints included mechanical ventilation free days, icu acquired weakness and barotrauma. the search obtained 6 studies for the analysis [1] [2] [3] [4] [5] [6] (figure 1 ). the early use of neuromuscular blockers in ards showed no increase in mortality, but the results should be taken with caution. there was no differences in mechanical ventilation free days. barotrauma is less with the use of nmb. ultrasound is fairly sensitive in the detection of lung infiltrates in patients with hematologic malignancies. in patients with pneumonia requiring intensive care (icu) admission, we hypothesise that abnormal right ventricular (rv) function is associated with an increased 90-day mortality. rv dysfunction in critically ill patients has a well-known association with adverse outcomes [1] . however, its impact on mortality in patients with pneumonia has not been directly studied. patients admitted to the queen elizabeth hospital birmingham icu between april 2016 and july 2019 with a diagnosis of pneumonia who had a formal cardiologist tte were included. abnormal rv function was defined by either depressed function, dilated size or moderate to severe risk of pulmonary hypertension (phtn). abnormal lv function was defined by an lv ejection fraction £ 45% or grade ii or more diastolic dysfunction. patients with a clinical suspicion of pulmonary embolism were excluded. the primary outcome was 90-day mortality. continuous data is presented as median (iqr). categorical data is presented as % and analysed using a chi-squared test. results: 942 patients were admitted to icu with pneumonia, of which 347 (37%) had a tte. patients were 59% male, had a median age of 67 (46-88) and 90-day mortality of 31%. abnormal rv function was present in 30% (n=103), with 15% depressed, 15% dilated and 14% with moderate to severe risk of phtn. rv dysfunction was associated with an increased 90-day mortality compared to normal rv patients (62% vs. 18%, p<0.0001). lv function was abnormal in 25% (n=88) and was not associated with a higher 90-day mortality compared to normal lv patients (38% vs 29%, p = 0.20). rv dysfunction was associated with a higher 90-day mortality than lv dysfunction (62% vs 38%, p = 0.001). conclusions: this is one of the first studies to demonstrate that abnormal rv function is associated with an increased mortality in icu patients with pneumonia. interestingly, abnormal lv function was not associated with an increased mortality. rakuno gakuen university, anesthesiology, hokkaido, japan critical care 2020, 24(suppl 1):p097 we previously reported a simple correction method of estimating pleural pressure (ppl) by using central venous pressure (cvp) and that it can be used to estimate ppl and transpulmonary pressure in pediatric patients with respiratory failure. however, it remains unknown that this method can be applied to patients with various levels of chest wall elastance and/or intravascular volume. the objective of this study is to investigate whether our method is accurate in various conditions of chest wall elastance and intravascular volume. the study was approved by the animal care and use committee of rakuno gakuen university. ten anesthetized and paralyzed pigs (43.2 ± 1.8kg) were mechanically ventilated and subjected to lung injury by saline lung lavage. each pig was subjected to 3 different intravascular volume and 2 different intraabdominal pressures; in each condition, the accuracy of our method was tested. specifically, airway flow, airway pressure (paw), esophageal pressure (pes), and cvp were recorded in each condition, then changes in pes (δpes) and δppl calculated using a corrected δcvp (cδcvp-derived δppl) were compared. cδcvp-derived δppl was calculated as κ × δcvp, where κ was the ratio of the δpaw to δcvp during the occlusion test. means and standard deviations of the two variables that reflect δppl (δpes and cδcvp-derived δppl) in all pigs with all conditions were 6.1 ± 4.1 and 6.4 ± 5.3 cmh 2 o. the bland-altman analysis for the agreement between δpes and δcvp showed a bias of -0. 3 the activity and functionality of the diaphragm are difficult to measure in patients ventilated in intensive care. ultrasound can be a useful tool for monitoring diaphragm muscle activity during different ventilation modes. few data currently exist on diaphragm muscle activity in critically ventilated patients [1] . our goal is to evaluate the respiratory muscular work of the diaphragm with different settings of the respirator by means of an ultrasound scan. the ultrasound assessments of the diaphragm were performed with a 10mhz linear probe at the apposition zone. we measured the thickening of the diaphragm with the respiratory acts, through the thickening fraction (thickening fraction, tf), defined as:tf = (tdimax -tdimin / tdi min)% tdimax: diaphragm thickness at the end of inspiration (maximum thickness) tdimin: diaphragm thickness at the end of expiration (minimum thickness). ventilatory support was divided into 4 classes: 1 -spontaneous breathing (sb) or continous positive airway pressure (cpap); 2 -pressure support ventilation (psv) with low pressure support (5-12cmh2o); 3-psv with high pressure support (> 12 cmh2o); 4 -controlled mechanical ventilation (cmv). a total of 223 assessments were performed in 70 patients. the evaluations were all possible at the right hemidiaphragm, while on the left they were not possible in 7% of the cases. the median tf (iq range) of the 4 ventilation classes was respectively: 42% (25-62%) in sb / cpap; 26% (17-31%) in low-psv; 17% (9-22%) in high psv; and 5% (2-13%) in cmv. the kruskal-wallis test confirms a significant difference between the groups (p <0.0001). the ultrasound of the diaphragm can be a valid tool for monitoring respiratory muscle activity during mechanical ventilation. introduction: extubation failure is defined as reintubation after 48 hours of extubation in mechanically ventilated critically ill patients. it is associated with morbidity and mortality. the aim of our study was to assess reintubation rates in a busy district general hospital and evaluate the impact of high flow nasal oxygen therapy (hfno) on reintubation rates. we performed a retrospective observational study looking at patients admitted to our 7 bedded level 3 critical care unit (370 patients a year) for a period of 5 years between 1 st november 2014 and 31 st october 2019. we included patients over 16 years of age who were mechanically ventilated and length of stay was greater than 48 hours. exclusions were age < 16 years, tracheostomy and patients requiring ventilation for < 48 hours. data was collected from ward watcher, a sicsag database and electronic patient records. our study failed to show any impact of hfno on reducing extubation failure. further work is needed to develop a standardized approach to weaning and to consider routine application of noninvasive ventilation to reduce reintubation rates [1] . fig. 1 (abstract p097) . the bland-altman analysis for the agreement between δpes and cδcvp-derived δppl in various conditions. low: low intravascular volume, normal: normal intravascular volume, high: high intravascular volume, abd-: without an abdominal compression band, abd+: with an abdominal compression band oral endotracheal intubation is common to critically ill patients in intensive care unit. oral care for an intubated patient is important to maintain the moisture of oral mucosa. also, the securement method of oral endotracheal tube developed from cloth tape to commercial tube holder. training powerpoint and video for microteaching was prepared to train up 30 icu nurses to perform the new practice. demonstration and re-demonstration was arranged to assess skills of every nurse. afterwards, each nurse answered a quiz to evaluate the understanding of oetth and its special techniques in application. questionnaire was designed to collect the feedback from all nurses too. the result showed there was 21 nurses (72%) out of 30 nurses achieved full marks in the post-quiz which demonstrated their full understanding of the use of oral ett holder and its nursing care. about the feedback from nurse, 72% of nurses claimed that they were confident in using the new oetth in clinical setting after training. 96% of nurses agreed in time-saving of nursing care routine with the use of an oetth. however, only 56% of nurses agreed that the oetth is effective in prevention of oral mucosa injuries and another 24% of nursing staff disagreed on its function in improving the patient's oral care. in conclusion, some of the nurses did not agree the prevention of oral mucosa injuries by the new securement method with oetth while some nurses welcomed the new oetth as more easy and effective in oral care to intubated patients. execution of percutaneous dilatational tracheostomy using the standard laryngeal mask airway for ventilation: a prospective survey study g gagliardi 1 , v gagliardi 2 , c chiani 3 , g laccania 4 , f michielan 3 1 aulss 5 -veneto, anesthesia and intensive care, adria, italy; 2 aulss 5 -veneto, university of padua, adria, italy; 3 aulss 5 -veneto, anaesthesia and intensive care, adria, italy; 4 aulss 6 -veneto, anaesthesia and intensive care, padua, italy critical care 2020, 24(suppl 1):p101 we fulfilled a survey study dealing with bronchoscope-guided percutaneous dilatational tracheostomies (pdt), using the classic laryngeal mask airway (lma) for the airway management [1] . the aim was to verify the safety and the effectiveness of the aforementioned procedure methods: we performed an observational prospective survey study enrolling 150 patients hospitalized in the intensive care unit. before performing the tracheostomy, the endotracheal tube has been replaced by the laryngeal mask airway. arterial blood gases, ventilation pressures and tidal volumes have been monitored, registered and compared. the median peak inspiratory pressure has been detected stable in all patients. furthermore, during the ventilation with the laryngeal mask, the tidal inspiratory and expiratory volume difference observed between before and after the bronchoscope positioning, has shown a statistically significant variation. finally, in all cases etco 2 , spo 2. , pao 2, and blood ph values persisted within the normal range. the standard lma provides for a reliable airway management and allows an effective ventilation while performing the pdt. once positioned in the supraglottic zone, the lma does not need to be moved throughout all the pdt performance, avoiding risks of displacement, glottic harm and airway device damage, and permitting an easy handling of the bronchoscope, which gives an appropriated visualization of the trachea and a more efficient aspiration. in consequence to the large internal diameter of the lma tube, ppeak has continued to be stable in all patients, providing for minor resistance and inspiratory work. eventually, no late complications, such as tracheal stenosis and infections, have occurred. tracheostomies are the most common surgical procedure performed on critically ill patients. randomized control trials comparing tracheostomy timing in intensive care patients have been equivocal. in order to perform non-urgent tracheostomy in our icu, consent is required from the patient or a formal guardian appointed ad hoc by the courts. since tracheostomies are practically the only elective surgery performed in the critically ill, icu requested guardianship almost always indicates a clinical decision to perform tracheostomy. as appointing a guardian and arranging a tracheostomy takes about a week, the decision to appoint a guardian offers a unique "intention to treat" opportunity to evaluate outcomes in patients for whom tracheostomy is planned. we performed a retrospective analysis over 3 years on patients for whom guardianship was sought excluding those requiring urgent tracheostomy and those with a do-not-resuscitate order. patients were divided according to outcome (tracheostomy, extubation or death prior to tracheostomy) and compared. guardianship was sought for 233 ventilated patients. a decision to withhold tracheostomy was made for 13 patients, who were excluded, leaving 220 patients for analysis. tracheostomy was performed for 131/220 (60%) patients, 62/220 (28%) were extubated and 27/220 (12%) died while waiting for tracheostomy (from nonairway related reasons). tracheostomy was performed on mean ventilation day 16±1. comparing extubated patients to those who had tracheostomy (table) shows similar demographics, but significantly lower mortality and hospital length of stay. a significant proportion of patients initially planned for tracheostomy were successfully extubated. despite demographic similarities, mortality in this group was significantly lower than for patients undergoing tracheostomy. for a selected subgroup of possibly difficult to characterize patients, delaying tracheostomy may be beneficial. figure 1 ). ptis were analysed by speciality and by outcome. complications occurred in 6 cases (incidence 6.5%). there were 3 cases of subcutaenous emphysema, 1 pneumothorax (occuring d6 post procedure) and 1 case each of stoma and suture site infection. there was 1 unplanned cannula change within 7 days of insertion. 24% of cases had cuff inflated on discharge from icu. handover of care was suboptimal; follow up care plans were documented in 18% of cases. a supervising consultant was present for all ptis. there was a trend of increased insertion by consultant and increased reliance on theatre, with corresponding decrease in the number inserted by trainees. pti in our training icu appears safe with low incidence of complications and good senior support for tracheostomy insertion. emphasis must continue on training junior intensivists in pti. transition of care beyond icu requires further work where currently there is suboptimal handover of care and safety netting for non-icu colleagues. supplemental oxygen administration is ubiquitous in the critical care environment, yet evidence is mounting for the deleterious effects of hyperoxia [1] . concerns over the adverse effects from hypoxaemia often exceed those of hyperoxaemia in developing world settings, and inconsistent availability of blood gas monitoring may limit judicious oxygen titration. the aim of this project was to audit oxygen delivery practice and introduce qi measures to avoid excess oxygen delivery in a tertiary icu in lusaka, zambia. a prospective snapshot of ventilatory parameters were recorded for critically ill patients over a 5-week period, including positive end expiratory pressure (peep), fio 2 , and time-course spo 2 . systematic education was provided through group and one to one tutorials to empower nursing and medical staff to titrate oxygen safely and appropriately. repeat data collection was then performed over 4 weeks. initially 18/30 patients (60%) were over-oxygenated, as defined by fio2 >0.5 and spo 2 consistently >95%. 12/18 patients with an fio 2 of >0.5 had peep ≤ 5cm (67%). no patient had a pao 2 recorded in the past 24 hours. education was provided as well as implementation of unit protocols above all patient beds documenting a stepwise approach to titration peep and fio 2 . post intervention fewer patients were over-oxygenated: 7/21 (33%) had fio2 >0.5 and spo 2 consistently >95%, and 7/18 with an fio 2 >0.5 (39%) had a peep ≤ 5cm. in addition, 7/21 (33.3%) had a pao 2 recorded within 24 hours. this qi project has shown that nurse engagement and systematic education to titrate fio2 and peep can be achieved in a resource poor setting and may decrease the incidence of hyperoxia in critically ill patients. availability of blood gas monitoring and knowledge of interpretation was a major barrier to oxygen titration tracheal intubation (ti) in adult burn patients might be unnecessary in 30 to 40% of cases [1, 2] . in pediatric burn patients, there is little data on both the rate of ti and the rate of early extubation [3] . it has been common practice for a child with a facial burn and/or a suspected airway injury to be intubated early due to the risk of losing airway patency. however this risk should be mitigated against the potential risks of ti and mechanical ventilation in children. therefore the aim of this study was to describe the airway status of child burn victims taken in charge of in our pediatric burn intensive care unit. focused on patients arriving with ti, we investigated the rate of early extubation. in addition we compared non intubated patients with those with prolonged ti. this retrospective study described a cohort of 1520 patients hospitalized between 2010 and 2018. data was retrospectively recorded from the patient's paper clinical chart. the mean age of our patients was 2.8 ±3.1 years [mean±sd] with an average burn area of 14±11%. 86% had scald burns and 45% had facial burns. 4% of the children were admitted in the burn icu with ti. for 36% of them, tracheal tube was removed within the first 48 hours after admission. the probability of prolonged ti increased independently with the burned skin area (bsa) (p <0.0001), the presence of facial burns (p = 0.001), and in case of flame burns (p = 0.007) ( figure 1 ). among patients with more than 70% bsa, 85% were intubated more than 48h. among patients with less than 20% bsa, 0.5% were intubated more than 48h. according to our retrospective data, it seems appropriate to intubate children with 70% and more bsa, while for patient with less than 70% bsa, it might be relevant to seek guidance from physician of the nearest burn center. under 20% bsa, ti seems rarely required. an analysis of the predictive applicability of initial blood gas parameters for the need for intubation and the presence of inhalation injury in patients with suspected inhalation injury c pirrone 1 , m chotalia 2 , t mangham 1 , r mullhi 1 , k england 1 , t introduction: we hypothesise that initial blood gas parameters have a good predictive applicability in detecting the need for intubation and the presence of inhalation injury in patients with suspected inhalation injury. to the best of our knowledge, this has not been directly studied in the literature. patients with suspected inhalation injury admitted to the icu at queen elizabeth hospital, birmingham between april 2016 and may 2019 were included. the initial blood gas parameters analysed were pao 2 (kpa), paco 2 (kpa), ph, carbon monoxide level (cohb; %) and pao 2 /fio 2 (pf) ratio. receiver operator characteristics (roc) for these parameters were plotted against the need for intubation for more than 48 hours and the presence of inhalation injury as detected by bronchoscopy and laryngoscopy. area under the curve (auc) for each parameter was calculated. results: 85 patients were admitted with suspected inhalation injury to the icu. 68% were intubated for more than 48 hours. of patients who were intubated, 69% had inhalation injury as indicated by bronchoscopy or laryngoscopy. table 1 outlines the auc for initial blood gas parameters in detecting the need for intubation for more than 48 hours and the presence of inhalation injury. ph was the parameter with the most prominent auc, with reverse correlation indicating fair accuracy. no clear inflection point was identified, although all patients with ph < 7.25 required intubation and had inhalation injury. paco 2 had a fair predictive applicability in detecting the need for intubation. pf ratio, pao 2 and cohb had poor accuracy. conclusions: initial blood gas parameters had a broadly poor predictive applicability for the need for intubation and the presence of inhalation injury in patients with suspected inhalation injury. severe acidosis (ph < 7.25) was the most useful blood gas parameter. clinicians should be cautious in using blood gas parameters alone to inform intubation decisions. lung cancer surgery is associated with a high rate of pulmonary complications including ards and mandates lung protective ventilation strategies [1, 2] . such strategies include non-intubated video assisted thoracic surgery (nivats) with spontaneous breathing [3] . currently neither data on respirator settings nor on gas exchange have been reported for applying the latter. this data constitutes a prerequisite for meaningful evaluating the respiratory consequences of non-intubated spontaneous breathing during lung cancer surgery. the aim of this case series was for the first time providing such data from lung cancer surgery including pneumonectomy. during a 12 month period 32 patients without contraindications [3] scheduled for video assisted thoracic surgery (vats) for non-anatomical and anatomical lung resection including one pneumonectomy (px) were offered non-intubated spontaneous breathing. all patients gave informed written consent to the procedure as well as for analysis and publication of data. anaesthetic management included target controlled infusion of propofol and remifentanil, laryngeal mask airway, and pressure support ventilation. we present early data that early trials of cuff deflation within 48 hours of tracheostomy insertion can be achieved using a standardized protocol. its impact on length of stay, duration of ventilation and patient-centered outcomes needs to be investigated in larger multi-centre trials. preventing underinflation of the endotracheal tube cuff with a portable elastomeric device. a randomized controlled study je dauvergne 1 , al geffray 2 , k asehnoune 2 , b rozec 1 , k lakhal 1 1 hopital laënnec -chu de nantes, service d´anesthésie-réanimation, nantes, france; 2 hotel-dieu -chu de nantes, service d´anesthésieréanimation, nantes, france critical care 2020, 24(suppl 1):p112 the management of the endotracheal tube cuff pressure (p cuff ) is routine practice for critical care nursing staff. underinflation could lead to ventilator-associated pneumonia [1] whereas overinflation exposes to tracheal damage [2] . multi-daily check and adjustment is recommended to ensure that p cuff lies between 20 and 30 cmh 2 o [3] . to automate this task some devices exist but may be inconvenient, bulky and/or ineffective. their use is not supported by guidelines. a portable elastomeric device could be appealing for p cuff automated regulation. this prospective randomized controlled study tested whether the tracoe smart cuff manager tm reduced the rate of patients undergoing ≥1 episode of underinflation (p cuff <20 cmh 2 o), as compared with routine manual p cuff adjustment. monocentric, randomized controlled study. patients with acute brain injury and receiving mechanical ventilation were prospectively allocated to one of the two arms: manual reading and adjustment of p cuff at least every 8h (routine care) or adjunction of the smart cuff manager tm (intervention). this study was approuved by an institutional review board. among 60 randomized patients (routine care in 32, smart cuff manager tm in 28), 506 measurements were performed in 48h. with routine care, a higher rate of patients experienced at least one episode of underinflation (62.5 vs. 17.8%;p<0.001). episodes of underinflation episodes (15% vs. 2%;p<0.001) and manual adjustments (77% vs. 56%;p<0.001) were more frequent with routine care. for overinflation, there was no between-arms difference (p>0.99). the adjunction of continuous p cuff control with the tracoe smart cuff manager tm reduced the incidence of p cuff underinflation as compared with manual intermittent adjustments. overinflation was not promoted by this device. direct laryngoscopy as a technique for tracheal intubation is a potentially lifesaving procedure that healthcare professionals in a variety of fields are taught. however, this skill is challenging to acquire and difficult to maintain. poorly performed intubation technique can lead to potentially serious complications [1] . the intersurgical iview video laryngoscope is a new intubation tool which may have advantages over direct laryngoscopes, such as the macintosh, in the hands of novice personnel. a prospective randomized counterbalanced trial of 30 medical students, who did not have previous airway management experience, was conducted. each student received brief didactic teaching,following this, participants were directly supervised performing laryngoscopy and intubation using the macintosh and iview devices in an alternating pattern. students were permitted up to three attempts to successfully intubate under four conditions, three laryngoscopy conditions using alaerdal intubation trainer and one using a laerdal simman manikin. there was no significant difference in the success rate of intubation or time to intubation between the two devices. the iview outperformed the macintosh in time to intubation in the normal airway in the final scenario, once students gained experience with both devices. no significant difference was found in the number of optimisation manoeuvres, or intubation attempts between groups. areas where the iview outperformed the macintosh included severity of dental trauma and participants' perception regarding ease of use ofthe device. the iview may prove to be a useful teaching tool for novice personnel who are acquiring the skills of tracheal intubation. patients with a primary pulmonary pathology were more likely to respond to aprv. this association has not been described before and warrants further multi-centre exploration in a larger patient group. introduction: airway suctioning is common during mechanical ventilation, using either an open endotraqueal suctioning or closed endotracheal suctioning (ces). closed circuits were developed to prevent arterial desaturation and atelectasis associated to ventilator disconnection. however, ces may cause substantial loss of lung volume. the purpose of this study was to investigate the effects of a compensation method to prevent the loss in aeration during ces. the suctioning technique was performed for 15 seconds, negative pressures limited at 150 mmhg. closed suction catheters with 14fr (halyard health, georgia, eua) were used. electrical impedance tomography (eit) monitoring and arterial blood gas were collected. a nihonkoden mechanical ventilator (nkv550, california, eua) was applied, having a newly developed algorithm for suctioning which overcomes any pressure loss during suctioning (inlinesuction-app). when activated, the app delivers pcv ventilation, adding 2 cmh 2 o of end-expiratory pressure above peep, and delivering driving pressures of 15 cmh 2 o. results: pigs (30±5.4kg) with injured lungs and mechanically ventilated. we tested the aspiration procedures using low peep=5cmh 2 o, or high peep=±12.3cmh 2 o with v t2 o), whereas maintenance of compliance was observed when the app was on (from12.2±1.4 ml/cmh 2 o to 12.5±4.5 ml/cmh 2 o. blood gas in a representative animal showed a drop in pao 2 when app was off (from 247, to 149 mmhg after 2 min, and to 176 mmhg after 10 min) ( figure 1 ). with app on the pao 2 changed from 259 (pre-suction), to 223 (2 min), to 253 mmhg (10 min). the new nksoftware, delivering pcv ventilation during suctioning, could prevent atelectasis and functional loss associated to the procedure. tyrosine kinase inhibitor: an effective tool against lung cancer involvement responsible for acute respiratory failure in icu y tandjaoui-lambiotte 1 patients with advanced-stage non-small-cell lung cancer have high mortality rates in the intensive care unit (icu). in the last two decades, targeted therapies have changed the prognostic of patients with lung cancer outside the icu. the fast efficacy of targeted therapies led some intensivists to use them as rescue therapy for icu patients. we performed a national multicentric retrospective study with the participation of the grrroh (groupe de recherche en réanimation respiratoire en onco-hématologie). all patients with non-small-cell lung cancer admitted to the icu for acute respiratory failure between 2009 and 2019 were included in the study if a tyrosine kinase inhibitor was initiated during icu stay. cases were identified using hospital-pharmacies records. the primary outcome was overall survival 90 days after icu admission. results: thirty patients (age: 60+/-14 years old) admitted to a total of 14 icus throughout france were included. seventeen patients (59%) were nonsmoker. adenocarcinoma was the most frequent histological type (n=21, 70%). most patients had metastatic cancer (n=21, 70%). epithelial growth factor receptor mutation was the most common oncologic driver identified (n=16, 53%). during the icu stay, 17 (57%) patients required invasive mechanical ventilation, 13 (43%) catecholamine infusion, 3 (10%) renal replacement therapy and one (3%) extracorporeal membrane oxygenation. eighteen patients (60%) were discharged alive from icu and 11 (37%) were still alive after 90 days (see figure) . moreover, 6 patients (20%) were alive one year after icu discharge. despite a small sample size this study showed that, in the context of lung cancer involvement responsible for acute respiratory failure, the use of tyrosine kinase inhibitor should not be refrained in patients with severe condition in icu. the burned patient is one of the most complex patients whith a very high mortality. those patients with inhalation injury have a worst prognosis, typically associated with respiratory complications. the aim of our study is to evaluate the mortality of burn patientes with inalation injury in a critical burn unit. a prospective, observational and descriptive study was conducted over a period of 3 years. inhalation injury was defined with these criteria (≥ 2): history of injury in an enclosed space, facial burns with singed nasal hair, carbonaceus sputum and stridor. if they were intubated it was diagnosed by bronchoscopy. demographic data, tbsa, absi, baux score, apache ii, sofa, mechanical ventilation (mv), complications, length of stay, hospital course and mortality data were collected. results: 362 burns patients were admitted. 24% (84 patients) had inhalation injury. mortality among patients with inhalation injury was 28,6% (24 patients). most patients were men and those who died were older and with higher severity scores (fig. 1) . we found no significant differences between groups in the need for mv (95% vs. 85%) or in the percentage of tracheostomy performed (33.3 vs. 28.3). however, patients who died had more respiratory complications like ards, and also shock, renal failure and need of renal replancement therapies although infectious complications were similar in both groups. there was no statistically significant difference in volume used during initial resuscitation in the different groups. patients with inhalation injury who died had higher severity scores at the begining. although there were no differences in the need for mv patients who died had more respiratory complications as well as shock, renal failure and need of rrt, but no infectious complications.the volume used during inicial resuscitation, that was always related to the prognosis, was similar in both groups. further studies are needed to see if this greater initial severity corresponds to the degree of inhalation. aerogen, medical affairs, galway, ireland; 2 aerogen, science, galway, ireland critical care 2020, 24(suppl 1):p120 patients with acute exacerbations such as asthma are prescribed aerosol therapy from presentation in the emergency department to progression through to the intensive care unit. however, the variability in dose delivery to the lung across the possible patient interventions is not well characterized. here, we assess the predicted lung dose of a bronchodilator in a simulated spontaneously breathing adult patient via both facemask and nasal cannula, and via tracheostomy during mechanical ventilation. a standard dose of 2.5 mg in 2.5 ml salbutamol was aerosolized using the aerogen solo nebulizer (aerogen, ireland). for facemask testing, the nebulizer was used in combination with the aerogen ultra with 2lpm supplemental oxygen flow. for nasal cannula testing, the nebulizer was used in combination with the airvo 2 system (fisher and paykel, nz) system at both 10 and 50lpm gas flow rate. tracheostomy-mediated ventilation was assessed in combination with a hme, with the nebulizer placed between the hme and the tracheostomy tube. international standard iso27427 adult breath settings (vt 500ml, bpm 15, i:e 1:1) were used across all tests, and generated using a breathing simulator (asl5000, ingmar medical, usa) or mechanical ventilator (servo-u, maquet, sweden). the dose delivered to the lung was assessed using a capture filter at the level of the trachea, with drug mass determined using uv spectrophotometry at 276nm and interpolation on a standard curve. the results of testing are illustrated in figure 1 . the bronchodilator dose delivered to the simulated patient was seen to be relatively consistent between progressive interventions, except during high flow therapy, with the more clinically relevant 50lpm gas flow rate having a profound effect on the dose. these results may go some way towards explaining how different patient interventions can affect aerosol dose. the the mechanical ventilation (mv) have been identified as an independent factor indicating a worse prognosis for lung cancer patients [1] . this study was conducted in order to assess the results of noninvasive mechanical ventilation (niv) and/or invasive mechanical ventilation (imv) modalities in lung cancer patients admitted to the icu with acute respiratory failure (arf). in this study, lung cancer patients with respiratory failure who were admitted to the icu between january 2017 and december 2018 were evaluated retrospectively. results: 93 patients were included in the study. the mortality rate was 18.3%. 83 patients had niv. imv was applied to 10 patients. in the first 24 hours, 39 of the 83 patients who were initially treated with niv were administered imv. the duration of hospital stay, diagnosis of pneumonia and mortality rate were found to be significantly lower in patients treated with niv alone (p≤0.001, p=0.004, p=0.025), but glaskow coma score (gcs) was significantly higher in this group (p≤0.001). the mortality rate was similar between the patients who were initially treated with imv and those who were treated with imv in the first 24 hours. charlson comorbidity index (cci) and mv duration were significantly higher in patients who died (p=0.01, p= 0.021), but gcs was significantly lower in this group (p=0.032). in the linear regression model for the likelihood of mortality, ccl≥9 and unsuccessful niv increased the mortality rate by 3.4 (1.1-10.5) and 5.2 times (12-23.6) respectively (p=0.036, p=0.032). niv has been an effective modality for respiratory support in most lung cancer patients presenting with arf. however, failed niv seems to be a factor for increased mortality. therefore, the choice of respiratory support modality to be applied in this patient group should be decided by considering the gcs, cci and etiology of arf. the interaction between ventilator settings and the occurrence of acute kidney injury is not fully elucidated. this study aimed at investigating the effect of stepwise increase in peep level on the risk of acute kidney injury as evaluated with the renal resistivity index (rri).the primary outcome is to investigate whether increased levels of peep could lead to increase rri and whether rri could predict the occurrence of aki. methods: patients mechanically ventilated for at least 48 hours and without aki at admission were included in the study. rri was calculated at icu admission. posterolateral approach was used for kidney ultrasound. the peak systolic velocity (v max ) and the minimal diastolic velocity (v min ) were determined by pulse wave doppler, and the rri was calculated as (v max -v min )/v max . the exam was performed modifying the peep levels: 5, 10 and 15 cm h 2 o in random order for 15 minutes. occurrence of aki was defined within 7 days according to kdigo criteria. sixty-four patients were enrolled in the study and incidence of aki was 14/64 (22%). demographical and clinical characteristics are reported in table 1 . increase in peep showed a significant increase in rri from peep 5 to peep 10 (p<0.001) and from peep 10 to peep 15 (p=0.001) ( figure 1 ). the area under the roc curve of rri to predict aki was 0.845 at peep 5, 0.898 at peep 10 and 0.894 at peep 15 (all p<0.001). the youden index analysis showed an rri>0.70 as the best cut off for aki with a sensibility of 65% and a specificity of 96%. patients with rri>0.70 were 11/64 (17%), 13/64 (20%) and 22/64 (34%) at peep 5,peep 10 and peep 15 respectively. patients ventilated with a peep value associated with rri>0.70 had higher incidence of aki (11/14 vs 6/50, p<0.001). the application of peep can increase intrarenal vascular resistance,which is associated occurrence of aki; peep level should therefore be balanced taking into account the rri. the rri seems able to predict occurrence of aki in mechanically ventilated patients. alveolar and respiratory mechanics modifications produced by different concentrations of oxygen in healthy rats subjected to mechanical ventilation with protective ventilatory strategy d dominguez garcia 1 , r hernandez bisshopp 1 , jl martin barrasa 2 , d viera camacho 1 , a rodriguez gil 1 , j arias marzan 1 , s garcia hernandez 3 high oxygen can damage tissues [1] . in this study, we analyze the histological and pulmonary mechanics modifications that can occur when identifying different inspiratory oxygen fractions (fio 2 ) in lungs of healthy rats during protective mechanical ventilation. we use sprague-dawley rat. 4 groups were designed, each with 6 animals, the tidal volume (6 ml/kg), peep (3 cmh 2 o) and respiratory rate (90 rpm) were kept constant, changing the fio 2 between the groups. four groups were established: fio 2 0.21, 0.4, 0.6 and 1. after 4 hours, the lungs were removed for histological study and obtaining the wet/dry index. the histological modifications studied were: alveolar septa (as), alveolar hemorrhages (ah), intraalvelolar fibrin (if) and inflammatory infiltrates (ii). each parameter was rated from 0 to 3 [2] . peak pressure (pp) and pulmonary compliance were monitored every 60 minutes. different statistical tests will be used to analyze the data. results: references to the damage produced in the as, ah, if, ii and the global histological pattern were identified in the groups with the highest fio 2 and there was more damage (p <0.00001) ( figure 1 ). the wet/dry index rose significantly as the oxygen concentration increased (p = 0.001). in the groups to which a fio 2 of 0.6 and 1 was administered, the pp selected specific values with respect to the baseline intake from the first 60 minutes, an aspect that was not appreciated in the other groups (p <0.0001). regarding pulmonary compliance, it will be seen that, in the fio 2 0.6 and 1 groups, it decreased from the first 60 minutes, finding differences with respect to the other groups (p <0.0001). conclusions: mechanical ventilation applied for 4 hours in healthy animals produces disorders that are more pronounced as oxygen concentration increase. fio 2 greater than or equal to 0.6 should be avoided without clinical justification. introduction: patients requiring prolonged acute mechanical ventilation (pamv, defined as 4+ days on mv) are sicker and incur disproportionate morbidity and costs relative to patients on short-term mv (stmv, <4 days of mv). we quantified specific clinical outcomes among patients requiring pamv vs. stmv in a contemporary database. we conducted a multicenter retrospective cohort study within~700 hospitals in the premier database, 2014-2018. using icd-9-cm and icd-10 codes we identified pamv and stmv patients, and compared their baseline characteristics and hospital events. because of the large sample size, we omitted hypothesis testing. a total of 691,961 patients met the enrollment criteria, of whom 266,374 (38.5%) received pamv. at baseline, patients on pamv were similar to stmv with regard to age (years: 62.0 ± 15.8 pamv vs. 61.7 ± 17.2 stmv), gender (males: 55.6% pamv vs. 53.9% stmv), and race (white: 69.1% pamv vs. 72.4% stmv). pamv group had a higher comorbidity burden than stmv (mean charlson score 3.5 + 2.7 vs. 3.1 + 2.7). the prevalence of each of the indicators of acute illness severityvasopressors (50.3% vs. 36.9%), dialysis (19.4% vs. 10.3%), severe sepsis (20.3% vs. 10.3%), and septic shock (33.5% vs. 15.9%)was higher in pamv than stmv, as were hospital mortality and combined mortality or discharge to hospice (figure 1 ), extubation failure (12.3% vs. 6.1%), tracheostomy (21.6% vs. 4.5%), development of c. difficile (4.5% vs. 1.7%), and incidence density of ventilator-associated pneumonia (2.4/1,000 patient-days vs. 0.6/1,000 patient-days). conclusions: over 1/3 of all hospitalized patients on mv require it for 4 days or longer. pamv patients exhibit a higher burden of both chronic and acute illness than those on stmv. commensurately, all clinical outcomes examined are substantially worse in association with pamv than stmv. identifying the readiness of patients recovering from critical illness for liberation from invasive mechanical ventilation (imv) is not always straightforward [1] . the scottish intensive care society (sics) trainee audit 2018 conducted a scotland-wide study to understand current practices relating to liberation from imv. data were prospectively collected on patient demographics, indication for intubation, spontaneous breathing trial (sbt) practices, physiological markers, icu outcome and icu los. all patients >18 years ventilated with imv for > 24hrs from the 1 st nov. 2018 -30 th nov. 2018 were eligible for inclusion. exclusion criteria included extubation for end-of-life, death whilst intubated and presence of tracheostomy. logistic regression was performed to detect factors associated with extubation failure (ef). results were analysed via excel 2010 and stata v.14.1. patient benefit and privacy panel approval was granted. total population of 172 patients were included: 108 (63%) male and median apache2 score 19 (iqr 13-23). ef at first attempt occurred on 27 occasions (15.7%), median icu los of 10 days (iqr 7-12), mortality rate 22.2%. the cohort successfully extubated first time had a median icu length of stay of 5 days (iqr 3-9) and mortality rate of 1.4%. methods of sbt and extubation outcomes detailed in table 1 . no sbt prior to extubation had higher odds of ef (or 2.52, ci 1.09-5.84, p=0.03); patient ventilation for < 3 days had a three times higher odds of ef (or 3.31, ci 1.09-10.1, p=0.03). these were independently associated with ef on multivariate analysis conclusions: we found a reintubation rate of 15.7% in scottish icus. type of sbt most commonly used is divergent from the methods advocated in the literature. the lack of sbt and early extubation attempt was associated with failure, which in turn was associated with longer icu los and higher mortality. in patients undergoing prolonged invasive ventilation we hypothesise that abnormal right ventricular (rv) and left ventricular (lv) function are associated with increased 90-day mortality. whether changes in lv or rv function could aid in the prognostication of these patients has not been directly studied. patients admitted to the queen elizabeth hospital birmingham icu between april 2016 and july 2019 who were intubated and ventilated for more than 7 days and had a formal transthoracic echocardiogram (tte) whilst in icu were included. abnormal rv function was defined by the presence of depressed function, dilated size or moderate to severe risk of pulmonary hypertension. abnormal lv function was defined by the presence of lv depression (lv ejection fraction £ 45% or grade ii or more diastolic dysfunction) or a hyperdynamic lv (formally mentioned in tte report). patients who had a neurological cause for prolonged ventilation were excluded. the primary outcome was 90-day mortality. categorical data is presented as % and analysed using a chi-squared test. continuous data is presented as median (iqr). results: 871 patients required prolonged ventilation, of which 350 (40%) had a tte. patients were aged 62 (49-75), were 61% male and had a 36% 90-day mortality. the median ventilator days were 13 (6-20) and 77% required a tracheostomy. abnormal rv function was present in 26% (n=90) and was associated with an increased 90-day mortality compared to normal rv function (68% vs. 25%, rr 2.71 [2.10-3.50], p< 0.0001). lv function was abnormal in 27% (n=95) and was associated with an increased 90-day mortality compared to normal lv function (54% vs 28%, rr 1.91 [1.47 -2.49], p < 0.0001). abnormal rv function had a trend towards an increased mortality compared to abnormal lv function (68% vs 54%, rr 1.26 [1.00 -1.60], p = 0.07). in this study, abnormal rv and lv function were present in a quarter of patients undergoing prolonged ventilation and were associated with an increased mortality. introduction: tidal volume delivered by mechanical ventilation (mv) in sedated patients is distributed preferentially to ventral alveoli, causing overdistention and associated collapse in dorsal alveoli, driving volutrauma, atelectrauma and ventilator-induced lung injury [1] . temporary transvenous diaphragm neurostimulation (ttdn) stimulates diaphragm contraction [2] . when used in synchrony with mv, ttdn encourages increased dorsal ventilation due to the change in pressure gradients with diaphragm contraction, mimicking a more normal physiological pattern. this may improve gas exchange and reduce injury. a pilot study was conducted using 50 kg pigs undergoing mv in a mock icu. deeply sedated subjects were provided lung-protective volume-control ventilation at 8 ml/kg. ttdn diaphragm contractions were delivered in synchrony with inspiration on every second breath, reducing the ventilator pressure-time-product by 15-20% during mv+ttdn breaths. tidal volume distribution was recorded in each condition using electrical impedance tomography, and compared to never-ventilated, spontaneously breathing subjects (nv). results: dorsal ventilation changed from 49% during mv breaths to 54% during mv+ttdn breaths, compared to 60% in the nv group (p=0.035). ventral ventilation changed from 51% during mv breaths to 46% during mv+ttdn breaths, compared to 40% in the nv group (p= 0.042, figure 1 ). conclusions: ttdn diaphragm contraction used as an adjunct to mv yields a more physiological pattern of volume distribution. this translates into less overdistension in the ventral areas and less atelectrauma in the dorsal areas and reduces ventilator-induced lung injury. this technology introduction: by measuring the pes and its derivatives, we can measure the relationship that exist between the diaphragmatic excursion and the oscillation of the esophageal pressure curve: pswing (ps) so we infer that, just as with the pes, the variations of it might be related to a weaning failure [1, 2] . however, no nominal value exists in the bibliography to predict the test result. patients who meet with the inclusion criteria start the weaning process through a test of 30 minutes of spontaneous ventilation, t-tube (tt). and also the respiratory rate (rr) and the tidal volume (tv). from this analysis, an average ps (aps) is determined for each moment of the test (aps1, initial and aps2, final.).a quotient was obtained in relation to these variables using the value previously obtained (quotient dtv/dps x100. a total of 13 patients were included (n=13).regarding the evolution during tt, 9 (n=9) (69%) were successful, while 4 (n=4) (30.76%) failed when analyzing a rate that relates the variables tv and ps, a quotient was obtained in relation to these variables using the value previously obtained (quotient dtv/dps) for patients who were successful and who failed, (dtv/dps)/100 successful patients presented a value of 18.75 while those of the failure group presented a value of 45.83, (or 1,2 -3 p=0.082) ( table 1) . when presenting the relationship between tv and ps through the quotient (dvt/dps)/100, it is observed a tendency to have a higher quotient among patients who failed versus those who did not fail. the process of weaning from mechanical ventilation imposes an additional workload on the cardiovascular system, which may result in impaired myocardial function, increase in left ventricular filling pressure and respiratory distress. among surgical patients, those undergoing heart surgery are particularly susceptible to cardiac dysfunction induced by weaning because of inadequate cardiovascular reserve. the aim of our study was to depict the pathophysiological changes assessed by echocardiography during the steps of weaning and to identify possible predictors of weaning failure (wf). we enrolled 34 consecutive patients undergoing isolated coronary artery bypass grafting in our institution. data were obtained by intraoperative transesophageal echocardiography before sternotomy (t0) and by transthoracic echocardiography at the beginning of weaning (t1) and at the time of extubation (t2). wf was defined as deferral of planned extubation or respiratory failure needing reintubation or non-invasive mechanical ventilation within 48 hours. results: wf occurred in 7 patients (20.6%) and involved manifestations of respiratory distress in 5 (14.7%). we found a significant association between left ventricle outflow tract-velocity time integral (lvot-vti) and ventricular-arterial coupling measured at t1 and wf, with lvot-vti emerging as the best predictor of wf with an area under roc curve of 0.8669 ( figure 1 ); an optimal cutoff value of 15 cm provided 100% sensitivity and 71% specificity. significant increase in e/e' measured at t2 (13.44 vs 9.96, p 0.02) suggested a cardiac etiology of respiratory distress in patients who failed the weaning trial. our study showed that serial assessment of hemodynamic parameters by means of echocardiography is feasible in cardiac surgical patients and can provide insight into pathophysiological changes during weaning. although these preliminary data need to be confirmed in a larger population sample, lvot-vti emerged as a promising predictor of subsequent wf. compliance with guidelines for respiratory therapy in preclinical emergency medicine g jansen, n kappelhoff, s rehberg protestand hospital of the bethel foundation, anaesthesiology, intensive care and emergency medicine, bielefeld, germany critical care 2020, 24(suppl 1):p131 introduction: current guidelines on pre-hospital emergency ventilation are based on the guidelines for lung protective ventilation in the intensive care unit. the present survey was designed to determine the accordance of actual pre-hospital emergency ventilation by german emergency physicians (gep) with these recommendations. recommendations include a respiratory rate (rr) between 10-16/min, a tidal volume (vt) between 6-8 ml/kg, a maximum pressure (pmax) <30 mbar and a positive end-expiratory pressure (peep) of 5 mbar. an anonymous web-based questionnaire encompassing 7 questions was sent to gep from september to december of 2018. gep were asked to specify their level of education, their preferred ventilation settings and the usually chosen parameters employed to guide mechanical ventilation. statistical analysis was performed using the ch²-test with a significance level ≤0.05. 60% of the questionnaires were completed (159/261). 25% of the participants were trainees (tr), 75% consultants (co). as target parameters for guidance of ventilation, 87% of the tr and 91% of the co use capnometry. the vt controlled 62% of the tr and 54% of the co on the basis of body weight. 81% of the tr and 81% of the co reported to control oxygenation using spo2. table 1 shows our analysis of the given answers. there were no statistically significant differences between the groups. deviations from the guidelines of pre-hospital emergency ventilation settings are common and mainly concern the use of a guidelinecompliant peep. in addition, recommended target parameters for guidance of ventilation were not applied in a significant proportion of gep. prospective observational study including ltx recipients admitted to our icu from february2017 to january2019, who underwent a spontaneous breathing trial (sbt) using a t-piece for 30 minutes. clinical variables and arterial blood gas samples were recorded before starting sbt and after 20 minutes on the t-piece. diaphragmatic excursion (de) and thickening fraction (dtf) were also assessed using ultrasound(us) after 20 minutes on the tpiece. us-dd was defined as de<10 mm or dtf<0.3 of at least one hemidiaphragm. patients who successfully completed a sbt, defined according to clinical criteria,were extubated. extubation failure was defined as the need for reintubation within 48h. results are expressed as medians (iqr) or frequencies (%). 193 ltx recipients were admitted to the icu, 79 of whom underwent an sbt. 51 were male, and the median age was 58y. main indications for ltx were interstitial lung disease (43.0%), copd and cystic fibrosis. 59 were bilateral ltx, and 13 and 7 were left and right unilateral ltx respectively. 69 patients were extubated after sbt and 6 required reintubation within 48h. 53 presented us-dd, though there were no differences between patients who succeeded and those needing reintubation. in contrast, patients who succeeded showed higher pao2/fio2 after 20 minutes on the t-piece (table 1) . similarly, higher reductions in deltapao2/fio2 after 20 minutes on the t-piece were observed in patients who failed. oxygenation after sbt performed using a t-piece may predict extubation failure in ltx recipients with successful sbt. us-dd was not associated with the need of reintubation. descriptive study about the relationship between self-extubation episodes and patient-ventilator interaction s nogales 1 , introduction: to evaluate the relationship between self-extubation and patientventilator interaction, among other physiological variables, in order to predict and to prevent these events. self-extubation (se) are quality indicators in patients under invasive mechanical ventilations (imv) and are related with mortality [1] . planned secondary analysis of a prospective data base of clinical and physiologic signals of patients receiving imv. we included se episodes (2012-2018) with continuous record of ventilator and monitor signals (bclink bettercare®). we analysed demographic data, physiological parameters (peripheral oxygen saturation spo2, heart rate hr, respiratory rate rr and media arterial pressure map) and patientventilator interaction (asynchrony index ai, ineffective efforts during expiration iee and double cycling dc). we studied a period of 12 hours prior to the se episode. we used the wilcoxon non-parametric test and for a proper analysis a linear mixed effects model. we included 21 episodes of se, mean age 62±13years, 76%men, apache ii at admission 17±10, 4,6±3,8days under imv until the episode, reintubation rate 47.6%, icu stay 20,9±17,6days, icu mortality 14%. at the time of the se, 65% were under sedation, 65% with physical restraint. the 67% were in weaning. we observed a trend to increase in spo2, rr, hr, map and asynchronies in the 2-hour period prior to se episode. we compared these variables from this period with a 2-hour period before and we observed a statistically the data presented in this study show that our results are in accordance with the literature with favorable mortality and early postoperative complication rates and support that this procedure is an excellent alternative for surgery in the elderly patients. it is reported that patients with pulmonary hypertension (ph; systolic pulmonary arterial pressure (spap)≥35 mmhg)) have frequent cardiac complications after transcatheter aortic valve implantation (tavi). ph often gets worse in some patients despite the normal cardiac function after tavi. no studies have ever examined prognosis after tavi in patients with or without worsening of ph. therefore, we retrospectively examined the frequency of mid-to long-term heart failure and cardiac death in patients with and without deterioration of ph after tavi. among 113 patients who underwent tavi at our hospital between february 2014 and march 2016, we analysed 27 patients with ph (spap≥35 mmhg) before surgery. spap was measured in transthoracic echocardiography before and within 1 week after tavi. patients were divided into two groups according to whether spap worsened/ did not change or improved after tavi. we examined the frequency of admission due to heart failure or cardiac death (death caused by heart failure, angina, or myocardial infarction) during the period of 3 years after tavi. ph worsened or did not change after tavi in 9 patients, while it improved in 18 patients. the left ventricular ejection fraction measured within 1 week after tavi showed no difference between the two groups (56.6±11.9% vs 58.4±10.0%, p=0.71). the worsened/ no change group was higher in frequency of admission due to heart failure (logrank; p<0.05) and cardiac death (logrank; p<0.04). despite successful treatment for as by tavi, the frequency of heart failure and cardiac death was higher in patients who did not show improvement of ph after tavi, even in the absence of cardiac function decrease. vigorous intervention for ph worsening after tavi may be helpful to improve prognosis. the there are several different anti platelet drugs that can be used to treat acute cardiac events. currently there are no effective markers that can assess how these drugs modify coagulation profile and quality. a new functional biomarker that measures fractal dimension (df ) and clot formation time (tgp) has been developed [1] . df quantifies clot microstructure whereas tgp is a real-time measure of clotting time. we aimed to validate df and tgp in st elevation myocardial infarction (stemi) and assess the effect of two p2y12 inhibitors which have different pharmacological mechanisms: clopidogrel and ticagrelor. we prospectively recruited 72 stemi patients in the emergency setting. venous blood samples were collected 12 hours after admission, following treatment with either ticagrelor or clopidogrel, in accordance with the local guidelines at the time. the blood samples were tested using the df and tgp biomarker, platelet aggregometry, clot contraction and standard markers of coagulation. results: 36 patients received clopidogrel and 36 received ticagrelor. the df for clopidogrel was higher than ticagrelor (1.75±0.05 vs 1.73±0.06, p=0.18 which corresponds to a decrease in clot mass of 20% figure 1 ) and the tgp was reduced (205±91sec vs 257±89 sec, p=0.06 a 20% reduction in time). the results of the study suggest that clopidogrel is less powerful in its effects on clotting characteristics compared to ticagrelor. blood from patients receiving clopidogrel formed quicker and denser clots. this would suggest the risk of secondary events or stent occlusion is lower in those patients on ticagrelor, highlighting that df and tgp may be important in identifying patients at risk of future thrombotic events, the study is ongoing and will investigate the long term outcome in these patients. introduction: new onset atrial fibrillation (noaf) during critical illness frequently resolves prior to discharge. however long-term risks of noaf (i.e. heart failure, ischemic stroke and death)remains high [1] . previous studies noted that nearly half of noaf cases did not have diagnosis recorded [2] . addressing this may reduce post critical illness mortality by increasing af surveillance post intensive care (icu) discharge. retrospective data was collected from an electronic health record for icu admissions over a 10 month period from a biomarker is defined as a measurable indicator of some biological state or condition. combined with a good clinical evaluation, they can enable an early and safe diagnostic, thus a faster management for the patient. cardiac biomarker testing is not indicated in routine in the emergency department (ed) because of low utility and high possibility of false-positive results. however, current rates of testing are unknown. the aim of our study was to evaluate the importance of measuring cardiac biomarkers especially troponins, d-dimer, and btype natriuretic peptide in our daily practice, and to identify the latest recommendations for a better use of these biomarkers in the diagnostic and therapeutic approaches. we conducted a prospective observational study, over a 13 months periods performed in the ed of the university hospital center ibn rochd, casablanca, morocco, including all patients admitted during our study period and having a blood test for at least one biological marker. the dataset was analyzed by spss statistics 21.0. a total of 182 patients was enrolled. troponins were tested in 85.3% patients (high sensitive in 49.5% and troponin i tni in 35.8%), ddimer in 30.9%, bnp 19% and nt pro bnp in 9.5% of cases. the diagnostic impact was significant in 94.4% of cases for troponins, 84.6% of cases for d-dimer and 87.5% for bnp. the therapeutic impact was considered important in 80.6% cases for troponins, 69.2% for ddimer and 87.5% for bnp. cardiac biomarkers have an important role in the ed, not only do they confirm the diagnosis (including the role of troponins in acs) but also eliminate others (with a strong negative predictive value of d-dimer for thromboembolic disease) and prove the cardiopulmonary origin of acute dyspnea (the significant place of bnp in confirming the diagnosis of acute heart failure). a multicenter study on the comparison of inter-rater reliability of a new and the original heart score among emergency physicians from three italian emergency departments the heart (based on history,ecg,age,risk factors,troponin) score is a valid tool to stratify the acs in chest pain. but some reports suggest that its reliability could be low for heterogeneity in the assignment due to the subjective interpretation of the history. we used the chest pain score for the "history". in this study we compare the reliability of the new heartcps and original heart. this is a multicenter retrospective study conducted in 3 italian ed between july and october 2019 using clinical scenarios. ten physicians were included after a course on heart and heartcps score. we used 53 scenarios which included clinical and demographic data. each participant independently assigned scores to the scenarios using the heart and heartcps. we tested the interrater agreement using the kappa-statistic (k), the confidence intervals are bias corrected ; we used stata/se 14.2 statistical software . a p-value of < 0.05 defines statistical significance. the overall inter-rater reliability was good for heart and heartcps: kappa =0.63 (ci 95%;0.57-0.72)and 0,65(ci95%;0.63 -0.67); with good agreement among all the class of risk for heartcps but moderate in the medium class for heart . we found significant differences of inter-rater reliability among the senior and junior physicians who used the heartcps:k=0.56(ci95%;0.52-0.57)and 0.75(ci95%;0.70-0.79). heartcps score increased its history inter-rater reliability specially among the junior physicians from k=0.35 (ci 95%; 0.27-0.43) to k=0.69(ci 95%;0.62-0.71).the junior physicians seem to be more reliable than senior with the heartcps:k=0.75 (0.71-0.79) vs k=0.56 (ci95%;0.52-0.57). the heartcps showed inter-rater reliability better than original heart among the medium class of risk and the junior group. it could be proposed to young doctors to stratify the acs risk of chest pain. limit: we used scenarios rather than real patients. a hybrid approach as treatment for coronary artery disease: endo-cabg or pci first, does it matter? introduction: the aim of this study is to discuss the short-term results of a hybrid approach combining minimally invasive endoscopic cabg (endo-cabg) with a percutaneous coronary intervention (pci). to bypass the disadvantages and potential complications of conventional cabg via median sternotomy, we developed the endocabg technique to treat patients with single-and multi-vessel coronary artery disease (cad). this procedure is performed with three 5-mm thoracic ports and a mini-thoracotomy utility port (3 cm) through the intercostal space. this technique can be combined with pci: the hybrid approach. the sequence of the 2 procedures (endocabg followed by pci or vice versa) may result in different outcomes. from 02/2016 to 12/2017 data from 81 consecutive patients scheduled for a hybrid technique at jessa, belgium, were prospectively entered into a customized database. this database was retrospectively reviewed. subgroup analysis was performed to compare outcomes of patients who first received endocabg with patients who first received pci. a p-value < 0.05 is considered significant, a p-value < 0.1 is considered as a trend toward significance. four patients underwent revision surgery and 2 patients died within the first 30 days. in 79 patients the left anterior descendens artery (lad) was grafted with the left internal mammary artery (lima), the right coronary artery (rca) was the most stented vessel using pci. patients first treated with pci received more units of fresh frozen plasma after endocabg compared to those who were first treated with endocabg (p=0.03). there was also a trend toward significant more transfusion of packed cells in this small subgroup (p=0.07). the hybrid approach is a feasible technique as a treatment option for patients with multi-vessel cad. if cabg follows the pci, patients are more likely to receive transfusion. a possible explanation could be the need for dual antiplatelet therapy prior to surgery in this group, but this needs further investigation. prognostic difference between troponin elevation meeting the mi criteria and troponin elevation due to myocardial injury in septic troponin t (ctnt) elevation in critically ill patients is common and is associated with poor outcome. using common assays, 40-50% of patients in the icu will have elevated troponin level. our aim was to determine whether there is any prognostic difference between troponin elevation meeting the mi criteria (rise and fall more than 20% together with echo and ecg new abnormalities) and troponin elevation due to myocardial injury in septic patients. we enrolled 101 patients with sepsis and mean sofa score 5,2 respectively in which ctnt level was measured more than once and analyzed there ecg and echo findings. patients were classified into three groups:definite mi (rise and fall ctnt ≥ 20% and contemporaneous changes on ecg and/or echo),possible mi (rise and fall ctnt ≥ 20% and no other findings),myocardial injury (ctnt rise less than 20%) results: data from 101 patients were analyzed (49% female; mean age 61.9 (sd 16.9)). a total of 101 patients had at least one elevated ctnt more than 0.03 mkg/l. in 71 (70%) of patients ctnt level rised more than 20% from the first elevated measurement.64 (63%) of patients met mi criteria considering new ecg and echo findings. the overall mortality rate in all patients was 53.9%.the mortality rate didn't differ significantly in three groups: in the definite mi group 62.4%, in the suspected mi group 52%, in the non mi ctnt elevation group 56,4%, p=0,6. coronary angiography was performed in 46 (73%) of patients from the definite mi group,pci was performed in 18 (39%) of patients. the mortality rate in the invasive group was not significantly lower comparing to the nonivasive group 29% vs 37,8%, p=0,06. bleeding complications were significantly more frequent in the definite mi group 13% vs 7% and 8% respectively conclusions: ctnt level elevation is associated with poor outcome regardless coronary or non coronary injury. myocardial revascularization may be beneficial in patients with sepsis and definite mi, but it is also associated with increased bleeding risk. diagnostic interest of "marburg heart score" in patient consulting the emergencies department for acute chest pain chest pain is a common reason for emergency department visits, although this primarily refers to acute coronary syndrome (acs), this symptom may be frequently related to other non-ischemic etiologies. the aim was to validate the marburg heart score as a tool to exclude coronary artery disease in emergency department patients with nontraumatic acute chest pain. methods: a prospective, observational, descriptive and analytic cohort study conducted in the emergency department, from february 1st to march 31st, 2019, collecting patients consulting for nontraumatic acute chest pain, the "marburg heart" score was calculated for all these patients. telephone contact was made after 6 weeks to look for an ischemic cardiovascular event. we included 171 patients. the mean age was 57 +/-13 years, the sex ratio was 0.86. the majority of the patients (78.9%) consulted directly to the emergency department, 21.1% were referred by a primary care physician. the median time to consultation after the onset of chest pain was 24 hours. high blood pressure was the most common risk factor (43.9%), followed by smoking (31%), diabetes (24.8%) and dyslipidemia (23.4%). thirty-five patients (20.5%) had already coronary heart disease, ecg was pathological in 19.3% of patients, 8 patients had an acs with st segment elevation. at six weeks, 20.6% of the patients had an acute coronary event. according to the patients' answers on the 5 questions of the marburg heart score. the area under the roc curve of this score was 0.78 with a negative predictive value of 87.2%; the "marburg heart score" is a simple, valid and reproducible clinical score with a discriminatory power to rule out the diagnosis of coronary artery disease from the first contact with the patient presenting for chest pain in emergencies. the abdominal aortic aneurysm (aaa) surgery is a complex procedure in elderly patients with high cardiovascular risk. anesthesiological techniques should play special attention to the volume status during cross-clamping as well as to the blood loss. goal directed fluid therapies (gdt) in aaa surgery in elderly patients decrease the perioperative morbidity and mortality [1] . aim of this study is to investigate administration of fluid-based on either a gdt approach or a control method (fluid administered based on static preload parameters and traditional hemodynamic) in all phases of aaa surgery and especially in the phase of clamping and de-clamping. a total of 30 patients asa iii, randomly scheduled for elective, open aaa surgery were included in this clinical trial. they were randomly assigned to two groups i -gdt with targeting stroke volume variation (svv) and ii -control group where fluids were administered at the discretion of the attending anaesthesiologist. in both these groups hemodynamic parameters, central venous pressure (cvp), temperature, blood loss and diuresis were registered during the operation and 48 hours postoperatively. each group was assessed for postoperative complications. gdt group received less fluids and had a higher cardiac index (ci) (3.9± 0.6 vs. 2.9± 0.8 l/minute per m 2 , p < 0.01) and stroke volume index (55.1 ± 5.4 vs. 35.1 ± 5.8 ml/m 2 , p < 0.01) than the control group. there were significantly fewer complications in the intervention than control group (3 vs. 9, p = 0.02). gdt fluid administration enables less use of fluids, improved hemodynamic and fewer postoperative complications in elderly patients undergoing aaa surgery. ultrasonography is a valid diagnostic tool, used to measure changes of muscle mass. the aim of this study was to investigate the clinical value of ultrasound-assessed muscle mass, in patients undergoing cardiothoracic surgery that present muscle weakness postoperatively. for this study, 221 consecutive patients were enrolled, following their admission in the cardiac surgery intensive care unit (icu) within 24 hours of cardiac surgery. ultrasound scans, for the assessment of quadriceps muscle thickness, were performed every 48 hours for 7 days. muscle strength was also evaluated in parallel, using the medical research council (mrc) scale. of the 221 patients enrolled, ultrasound scans and muscle strength assessment were performed in 165 patients. the muscle thickness of rectus femoris (rf), was slightly decreased by 2.18% ([95%ci: -0.21; 0.15], n=9; p=0.729) and the combined muscle thickness of the vastus intermedius (vi) and rf decreased by 3.5% ([95% ci: -0.4; 0.22], n=9; p=0.530). patients whose combined vi and rf muscle thickness was below the recorded median values (2.5cm) on day 1 (n=78), stayed longer in the icu (47 ± 74 vs 28 ± 45 hours, p = 0.015). patients with mrc score ≤ 48 on day 3 (n=7), required prolonged mechanical ventilation support compared to patients with mrc score ≥ 49 (n=33), (44 ± 14 vs 19 ± 9 hours, p = 0.006). the use of muscle ultrasound seems to be a valuable tool in assessing skeletal muscle mass in critically ill patients after cardiothoracic surgery. moreover, the results of this pilot study showed that muscle wasting of patients after cardiothoracic surgery is of clinical importance, affecting their stay in icu. prediction of cardiac risk after major abdominal surgery s musaeva, i tarovatov, a vorona, i zabolotskikh, n doinov kuban state medical university, anesthesiology and intensive care, krasnodar, russia critical care 2020, 24(suppl 1):p147 the aim is to assess the incidence of cardiovascular incidents in major abdominal surgery [1] using the revised lee index. a study was conducted of 144 elderly patients who underwent major abdominal surgery in the krasnodar regional clinical hospital no. 2 under combined anesthesia. in the preoperative period, the risk of cardiovascular incidents was assessed using the revised lee index and the functional status was assessed by met. depending on the lee index, 3 groups were identified: group 1 (n = 69) -low risk (index value -1), group 2 (n = 52) -intermediate risk (index value -2); group 3 (n = 23) -high risk (index value> 3). we estimated the incidence of critical incidents in groups: hypo-, hypertension, arrhythmias, and bradycardia. in the general population, cardiac risk was 2.2 ± 0.7 points; functional status -7.7 ± 1 met. the greatest number of critical incidents was recorded in patients with high risk (58.4%), the smallest -in patients with low risk (9.1%), in patients with intermediate risk -26.5% (n <0, 05 between groups according to chi-square criterion). in the structure of critical incidents, hypotension was most often encounteredin 62 (43%) patients, while some patients revealed several incidents from the circulatory system (n = 116). overall, the lee scale showed good prognostic ability (auroc = 0.81) in predicting hemodynamic incidents. the revised lee index is a useful tool to help assess the risk of cardiovascular incidents and determine patient management tactics in the perioperative period. postoperative cognitive dysfunction (pocd) remains an unresolved problem due to lack of consensus on its etiology and pathogenesis. some believe that pocd is the result of the direct toxic effect of general anesthetics on the nervous system. others claim that surgical trauma activates proinflammatory factors that induce neuroinflammation. wistar rats were allocated into 2 groups: 1-minor surgery (n=20), 2major surgery group (n=20). after 5 days of handling and habituation rats undergone surgery under isoflurane general anesthesia (2 vol.%). group 1 rats underwent laparotomy with gentle gut massage followed by wound closure. rats in group 2 undergone left side nephrectomy. starting from the 4th postoperative day spatial memory in rats was studied in morris water maze which is a cylinder metal pool with a diameter of 1.5 and a height of 0.5 m filled with water (temp.26±1 o c) up to half. it has a platform with a diameter of 12 cm and a height of 1 cm below the water level. testing was preceded by a training stage, which included 8 sessions daily for 4 days. thus, rats developed spatial memory to the location of the platform. on the 5th day of the study test stage was conducted to assess spatial memory: rats were launched from 3 points into maze without platform and data were recorded for 60 seconds at each session. time spent on the target quadrant (ttq) and the number of target area crossings (tac) were registered. a second test was conducted 14 days after the first test to evaluate long-term spatial memory. the duration of surgery and anesthesia did not differ significantly between groups. there was a significant difference between groups in average ttq and tac in test 1 (table 1 ). in test 2 minor surgery group showed better results but they were less significant. major surgery is associated with a more pronounced deterioration of spatial memory in rats in early postoperative period compared to minor surgery. cardiac inflammatory markers in icu patients with myocardiac ischemia after non cardiac surgery (a pilot study) p manthou 1 , g lioliousis 2 , p vasileiou 3 , g fildissis 1 1 national kapodistrian university of athens, athens, greece; 2 national kapodistrian university of athens, general thoracic hospital´´sotiria´´, athens, greece; 3 national kapodistrian university of athens, university of athens, athens, greece critical care 2020, 24(suppl 1):p149 patients with known coronary artery disease have higher perioperative risk for myocardial ischemia [1, 2] . mortality is frequent following cardiac ischemia in the intensive care unit (icu) after non-cardiac surgery. the first group includes patients admitted to the intensive care unit for post-operative follow-up without myocardiac ischemia in the first 24 hours. the second group includes patients with myocardiac ischemia postoperatively and needs intensive care monitoring. cardiac risk assessment was made with the lee index,hemorrhagic risk assessment with the has-bled bleeding score and thrombotic risk assessment with cha2ds2-vasc score. postoperatively, pathological test values such as bnp, troponin, crp, calcitonin were estimated. the sequential organ failure assessment (sofa) systeme was used to assess sepsis. the nursing activity score (nas) scale was used to measure the workload of various nursing activities in the icu. according to the pilot study, the sample consists of 35 patients. 31.4% had myocardial ischemia. the lee index was significantly higher in patients with myocardial ischemia. the duration of hospitalization, the high dose of vasoconstrictive drugs, the length of stay in the icu, the duration of mechanical stay and the nursing workload were higher in patients with myocardial ischemia. ck-mb and troponin levels differed significantly between the two groups. creatinine, bilirubin and bnp during the 24 hours were significantly higher. patients with myocardial ischemia had significantly higher mortality. cardiac risk assessment, has-bled score and cha2ds2-vasc score in combination with cardiac enzymes such as troponin could predict myocardiac ischemia in severely ill icu patients. introduction: according to the literature an airway complication followed thyroid gland surgery are: difficult trachea intubation, tracheomalacia, postextubation stridor and bleeding [1, 2] . most common cause of death was problem with respiration and airway obstruction [3] . subsequent hypoxia could require emergency airway and even tracheostomy [3] . aim of our study was to determine the most common of airway complications and their association with type of surgery in our region. the retrospective cohort study included 400 pts., (369 women, 31 men) was performed in odessa regional hospital, oncology centre odessa. there were three types of patients: with euthyroid goiter -170 (43%), polynodos goiter -125(31%) and thyroid cancer -105 (26%) ( table 1) . airway complications were diagnosed after trachea extubation based on indirect laryngoscope, presence of stridor, desaturation. the pearson's criteria was calculated. the ratio of airway complications after thyroid surgery was 9.7% (39 pts). the main reasons of airway complications in thyroid surgery included: laryngeal edema -22 pts (5.5%); recurrent laryngeal nerve injury -12 pts (3.0%) and postoperative bleeding 5 pts (1.2%). thyroid gland cancer and polynodosal goiter associated with laryngeal edema and recurrent laryngeal nerve injury (pearsen criteria were 0.271 -moderate and 0.203 consequentially). it's may require more attention from the anesthetists after extubation and readiness for an urgent airway. serum iron level and development of multiple organ dysfunction syndrome in patients in the perioperative period s tachyla mogilev regional hospital, department of anesthesiology and intensive care, mogilev, belarus critical care 2020, 24(suppl 1):p151 recently there has been attention of researchers to the problem of perioperative anemia. it was found that it increases the risk of death and postoperative complications. threatening complication is multiple organ dysfunction syndrome (mods). the objective was to determine the level of serum iron in the perioperative period in patients with endoprosthetics of large joints, and with the presence of mods in abdominal surgery. a prospective cohort study was conducted in 77 patients, including 18 men and 59 women, age 61.9 ± 15.1 years. two groups were identified: 1st (control) -patients after endoprosthetics of large joints (n = 40), 2nd (main) -patients in abdominal surgery with the presence of mods (n = 37). the presence of mods was established based on the criteria for the 2016 sccm / accp conference. serum iron was monitored using an au 680 analyzer (usa). the study identified several stages: 1st -before surgery, 2nd -1st day after surgery, 3rd -3rd day, 4th -7th day, 5th -10th day. when studying the indicators of serum iron, its significant decrease (p <0.05) in the postoperative period was established. in the 1st group: 1st stage -15.2 (10-19.4) mmol / l, 2nd stage -5.2 (3.9-7.6) mmol / l, 3rd stage -6.6 (5-8.7) μmol / l, stage 4 -9.7 (8.6-12.1) μmol / l, stage 5 -9.4 (7.8-11 9) μmol / l. in the 2nd group: 1st stage -11.9 (10-15) mmol / l, 2nd stage -3.7 (1.7-4.1) mmol / l, 3rd stage -3, 6 (2.4-4.5) μmol / l, stage 4 -6.5 (4.4-8.2) μmol / l, stage 5 -7.6 (6.5-9 4) μmol / l. moreover, in both groups, iron increased at the 4th stage against the 2nd stage (p <0.05). when comparing the level of iron between the groups, significant differences were found (p < 0.05) at the 2nd, 3rd and 4th stages. in patients in the postoperative period, a decrease in serum iron is observed, the level of which rises by the 7th day, but does not reach the initial values. this decrease is more pronounced in patients with the presence of mods after abdominal surgery. kidney and pancreatic graft thrombosis happened in 5.6% and 18.9%, respectively, and bleeding in 21.1%. forty-one (45.6%) developed at least one infection during hospital stay. infection during icu was found in 13.3% and main pathogens were gram negative bacilli sensible to beta-lactam. after icu, the incidence of multi-drug resistant pathogen was 13.5%, predominantly gram negative bacilli. fungal infection was lower 4%. all-cause hospital mortality rate was 5.6%. infectious complications are the main cause of morbidity and mortality following spk transplantation. the administration of broadspectrum prophylactic antibiotics are leading to the appearance of multi-drug resistant pathogens. knowing local microbiological flora may be helpful, allowing more adequate antibiotic prophylaxis. introduction: cardiopulmonary bypass (cpb) is associated with thrombotic complications. occurrence of thrombosis after cpb is 12% which takes the third place between cpb-associated complications. our study determined preoperative predictors of thrombosis in children with congenital heart defects. 138 patients with congenital heart diseases in age up to 11 months 29 days (median age -4,7 months, youngest age -2 days after birth, oldest -11 months 29 days), underwent cardiac surgery with cpb, were enrolled in this study. all patients were divided into two groups: 1 st -without thrombosis, 2 nd -with thrombosis. protein c, ddimer, von willebrand factor and plasminogen plasma levels were assessed directly before surgery. thrombotic cases were proven by performing doppler ultrasound or mri. thrombotic complications were diagnosed in 30 children (21%). between all thrombotic complications ischemic strokes were diagnosed in 73% (22 cases), arterial thrombosis in 17 % (5 cases), intracardiac thrombus in 7% (2 cases) and mechanical mitral prosthetic valve thrombosis 3%(1). receiver operating characteristic (roc) curves are created for the listed indicators. area under the curve (auc) for protein c 0,64 (sensitivity(sn)-65%, specificity(sp) -50%), d-dimer is 0,65 (sn -65%, sp 50%), for plasminogen activity -0,62 (sn 60%, sp 40%) and for von willebrand factor level -0,64 (sn 80%, sp 55%). an roc curve was created for all three indicators, the auc was 0.7 (sn -80%, sp -40%). these parameters can be recommended as predictors of thrombosis in children after cardiac surgery. cpb is related with a large number of life-threatening complications. in our work, preoperative predictors of thrombosis were identified. based on this data, it is possible to create thrombosis risk scale change the tactics of the anaesthetic approach, the prevention of thrombosis in the postoperative period. further studies are needed to identify other possible predictors of thrombosis. introduction: abdominal ischemia occurs in 9% of patients submitted to aortic aneurysm repair. its early diagnosis requires an elevated index of suspiction, particularly in more severe patients. we hypothesized that earlier increase and higher levels of c-reactive protein (crp) may help to predict intra-abdominal ischemia. we performed a retrospective study of patients admitted to the intensive care department (icd) after abdominal aorta aneurism surgery. we included all patients admitted during a two-year period, that survived for more than 48 hours. primary outcome was splanchnic ischemia assessed by abdominal ct-scan. we also evaluated the presence of bacteremia, abdominal compartment syndrome and icd mortality. association between inflammatory parameters and ischemia was evaluated by multivariate logistic regression. introduction: crp (c-reactive protein) has been shown to be a useful biomarker in identifying complications after major abdominal surgery. gastrectomy is a high-risk surgical procedure that requires post-operative critical care support to monitor for complications which are predominantly infective in nature. the aims of this study were to determine whether there is a relationship between post-operative crp levels and patients who developed post-operative infective complications. a retrospective analysis was performed on patients undergoing elective gastrectomy for gastric cancer at a single centre between september 2011 and july 2016. post-operative crp levels for each day following resection were analysed for all patients. roc curve analysis was used to determine which post-operative day (pod) gave the optimal cut-off. of 144 patients included, the majority were male (61.8%), mean age was 68.5 years and 53.5% had node-negative disease. a total of 84 patients (58.3%) had an infective complication, which includes those who experienced an anastomotic leak. crp levels on post-operative day 3 gave the greatest auc for the gastrectomy group (0.765). crp cut-off of 220mg/l was significantly associated with infective complications (or7.29, 95% ci 3.42-15.58, p= <0.001) and gave a sensitivity of 70% and specificity 76% (ppv 67%, npv 78%). more patients with a crp >220 on post-operative day 3 experienced an infective complication (67% vs 21%, p = <0.001) or a leak in particular (17% vs 6%, p = 0.059). a crp level of less than 220 mg/l on pod3 may be useful to predict the development or exclude the likelihood of such infective complications in this group of patients prior to clinical signs (ppv 67%, npv 78%). this may prompt and facilitate decision-making regarding early investigation and intervention or prevent inappropriate early discharge from critical care, whilst providing more assurance in identifying those who could be stepped down to ward level care. vasoplegia is commonly observed after cardiopulmonary bypass surgery (cpb) and associated with high mortality. chronic use of reninangiotensin aldosterone system inhibitors (raasi) is associated with its incidence and ensuing need for vasopressor support after cpb. renin serves as marker of tissue perfusion [1] . we examined the role of renin in the setting of raasi exposure and vasopressor needs in the peri-cpb period. prospective observational study of 31 adult patients undergoing cpb, aged 66.0±10.5 years (22 men, 9 women). blood was collected 1) post induction, pre-cpb; 2) 30 min post cardioplegia, and 3) immediately post bypass. vital signs and perioperative medications were recorded. as control, blood was collected from 5 men and 4 women aged 53.5 ±10.7, not diagnosed with lung disease and not prescribed any raasi. baseline plasma renin in cpb patients tended to be higher than in control subjects (mean=38.5pg/ml±9.2 vs. 17.1 pg/ml ± 3.5, respectively, p=0.670). 30 minutes into cpb, mean renin was increased from baseline (77.6 pg/ml±17.5, p=0.211), and remained elevated immediately post cpb (74.6 pg/ml±19.1). patients using raasi prior to cpb tended to have a larger increase in renin post cpb (delta=55.3 pg/ ml±30.9) vs. those not previously on raasi (26.9 pg/ml±9.5, p= 0.092). renin was elevated in patients requiring vasopressor support in the 24 hours post cpb vs. those not requiring pressors (41.4 pg/ ml±15.7 vs. 25.1 pg/ml±16.1 p=0.0246). in those prescribed raasi and requiring pressors post cpb, there was a tendency toward greater renin increase than those not requiring pressors postoperatively (49.9 pg/ml±49.7 vs. 8.5 pg/ml±3.9, p=0.036). this study suggests a trend toward higher renin levels, particularly during cpb, in patients prescribed raasi, and a positive association between renin and postoperative vasopressor needs. we speculate that increased renin levels may predict postoperative vasoplegia. cardiac surgery is associated with perioperative blood loss and a high risk of allogenic blood transfusion. it has been recognized that high blood product transfusion requirement is associated with adverse clinical outcomes. 1 guidelines on patient blood management therefor aim at reducing blood loss and blood transfusion requirements in cardiac surgery. 2 as there remains controversy about the advantage of minimal invasive techniques on blood loss an transfusion requirements, 2 we wanted to investigate if the average blood loss and transfusion requirement in minimal invasive endoscopic coronary artery bypass graft surgery (endo-cabg) differ from conventional technique. we assessed the influence of pre-operative anticoagulant medication for blood loss. estimated average blood loss after conventional cabg 3 is 400ml (+/-200) and transfusion requirement 3,4 units packed red blood cells 4 . we performed a retrospective cohort study of our cardiac surgical database. from 01/01/2016 to 31/12/2017, we collected data from 423 patients undergoing endo-cabg. we analyzed blood loss, transfusion as well as pre-operative use of anti-coagulants as a risk factor for blood loss. we found that mean total blood loss in endo-cabg does not differ from conventional cabg, nonetheless mean transfusion requirement was lower in our cohort. use of direct oral anticoagulant is aossciated with increased blood loss and transfusion requirements (table 1) . total blood loss is not influenced by minimal invasive technique for cabg (endo-cabg). an explanation for the lower transfusion requirements is the use of a minimal extracorporeal circulation, which is known to reduce the risk of transfusion. another important factor is the implementation of a standardized transfusion-protocol based on available evidence. reducing transfusion requirements is an important component in improving patient outcome after cardiac surgery and is related to multiple factors in perioperative care of our patients. retinal microvascular damage associated with mean arterial pressure during cardiopulmonary bypass surgery v shipulin 1 retinal perfusion corresponds to cerebral perfusion and it is very sensitive to hemodynamic disturbances [1, 2] . we investigated the association between retinal microvascular damage and hemodynamic characteristics in patients undergoing coronary artery bypass grafting surgery (cabg) with cardiopulmonary bypass (cpb). methods: 10 patients with coronary artery disease and systemic hypertension were examined. ophthalmoscopy and optical coherence tomography were performed before and 10-14 days after cabg. the hemodynamic parameters during cpb were analyzed. results: 4 (40%) patients had changes in the retinal vessels and in the ganglionic fiber structure on 10-14 day after surgery: in 30% of patients the foci of ischemic retinal oedema appeared, in 10% the decrease of the thickness of ganglionic fiber were observed. these changes may be associated with intraoperative ischemia of the central retinal artery. in 6 (60%) patients the mean arterial pressure (map) during cpb was increased up to 90 mmhg. in 4 (67%) of them the association between map and foci of ischemic retinal oedema were revealed. the ischemic retinal changes were observed significantly more often if the delta of map during cpb was over then 20 mm hg compared with the patients where the delta of map was less than 20 mm hg (p=0.035). this is probably due to an intraoperative disorders of the myogenic mechanism of blood flow autoregulation in the retinal microvasculature in patients with coronary artery disease [3] . the level of map up to 90 mm hg during cpb is associated with retinal blood flow impairment and the foci of ischemic retinal oedema. delta of map more than 20 mmhg was associated with the foci of ischemic retinal oedema and decreased ganglionic fiber thickness in 67% of cases. atrial fibrillation after cardiac surgery: implementation of a prevention care bundle on intensive care unit improves adherence to current perioperative guidelines and reduces incidence introduction: atrial fibrillation after cardiac surgery (afacs) is a very frequent complication affecting 30-50% of all patients. it is associated with an increase in morbidity, mortality and hospital and intensive care unit (icu) length of stay. we aimed to implement an afacs prevention care bundle based on a recently published practice advisory [1] , focusing on early postoperative (re)introduction of β-blockers. baseline afacs incidence and β-blocker administration practices in our centre were audited for all patients undergoing valve surgery or coronary artery bypass graft (cabg) during a 6 weeks period. the afacs prevention care bundlean easy to follow graphical toolwas subsequently introduced to the cardiac icu by a multidisciplinary team and audited following a model of improvement approach. after exclusion of patients with preoperative af, differences between pre-and post-implementation groups were compared with chisquare and fisher's exact tests for categorical, and one-way anova for continuous variables, using spss. a total of 384 patients were analysed. patient and surgery characteristics did not differ between groups. significantly more patients received postoperative β-blockers after bundle implementation (82.7% pre-vs 91.3% post-bundle, p=0.019) with a higher proportion on day 1 (36.7% pre-vs 67% post-bundle, p<0.001, figure 1 ). the incidence of afacs was significantly reduced from 35.4% to 23.3% (p=0.009), with a particularly marked reduction in the age group 65-75 years and for isolated aortic valve and cabg surgery. there was no significant reduction in hospital length of stay for this cohort. introduction of an afacs prevention care bundle using a graphical tool improved adherence to current guidelines with regards to early β-blocker administration and significantly reduced afacs incidence. future care bundles should include preoperative interventions and might reduce hospital length of stay. in neonates with univentricular physiology, there is a delicate balance between pulmonary and systemic circulations, with a tendency towards generous pulmonary blood flow, and a risk of systemic underperfusion. preoperatively, the use of hypoxic gas mixture (hm) has been advocated as a therapy to increase pvr, with the aim of improving systemic oxygen delivery. it is a therapy which has been routinely initiated in our institution in the setting of signs of pulmonary overcirculation. we performed a retrospective analysis of all patients in our institution who underwent a norwood procedure and who received hm preoperatively. we compared peripheral saturations, arterial blood gas analysis, serum lactate, regional cerebral and renal saturations and invasive blood pressure, prior to, and then 4,8 and 24 hours after hm was commenced. between 2014 and 2018 (inclusive), 49 patients underwent the norwood procedure. 18 patients received preoperative hm. average fio2 was 17% during administration of hm. average peripheral saturations were 96.1% prior to hm, and dropped to 87.4% at 4 hours, and 88% at 8 and 24 hours after initiation (p < 0.05). there was no change in any of the measured markers of systemic oxygen delivery, including regional cerebral and renal saturations, lactate, urine output or blood pressure. there was an association between an extended period of hm (> 48 hours) and the need for pulmonary vasodilator therapy post norwood procedure. hypoxic gas mixture in patients with parallel systemic and pulmonary cicrculations causes desaturation and hypoxia. it does not lead to an increase in systemic perfusion and thus an improvement in systemic oxygen delivery. its ongoing use in this fragile population should be considered. introduction: analgesia in the critical patient, and especially in the neurocritical patient, is a basic goal in all therapeutic practices. patients in the icu are frequently administered prolonged and/or high doses of opioids. multiple serious complications due to the use of infusion of opioids at large doses has been described. to reduce high doses of intravenous opioids, multimodal forms of analgesia can be used. prospective observational study of the use of tapentadol enteral and buprenorphine in transdermal patches, at low doses, for the control of pain and its effect on reducing the use of fentanyl infusion in high doses on 84 patients admitted to neuro icu of indisa clinic during 2 consecutive years (2018-19). enteral tapentadol (through ng tube) 50 mg/6 hours, was considered in patients who required intravenous fentanyl in continuous administration. buprenorphine was also added at low doses (5 ug/hr) in a weekly transdermal patch, in cases of neurosurgical spine patients, fractures and long-term neuropathic pain. pain was controlled on behavioral pain scale (bps) and visual analogical scale (vas) scores, according to the conditions of each patient. their hemodynamic, gastrointestinal complications and the appearance of delirium episodes according to cam-icu scale were recorded. results: 84 patients received tapentadol. 32 of them also received transdermal buprenorphine. all managed to maintain adequate level of analgesia, not requiring fentanyl at doses greater than 0.5 ug / kg / hr. distribution by diagnoses: neurotrauma 21 patients, guillain barre 12, spine surgery 15, hsa 18, hice 10, malignant ischemic acv 8. complications: gastric retention 12 patients (7%), hypotension 1 (1%), acute hypoactive delirium 3 (3.5%), acute hyperactive delirium 8 (9%). no drug interactions were found. the introduction of enteral tapentadol and buprenorphine patches in neurocritical patients was safe and resulted in a decrease in the use of endovenous opioids and its adverse effects. we hypothesized that changing the pain management for our post cardiac surgical patients to an assessment-driven, protocol-based approach using fast acting and easily titratable agents will significantly improve patient satisfaction by reducing pain intensity in the first 24h after surgery as suggested by society of critical care [1] guideline. we prospectively assessed 101 and 99 (05.2018 vs 06.2019) consecutive patients before and after introducing our pain management protocol. the nursing and medical team received rigorous training on the guideline as well as the correct assessment using appropriate pain scores measured at least hourly (numeric pain score, ≥ 2 is timing of beta-blocker (re)initiation versus incidence of afacs before and after prevention care bundle implementation, per post-operative day and for postoperative days 1-5 (insets) moderate to severe or critical care observation tool, > 2 is moderate to severe). we introduced a multimodal approach with a combination of fast acting iv, long acting oral opiates, regular paracetamol and rescue iv boluses for difficult to control situations and we created a prescription bundle on our electronic prescribing record. among other variables we assessed hours spent in moderate to severe pain in the first 24h after surgery and compared to the data collected before the guideline was introduced. we analysed 101 patients from 2018 and 99 from 2019. baseline characteristics were similar between the two groups. in 2018 only 41.6% of the patients spent less than 5 hours and 29.4% spend more than 10 hours in moderate to severe pain. the 2019 data showed significant improvement in that 79.5% of patients spent less than 5 hours and only 5% patients who spent more than 10 hours in moderate or severe pain. (p <0.0001, chi square) ( figure 1 ). only 9% of the patient needed rescue medications. 3% of time was the protocol inadequate necessitating other approach. introducing an assessment driven, stepwise, protocolized pain management significantly improved patient satisfaction by reducing pain intensity in the first 24h on our cardiothoracic intensive care unit. introduction: proximal femur fractures are most common fractures in the elderly and associated with significant mortality and morbidity, with high economic and social impact. perioperative pain management influence outcomes and mortality after surgery with early mobilization being possible [1, 2] . the goal of the study was to compare the efficacy and safety of the compartment psoas block for perioperative analgesia in elderly patients with proximal femur fractures. the randomized controlled study was held in medical center "into-sana" (odesa, ukraine) from january 2018 till july 2019. patients with proximal femur fractures and older than 60 years were included in the study. they were randomly allocated to 2 groupscompartment psoas block group (bupivacaine analgesia was started as soon as possible before surgery and prolonged during and after surgery with additional ischiadicus block before surgery) and general (inhalational) anesthesia with systemic analgesia perioperatively. results: 60 patients were included in this study. perioperative compartment psoas block was associated better pain control, decreased opioid consumption, better sleep quality, earlier mobilization after surgery, decreased incidence of opioid-associated vomiting/nausea and myocardial injury. there were no difference in the incidence of hospital acquired pneumonia and delirium. perioperative compartment psoas block is effective and safe for perioperative analgesia in elderly patients with proximal femur fractures, and is associated with better pain control and decreased complications incidence. parenteral olanzapine is frequently used in combination with parenteral benzodiazepines for hospitalized patients with severe agitation. the fda issued a warning for increased risk of excessive sedation and cardiorespiratory depression with this combination based on post-marketing case reports with overall limited quality of evidence [1] . the purpose of this study is to evaluate the safety and efficacy of concomitant parenteral olanzapine and benzodiazepine for agitation. this retrospective chart review evaluated agitated patients who received concomitant parenteral olanzapine and benzodiazepine within 60 minutes from 1/31/2016 to 9/1/2019 . the primary end points were rate of respiratory depression requiring mechanical ventilation and hypotension requiring vasopressors. the secondary end points were percentage of patients requiring additional sedatives for agitation during the same time frame, cumulative dose of olanzapine and benzodiazepine (midazolam equivalent) received, and rate of cardiac arrest and death. a total of 208 patients were included with notable baseline characteristics: median age of 35 years old, 59% with a history of substance abuse, and 40% with a history of psychiatric illness. for the primary outcomes, 2.9% of patients required mechanical ventilation and 0% required vasopressors. additionally, 27.9% patients received additional sedating agents to control agitation. refer to table 1 for more details. no cardiac arrests or deaths were observed. concomitant use of parenteral olanzapine and benzodiazepine within 60 minutes for the treatment of agitation appears to have a small risk of respiratory depression without significant hypotension. hip fracture is very common in the elderly,it causes moderate to severe pain often undertreated. ficb is a simple safe method, easy to learn and use. the aim of our study is to assess the efficacy and safety of preoperative ficb compared with intravenous analgesia for elderly patients with femoral fracture and hip surgery in terms of opioid consumption and perioperative morbidity methods: after informed consent obtained,54 patients 50-98 yo asa i-iii with hip fracture were randomized to receive either an us guided ficb(40 ml of ropivacaine 0,35%) or a sham injection with normal saline 30' before surgery. both groups were operated under general anesthesia. postoperative analgesia was done according to vas: vas 0-30 mm, paracetamol 1g iv at 8 h, vas 30-60 mm, ketoprofen 100 mg iv at 8 h, vas>60, morphine 0,1mg/ kgbw iv. the primary outcome was the comparison of vas score at rest over the first 30'following the procedure, at the end of the surgery and at 6h intervals for 24h. the secondary outcome were the incidence of the cardiovascular events, of the ponv and of the confusion episodes, the amount of morphine consumption for 24h results: at baseline, ficb group (a) had a lower mean pain score than the sham injection group (b). the same difference was observed over 24 h of follow-up (p<0.05). there was a significant difference between the two groups in total cumulative iv morphine consumption at 24 h and in the incidence of ponv and confusion episodes ( figure 1 ). ficb provides effective analgesia for elderly patients suffering from hip fractures, with lower morbidity and lower opioid consumption compared with intravenous analgesia. pain assessment in chronic disorders of consciousness patients with ani monitoring e kondratyeva, m aybazova, n dryagina almazov national medical reseach centre, minimally conscious research group, st petersburg, russia critical care 2020, 24(suppl 1):p166 pain and suffering controversies in doc to be debated by the scientific, legal and medical ethics communities. methods: ani (anti nociception index) monitor was used to assess pain in patients with chronic disordersof consciousness (doc) age range 22 to 56 years -9 in vegetative state/ unresponsive wakefulness syndrome (vs/uws) and 20 minimal consciousness state (mcs). average age: in mcs group 31,8±11,29 and 42,1±8,46 in vs/uws group. neurological status was assessed using crs-r scale. the average score on the crs-r scale was 5±1.4 in vs/uws and 10.45±4.5 in mcs. pressure on the nail phalanx was used as a pain impulse. ani and nociception coma scale was evaluated before the application of pain stimulus, immediately after and past 30 minutes. prolactin level was measured before the pain stimulus application and 10 minutes after. ani less than 50 indicates pain, 70-100 hypoalgesia, 30 severe pain. the mean value of the ani in mcs patients: before the pain stimulus 66.25±14.11, after the pain stimulus application 45±16.12 and 30 minutes later 66.55±18.13. prolactin level in mcs patients before pain 13.01±9.06 ng/ml; after pain 13.75±8.73 ng/ml (p>0.05). prolactin in vs/uws patients before pain 10.79±7.2 ng /ml, after pain 14.5 ±8.88 ng / ml (p> 0.05). conclusions: ani monitor revealed that vs/uws and mcs patients react equally to the pain impulse. prolactin dynamics showed poor statistical mean and can not be consider as a marker of nociception in this group of patients. it is possible that the level of pain impulse was insufficient neuroendocrine response activation or the increase of prolactin level occurs in the long term (more than 10 minutes). in all patients the total hip arthroplasty tha is one of the most common major surgical procedures associated with significant postoperative pain that can adversely affect patient recovery and could increase morbidity. effective perioperative pain management allows an accelerated rehabilitation and improve the functional status of these patients. multimodal analgesia mma combines analgesics with different mechanism of action which by synergistic and additive effects enhance postoperative pain management and reduce complications. the aim of our study is to assess if perioperative association of very low dose of ketamine, a potent nmda antagonist and dexamethasone, by antiemetic and antiinflammatory properties could decrease opioid consumption and postoperative morbidity of patients with tha. after informed consent, 58 patients scheduled for primary hip joint replacement surgery aged 55-91 yo asa i-iii were prospective randomized in two groups. both groups were operated under general anesthesia fentanyl/sevoflurane. supplementary, patients in group a received 12 mg iv dexamethasone and 8mg at 12 h and ketamine 10 mg iv bolus at induction and 10mg/h iv during surgery. postoperative analgesia was done according to vas, 0-30 mm paracetamol 1 g iv at 8 h, 30-60 mm ketoprofen 100 mg iv at 12h, vas>60 mm morhine 0,1 mg/kgbw iv. we recorded perioperative opioid consumption, the number of intraoperative cardiac events, vas score at the end of surgery and at 24 h, the incidence of ponv and persistance of chronic pain at 3 months. we obtain a significant less pain score at the end of surgery p<0.05 in group a, no significant difference at 24 h, a significant less chronic pain at 3 months, a fewer npvo and cardiovascular events in group a, p<0.05 ( figure 1 ). a multimodal approach with very low doses of ketamine and dexamethasone could be efficent in the treatment of pain for elderly patients with hip arthroplasty, decreasing postoperative side-effects and reducing chronic pain persistance. introduction: treatment in an intensive care unit (icu) often necessitates uncomfortable and painful procedures for patients. chronic pain is becoming increasingly recognized as a long term problem for patients following an icu admission [1] . throughout their admission patients are often exposed to high levels of opioids, however there is limited information available regarding analgesic prescribing in the post-icu period. this study sought to examine the analgesic usage of icu survivors pre and post icu admission. methods: 183 patients enrolled in a post-intensive care programme between september 2016 and june 2018. intensive care syndrome: promoting independence and return to employment (ins:pire), is a 5-week multicentre, multidisciplinary rehabilitation programme for icu survivors and their caregivers. patients' level of analgesia was recorded pre-admission and upon attending ins:pire, their level of prescribed analgesia was categorized using the word health organisation (who) analgesic ladder [2] . results: 33.3% of patients (n=61) were prescribed regular analgesia preadmission; this increased to 60.7% (n=111) post-admission, representing a significant absolute increase of 27.4% (95% ci: 20.2% -34.4%, p<0.001) in the proportion of patients who were prescribed regular analgesia pre and post icu. in addition, pre-admission, 22.4% (n=41) of patients were prescribed a regular opioid (step 2 and 3 of the who ladder) compared to 38.7% (n=71) post-admission, representing an absolute increase of 16.3% (95% ci: 9.8% -22.8%, p< 0.001). this study found a significant increase in analgesic usage including opioids in icu survivors. follow-up of this patient group is essential to review analgesic prescribing and to ensure a long term plan for pain management is in place. introduction: pain, agitation, and delirium (pad) are commonly encountered b patients in the intensive care unit (icu). delirium is associated with adverse outcomes, including increased mortality and morbidity. clinical guidelines suggest that routine assessment, treatment and prevention of pad is essential to improving patient outcomes. despite the well-established improvements on patient outcomes, adherence to clinical guidelines is poor in community hospitals. the aim of this quality improvement project is to evaluate the impact of a multifaceted and multidisciplinary intervention on pad management in a canadian community icu. a pad advisory committee was formed and involved in the development and implementation of the intervention. the 4-week intervention targeted nurses (educational modules, visual reminders), family members (interviews, educational pamphlet, educational video), physicians (multidisciplinary round script), and the multidisciplinary team (poster). an uncontrolled, before-and-after study methodology was used. adherence to pad guidelines in the assessment of pad by nurses was measured 6 weeks pre-intervention and 6 weeks post-intervention. data on 430 patient-days (pd) and 406 pd were available for analysis during the pre-and post-intervention, respectively. the intervention significantly improved the proportion of pd with assessment of pain and agitation at least 4 times per 12-hour shift from 68.0% to 87.5% and from 69.7% to 82.2%, respectively ( figure 1 ). proportion of pd with delirium assessment at least once per 12-hour shift did not significantly improve. a multifaceted and multidisciplinary pad intervention is feasible and can improve adherence to pad assessment guidelines in community icus. quality improvement methods that involve front-line staff can be an effective way to engage staff with pad. oversedation introduction: sedation is a significant part of medical treatment in icu patients. a too deep sedation is associated with a longer time of mechanical ventilation, lung injury, infections, neuromuscular disease and delirium, which can lead to a longer duration of icu hospitalization, as well as an increase of morbility and mortality. many patients spend a considerable amount of time in a non-optimal sedation level. a continuous monitoring system of the sedation level is therefore necessary to improve clinical evaluation. our goal was to evaluate the incidence of non-optimal sedation (under and over sedation) comparing the parameters expressed from ngsedline with clinical evaluations and to correlate oversedation and the incidence of delirium. we have studied a cohort of patients admitted to the icu of spedali civili of brescia university hospital requiring continuous sedation for more than 12 hours. in addition to standard monitoring, the patients have been studied using next generation sedline (masimo). sedation depth was evaluated through rass scale and the presence of delirium was evaluated with cam-icu scale. we collected data from 50 adult patients. our data showed high incidence of oversedation. 45 of our 50 patients had a sr>2 and 48 had a psi level<30. a logistic regression analysis was performed and it showed statistically significant association between incidence of delirium and the age of the patients (p 0.009). the association between delirium incidence and suppression rate time was at the limits of statistics significance (p 0.059) and was statistically significant for non neurocritical patients (p 0.049). our study didn't show an association between delirium and the total time of sedation. non-optimal sedation is an unsolved problem in icu, affecting lot of patients, with a major incidence of over-sedation compared to under-sedation. our study shows an association between sr levels and the incidence of delirium. predictors of delirium after myocardial infarction, insights from a retrospective registry m jäckel, v zotzmann, t wengenmayer, d dürschmied, c von zur mühlen, p stachon, c bode, dl staudacher heart center freiburg university, department of cardiology and angiology i, freiburg, germany critical care 2020, 24(suppl 1):p172 delirium is a common complication on intensive care units. data on incidence and especially on predictors of delirium in patients after acute myocardial infarction (mi) are rare. by analyzing all patients after acute mi, we aim to identify incidence and potential risk factors for delirium. in this retrospective study, all patients hospitalized for acute mi treated with coronary angiography in an university hospital in 2018 were included and analyzed. incidence of delirium within the first 5 days of care attributed to the mi and was defined by a nudesc score ≥2, which is taken as part of daily care three times a day by especially trained nurses. this research is authorized by ethics committee file number 387/19. results: 626 patients with acute mi (age 68.5±13.3 years, 260 stemi, mortality 3.4%) were analyzed. delirium occurred in 70 (11.2%) patients and was associated with a longer hospital stay (12±15.9d vs 5.5±4.3d, p< 0.001). patients with delirium were significantly older than patients without (76.3±11.14 vs. 67.5±13.10 years, p<0.001) and had more often preexisting neurological diseases (24.3% vs. 10.8%, p<0.001) and dementia (11.4% vs. 1.4%, p<0,001). multivariate logistic regression analysis suggested that odds ratio for delirium was higher in patients after resuscitation or 7.5 (95% ci 2.1-26.7), preexisting dementia or 28.9 (ci 3.1-268) and in patients with alcohol abuse or 18 (ci 2.7-120). while maximum lactate was also connected to delirium or 1.4 (ci 1.1-1.9), infarct size or type had no effect on the incidence of delirium. in patients with mi, delirium is frequent. incidence is associated with clinical instability and preexisting neurological diseases rather than infarct size. incidence and risk factors of delirium in surgical intensive care unit ma ali, b saleem aga khan university, anaesthesia, karachi, pakistan critical care 2020, 24(suppl 1):p173 introduction: delirium in the critically ill patients is common and distressing. the incidence of delirium in the icu ranges from 45% to 87%. although delirium is highly common among intensive care patients, it is mostly underreported. to date, there have been limited data available related to prevalence of delirium in surgical patients. in a study published in 2008, the risk was observed 73% in surgical and trauma patients [1] . the purpose of this study was to find out the incidence and associated risk factors of delirium in surgical icu (sicu) of a tertiary care hospital. we conducted prospective observational study in patients with age more than 18 years and who were admitted to the surgical icu for more than 24 hours in aga khan university hospital from january 2016 to december 2016. patients who had preexisting cognitive dysfunction or admitted to icu for less than 24 hours were excluded. delirium was assessed by intensive care delirium screening checklist icdsc. incidence of delirium was computed and univariate and multivariable analyses were performed to observe the relationship between outcome and associated factors. delirium was observed in 19 of 87 patients with an incidence rate of 21.8%. multivariable analysis showed that copd, pain >4 and .76] were also the strongest independent predictors of delirium while analgesics exposures was not statistically significant to predict delirium in multivariable analysis. delirium is significant risk factor of poor outcome in surgical intensive care unit. . there was an independent association between pain, sedation, copd, hypernatremia and fever in developing delirium delirium is an acute mental syndrome which may cause negative consequences if it is misdiagnosed [1, 2] . the aim of this study was to determine the incidence of delirium in different intensive care units and reveal the risk factors. the study was performed with 212 patients hospitalized in intensive care units of anesthesia, neurology and general surgery departments. written informed consent was obstained from patients or relatives. delirium screening test was performed twice daily with camicu (confusion assessment method for the icu). patients who met the study criterias, were evaluated for the possible risk factors of delirium and the data was recorded daily. patients were reevaluated after the treatment. the incidence of delirium was 32.5%. delirium was found to increase with the length of stay (p <0.001). the mean age of the patients with delirium was 67.46. this was higher than the patients without delirium (52.48) (p<0.001). visual impairment (p<0.001), hearing impairment (p=0.001), educational status (p=0.024), hypertension (p=0.002), mechanical ventilation (p = 0.001), oxygen demand (p=0.002), midazolam infusion (p=0.025), propofol infusion (p=0.042), infection (p < 0.001), sofa (p = 0.001), apache ii (p <0.001), nasogastric catheter (p=0.012), aspiration (p <0.001), number of aspirations (p<0.001), enteral nutrition (p<0.025), albumin (p=0.025), steroid (p=0.024), hypercarbia (p=0.039) hypoxia (p=0.039), sleep disturbance (p<0.001) were found risk factors for delirium. oral nutrition (p<0.001) and mobilization (p=0.003) were found to prevent delirium development. various factors are important in the development of delirium. these risk factors should be considered in reducing the incidence of delirium in intensive care units. ). an unplanned and brutal stop of alcohol consumption, as it can occur during icu admission, may lead to an alcohol withdrawal syndrome (aws). the most severe clinical manifestation of aws is described as delirium tremens (dt). there are no current guidelines available for aws treatment in icu. the study's aim was to describe the clinician's practices for dt treatment and the outcome of dt in icu patients. observational retrospective cohort study in two icus of a universityaffiliated, community hospital in france. patient diagnosed for dt during their icu stay, as defined by dsm-v classification, were enrolled in the study. results: 61 patients with dt were included between 2014 and 2017. benzodiazepines was administered to 23% of the patients in order to prevent an aws. as associated measures, vitamin therapy was administered to 83% of the patients and 59% had an increased fluid intake (mean 2.5l+/-0.7). concerning the curative approach of aws, the treatment's heterogeneity was notable. there was a high frequency of treatment's association (66% of the patients), every patient had benzodiazepines and the use of second line treatments such as neuroleptic, alpha-2 agonist, propofol was variable ( figure 1 ). complications of dt were the following: need for mechanical ventilation due to unmanageable agitation or acute respiratory distress (33% of the patients) self inflicted injuries such as pulling out of central lines, tubes, surgical drain (46%) falls (7%). seizures (33%). delirium tremens is a severe complication of an untreated aws, which can lead to serious adverse events in icu. the current lack of evidence concerning the management of aws in icu probably explains the heterogeneity of treatments. given the potential severity of aws in icu, further evidences are required to optimize care of aws in icu patients. the incidence and related risk factor of delirium in surgical stepdown unit s yoon 1 , s yang 2 , g cho 2 , h park 2 , k park 2 , j ok 2 , y jung 2 1 asan medical center, nursing department, seoul, south korea; 2 asan medical center, seoul, south korea critical care 2020, 24(suppl 1):p177 step down units (sdus) provide an intermediate level of care between the icu and the general medical-surgical wards. the critically ill patients who are in recovery after long-term intensive care or who require monitoring after acute abdominal surgery are admitted to sdus. delirium in critically ill patient is common and leads to poor clinical outcomes. it is, however, preventable if its risk factors are identified and modified accordingly. to determine risk factors associated with delirium in critically ill patients to admitted surgical sdu at asan medical center. this is retrospective study conducted on critically ill patients who were admitted to the sdu from september 2018 to april 2019 and able to express themselves verbally. delirium status was determined using the short-cam tool. data were analyzed by spss 13.0 software, using t-test, fisher's exact test and logistic regression. the incidence of delirium was 32.1%(25 of 78 patients) and hypoactive delirium(12case, 48.0%) was the most commonly assessed, followed by hyperactive delirium(9case, 36.0%), mixed type(4case, 5.1%). risk factors associated with developing delirium identified from univariate analysis were age(p=0.048), admission via icu (p= 0.041), tracheostomy (p=0.037), chronic heart failure (chf) (p=0.017), invasive hemodynamic monitoring (p=0.041), heart rate (p= 0.037). after adjusted in multivariate analysis; factors those remained statistically significant were old age (rr we identified risk factors consistently associated with incidence of delirium following admitted to surgical sdu. these factors help to focus on patients at risk of developing delirium, and to develop preventive interventions that are suitable for those patients. patients with sepsis frequently develop delirium during their intensive care unit (icu) stay, which is associated with increased morbidity and mortality. the prediction model for delirium in icu patients (pre-deliric model) was developed to facilitate the effective preventive strategy of delirium [1] . however, the pre-deliric model has not yet been validated enough outside europe and australia. the aim of this study is to examine the external validity of the pre-deliric model to predict delirium using japanese cohort. this study is a post hoc subanalysis using the dataset from previous study in nine japanese icus, which have evaluated the sedative strategy with and without dexmedetomidine in adult mechanically ventilated patients with sepsis [2] . these patients were assessed daily throughout icu stay using confusion assessment method-icu. we excluded patients who were delirious at the first day of icu, were under sustained coma throughout icu stay and stayed icu less than 24 h. we evaluated the predictive ability of the pre-deliric model to measure the area under the operating characteristic curve. calibration was assessed graphically. of the 201 patients enrolled in the original study, we analyzed 158 patients in this study. the mean age was 69.4 ± 14.0 years and 99 patients (63%) were male. delirium occurred at least once during their icu stay in 63 patients (40%). to predict delirium, the area under the receiver operating characteristics curve of the pre-deliric model was 0.60 (0.50 to 0.69). graphically, the prediction model was not well-calibrated ( figure 1 ). to predict delirium in japanese icus, we could not show the well discrimination and calibration of the pre-deliric model in mechanically ventilated patients with sepsis. introduction: delirium is a serious and common complication and in some cases it treatment is difficult. aim of the study was an evaluation of the prevalence, structure of delirium and efficacy of dexmedetomidine and haloperidol sedation in geriatric patients after femur fracture. after local ethic committee approval 207 case-records of geriatric patients with femur fracture in the period from 2017 to 2018 in the institute of traumatology and orthopedics in astana were analyzed. patients was divided for 2 groups: in dpatients with delirium treated by i/v dexmedetomidine (0.2-1.4 mkg/kg per hour), in g group patients with delirium treated by i/v galoperidol (0.10-0.15 mkg/kg). delirium was assessed by rass at day of permission and every day at 8 a.m. the prevalence, structure of delirium and efficacy of sedation were analysed. results: by anthropometric and gender characteristics of the group did not differ. the average age in the d-group with delirium was 81.8±0.9 years old, which was comparable to the g-group -79.7±0.7 years old (p = 0.06). all study participants had similar comorbidities. delirium in all patients debuted at 2.0±1.4 days, with an average duration of 2.2±1.2 days. the effect of dexmedetomidine was better and expressed in 52% decrease in the duration of delirium in compare to haloperidol (p <0.05). dexmedetomidine provided a more controlled and safe sedation compared with haloperidol. the average consumption of narcotic analgesics in the subgroup with dexmedetomidine was two times less than in the subgroup with haloperidol. thus, the average consumption of trimeperidine hydrochloride in patients of group d was 6.9 mg versus 14.1 mg in group g (p = 0.004). in gerontological patients with femur fracture treatment delirium by dexmedetomidine was more effective in compare with haloperidol. when using dexmedetomidine, the consumption of narcotic analgesics in postoperative period was 50% less than with haloperidol. live music therapy in intensive care unit mc soccorsi 1 , c tiberi 1 , g melegari 1 , j maccieri 2 , f pellegrini 2 , e guerra 1 intensive care units (icu) are not comfortable for patients, relatives or next of kin. in the last years many news approaches were described to implement the humanization of medical treatments. the positive effect of music therapy in icu is well described, especially reducing delirium risk [1] . the aim of this paper is describing the effect in patients and their family of a music live performance in icu. after ethical committee approval (procedure aou 0018356/18, italy) for three months (november 2018-january 2019) patients in icu were treated twice a week with live music therapy performed by coral vecchi-tonelli of modena, italy (fig. 1 ). data were collected all awake and conscious patients. vitals parameters, gcs, raas and cam icu were collected before, during and after the treatment, at every performance. after the treatment a feedback questionnaire were given to patients and to next of kin. results: 18 subjects were enrolled in the research with mean age of 66.66 years old, delirium rate before the treatment was 16.38% later 15.38%, raas does not show any difference. over 85% of patients were satisfied, and relatives felt less anxiety. we recorded also a satisfaction also in relatives not enrolled. the study does not demonstrate a delirium risk reduction for the small sample and the length treatment, anyway it was recorded a low delirium rate. the safety and the potential effect of music therapy are well known, surely the research underlines the feeling of patients and their next of kin: icu is the most stressful setting for admitted patients and its humanization is a current topic for medical literature. live performances could be an entertainment moment and probably create a moment of an interaction among patients, their family and medical and nurse: icu become more human. the high level of satisfaction push us to continue this experience. introduction: patients undergoing medical procedures benefit from distraction techniques to reduce the need for drugs alleviating pain and anxiety. this study investigates if medical hypnosis or virtual reality glasses (vrglasses) as adjuvant method reduces the need for additional drugs. in a prospective, randomized, interventional trial, patients undergoing procedures were stratified in four age groups, and randomly assigned into three arms by means of a closed envelope system. all patients received standard care for pain before the procedure; the control group received further drugs for pain and stress as indicated by the visual analog scale (vas; threshold 3/10) and comfortscore (threshold 14/30), two index groups received either medical hypnosis or vr glasses as a plus before and during the procedure. vas and comfort were scored continuously and analysed with the kruskal-wallis test. patients, parents and healthcare providers scored their satisfaction at the end. of 104 included patients 6 to 86 years old, 47% were female. regardless of age, pain and comfort scores were similar before and at the start of the procedure (vas 3.7-4.2; comfort 16-16.7), but as of one minute after starting the procedure, both vas and comfort reduced significantly more in both index groups compared to the control (p< 0.001), remaining far below the threshold for both pain and stress ( figure 1 ). there was no advantage of one index group over the other (p=0.43). there were no adverse effects. patients in the vr group were more satisfied than in the standard group (p=0.02) or in the hypnosis group (p=0.04). there was no significant difference in satisfaction of parents or healthcare providers. from the very start of the intervention, the application of either medical hypnosis or vr glasses significantly reduces pain and anxiety in patients undergoing medical procedures. more studies are needed but both are promising safe adjuvant tools to standard pharmacological treatment. music to reduce pain and distress due to emergency care: a randomized clinical trial ne nouira, i boussaid, d chtourou, s sfaxi, w bahria, d hamdi, m boussen, m ben cheikh mongi slim academic hospital, emergency department, tunis, tunisia critical care 2020, 24(suppl 1):p182 recent clinical studies have confirmed the benefits of music therapy in managing pain and improving quality of care in the emergency department. the aim wasto evaluate the impact of receptive music therapy on pain and anxiety induced by emergency care methods: a randomized controlled study in patients consulting the emergency department. two groups: the music therapy group; patients needed venous sampling, peripheral venous catheter or arterial catheter. will bless ten minutes music therapy by headphones and a second control group of patients with the same care without music therapy. consent was requested from all participants. the level of pain caused by the act of care was assessed by visual analogic scale. heart rate, blood pressure and the mood of the patient were assessed before and after emergency care. we assessed patient satisfaction, adverse events. patients admitted to the emergency room, patients with communication difficulties and non-consenting patients were not included results: two hundred and forty patients were included randomized in both groups, 123 with music therapy and 117 without music therapy, the results showed comparable characteristics between the two groups: demographic data, pathological history, and initial clinical presentation. after the session of music therapy a difference was noted in the evaluation of the mean vas who was in the group with music of 2.87 ± 1.82 versus 3.60 ± 2.06 in the control group p< 0.004 ci 95% [-1.23; -0.23], and the mean of diastolic blood pressure which was 71, 07 mmhg in the first group against 74.27 mmhg for the control group p = 0.048 ci 95% [-6.37; -0.25]. as for the mood, the patients were more smiling after the act of care in the group music therapy. all patients were satisfied with their experience and 93% recommend this therapy to their relatives . music therapy may reduce pain and anxiety in patients during emergency care. the music therapy is the intervention of music and/or its elements to achieve individual goals within a therapeutic.the music has proved to have positive physiological and psychological effects on patients [1] . patients admitted to the intensive care unit (icu) experience anxiety and stress even when sedated, negatively influencing recovery [2] . methods: two groups are established, a music therapy group (mg) and a control group (cg). the first one undergoes music therapy interventions, it consists of 10-minutes sessions of live music. patients of the gc will receive the usual treatment established by the service protocol for weaning management and the data are collected during the same time interval. data collection includes mean arterial pressure (map), heart rate (hr), respiratory rate (rr), oxygen saturation (sao2) and temperature (t). a total of 28 patients were recruited, of which 6 patients had to be excluded for meeting any of the exclusion criteria (n=22). of which 13 (n=13) were randomized in the gm and the rest to the gc (n=9) ic95%. regarding delirium in gm 9 (40.9%) presented a positive cam-icu, while in the cg were 13 (59.9%) (p=0.09). when analyzing the variables in the cg and gm, it was observed that there were no differences with respect to hr, rr and map variable ( figure 1 ). according to the results, we can say that music therapy as a nonpharmacological strategy for management of anxiety and delirium in patients of critical care units, might be an useful tool for the management of patients in weaning of mechanical ventilation introduction: coagulopathy and basopenia are common features of anaphylaxis, but the role of coagulopathy in anaphylaxis remains uncertain. the aim of this study is to evaluate the association between coagulopathy and clinical severity or basopenia in patients with anaphylaxis. we conducted a single-center, retrospective study of patients with anaphylaxis about their coagulopathy. levels of fibrin degradation products (fdp) and d-dimer were analyzed with the cause of anaphylaxis, clinical symptoms, medications and outcomes. we also studied the levels of intracellular histamine as a biomarker of basophil degranulation in the peripheral blood in relation to fdp and ddimer. in total, sixty-nine patients were enrolled to the study, and the levels of intracellular histamine were analyzed in 14 patients. the symptoms included respiratory failure (n=47), shock (n=56), abdominal impairment (n=20), and consciousness disturbance (n=37). thirty-two patients needed continuous intravenous vasopressors for refractory shock. the increase of fdp was significantly associated with consciousness disturbance (p=0.029) and refractory shock (p<0.0001). the increase of d-dimer was also significantly associated with refractory shock (p=0.0066). there was no correlation between the levels of intracellular histamine and either of fdp or d-dimer (p=0.13 and p=0.16, respectively). the increase of fdp and d-dimer were associated with severe symptoms of anaphylaxis, while they were not correlated with intracellular histamine. these results suggest that anaphylaxis is closely associated with coagulopathy in a mechanism which is different from basophile degranulation in anaphylaxis. cardiac manifestations of h1n1 infection in a greek icu population e nanou 1 , p vasiliou 1 , e tsigou 2 , v psallida 1 , e boutzouka 2 , v zidianakis 1 , g fildissis 1 1 agioi anargiroi hospital, attiki, greece; 2 agioi anargiroi hospital, icu, attiki, greece critical care 2020, 24(suppl 1):p185 introduction: cardiovascular involvement in influenza infection occurs through direct effects on the myocardium or through exacerbation of pre-existing cardiovascular disease [1] . the aim was to study cardiac manifestations in all pts admitted to the icu with severe influenza's attack. clinical, laboratory, electrocardiographic, echocardiographic and hemodynamic data were retrospectively recorded in all pts admitted to the icu due to influenza infection (winter 2018-spring 2019). diagnosis was established by pcr on bronchial aspirates the next 7 days after admission. myocardial injury was defined by troponin levels >116 pg/ml (10 fold uln). left ventricular systolic dysfunction was defined as ef <50% and was characterized as either global or regional. hemodynamic monitoring by fig. 1 (abstract p183) . comparison between mg and cg transpulmonary thermodilution method (picco) was recorded in pts with shock (norepinephrine >0.1 μg/kg/min). values are expressed as mean±sd or as median (ir). results: nine pts (5 males) with a mean age 49.78±17.01 years, apache ii 19±5.29 and sofa score 10.50±2.93 were assessed. icu admission was due to ards (7) and copd exacerbation (2) . icu los was 24.44± 14.19 days and mortality rate was 18%. no history of vaccination or coronary heart disease was referred. results are shown in table 1. levosimendan was administered in 2 pts with severe cardiogenic shock. in all survivors, shock and indices of myocardial dysfunction subsided till discharge. coronary angiography was performed in 1 pt showing no abnormalities. mortality was attributed to septic shock and multi-organ failure. myocardial involvement, though common in influenza pts admitted to the icu, didn't contribute to a dismal prognosis. the cardioprotective effects of levosimendan could be related to the modulation of oxidative balance. we aimed to examine the effects of levosimendan in patients with cardiogenic shock or with ejection fraction (ef) lower than 30% on cardiac systo-diastolic function and plasma oxidants/antioxidants (glutathione, gsh; thiobarbituric acid reactive substances, tbars). in 4 patients undergone coronary artery bypass grafting or angioplasty, cardiovascular parameters were measured at t0 (before the beginning of levosimendan, 0.1mcg/kg/min), t1(1 h after the achievement of the therapeutic dosage of levosimendan), t2 (at the end of levosimendan infusion), t3 (at 72 h after the end of levosimendan infusion), t4 (at the end of cardiogenic shock). the same time-course was followed for plasma gsh and tbars measurements. we found an improvement in cardiac output, cardiac index and systolic arterial blood pressure. ef increased from mean 25% to 45%. a reduction of central venous pressure and wedge pressure was also observed. moreover, indices of diastolic function were improved by levosimendan administration (e/e' from 14 to 6; e/a from >1 to <1) at early t2. it is to note that an improvement of gsh and tbars was observed early after levosimendan administration (t1), as well ( figure 1 ). the results obtained have shown that levosimendan administration can regulate oxidant/antioxidant balance as an early effect in low cardiac output patients. the modulation of oxidative condition could be speculated to play a role in exerting the cardio-protection exerted by levosimendan in those patients. table 1 . early administration of vasopressors and their use in the emergency department was associated with survival in septic shock. this seemed to be independent of median map recorded in the ed. we excluded all the traumatic or post-myocardial infarction forms. out of 83 patients, the tuberculous etiology was identified in 15 cases (18,1%), mean age was 34 years, 57,8% were men. 9 patients reported a tb contact in their environment, 5 had a medical history of pulmonary tb. after pericardiocentesis, the liquid was citrine yellow in 6 cases and hematic in 5 patients, no patient underwent surgical drainage in our serie. mycobacterium tuberculosis was found in the expectorations in 4 cases and ada was positive in 4 patients. hiv serology was negative in all our patients. a 6 months anti bacillary therapy with isoniazid, rifampin, pyrazinamide, and ethambutol was initiated in all our patients with a good evolution in 7 cases, 2 deaths, 1 chronic constrictive pericarditis, 2 small pericardial effusion and 3 lost to follow-up. althought cardiac tamponade is rarely caused by tuberculosis, this condition remains common in endemic countries such as morocco and affect younger population, hence the importance of a better knowledge of its prevalence and and multidisciplinary management and more importantly the treatment of the underlying cause using combined antibacillary medication that has shown satisfying results. 1. the main perceived limiting factor is the absence of a standardized didactic program, followed by mentor's availability in residents' perception and by mentor's experience in consultants' one. pocus teaching is present although not optimal and not homogenous in italian acc residency schools. standardisation of residents' ultrasound curriculum is suggested to improve ultrasound teaching. the study included a convenience sample of critically ill patients with supradiaphragmatic cvcs and a cxr for confirmation. us is used for direct confirmation of the guidewire in the internal jugular (ijv) or subclavian (scv) vein and visualizing the guidewire in the right atrium. to evaluate for pneumothorax, "sliding sign" of the pleura was noted on us of the anterior chest. results: 34 patients have been included, 35% of the catheters have been placed in the scv and 65% in the ijv. it was possible to confirm the position of the cvc tip for 70.6% (23 correct, 1 incorrect cxr) of 34 (figure 1 ). overall, it was not possible to identify the guide in the right atrium 11 cases (10 false negatives, 2 of them due to the presence of defibrillator leads). regarding the 1 case where an incorrect position was seen on cxr it was also detected on ultrasound: us of the inserted vein and a negative tte confirmation. in all cases it was possible to exclude a pneumothorax by us. these results show that bedside ultrasound might be a feasible technique to confirm the cvc positioning. it is important to note that the level of the operator's expertise is significant when assessing the feasibility of this method. we only had a limited sample size and the occurrence of only one misplaced catheter. these preliminary results need to be confirmed on a larger scale. central venous catheter (cvc) misplacement occurs more frequently after cannulation of the right subclavian vein compared to the other sites for central venous access. misplacement can be avoided with ultrasound guidance by using the right supraclavicular fossa view to confirm correct guidewire j-tip position in the lower part of the superior vena cava. however, retraction of the guidewire prior to the cvc insertion may dislocate the j-tip from its desired position, thereby increasing the risk of cvc misplacement. the aim of this study was to determine the minimal guidewire length needed to maintain correct guidewire j-tip position throughout an us-guided infraclavicular cvc placement in the right subclavian vein. methods: 100 adult intensive care patients with a computed tomography scan of the chest were retrospectively and consecutively included in the study. the distance from the most plausible distal puncture site of the right subclavian/axillary vein to the junction of the right and left brachiocephalic veins (= vessel length) was measured using multiplanar reconstructions. in addition, measurements of the equipment provided in commonly used 15-16 cm cvc kits were performed. the minimal guidewire length was calculated for each cvc kit. the guidewires were up to 90 mm too short to maintain correct j-tip position throughout the cvc insertion procedure in seven of nine commercial cvc kits. four of these are shown in table 1 . when us guidance is used to confirm a correct guidewire j-tip position, retraction of the guidewire prior to the cvc insertion must be avoided to ensure correct cvc-tip positioning. this study shows that most of the commonly used 15-16 cm cvc kits contain guidewires that are too short for cvc placement in the right subclavian vein. the reliability of lung b-lines to assess fluid status in patients with long period of supine introduction: ultrasound-guided cannulation is usually done using either longitudinal or transverse approach. the oblique approach utilizes advantages of both these approaches allowing visualization of the entire course of needle including tip and lateral discrimination of artery from vein [1] . the reported incidence of the complete overlap of femoral vein by the femoral artery is 8-10 percent [2, 3] . we describe the use of the oblique approach for successful cannulation of such a femoral vein which is not possible by usual approaches (figure 1 ). endothelial cells play a pivotal role in the atherogenic process. endothelial cell dysfunction (ed) is the main risk factor for cardiovascular diseases such as hypertension, coronary heart disease (chd) and peripheral occlusive disease (pod). these diseases significantly increase the risk for perioperative complications. therefore, identifying patients with ed is important and should influence our prospective perioperative strategy. however, sensitive tools to diagnose ed are still missing and do not belong to our standard of care. aim of this study was the validation of a new non-invasive method to detect ed and a correlation with a set of established an new endothelial biomarkers. the cohort includes 20 preoperative patients without anamnestic relevant cardiovascular disease and 20 patients with known peripheral occlusive disease (pod). we used non-invasive endopat® technology from itamar-medical to measure ed by changes in vascular tone before and after occlusion of the brachial artery and calculate a reactive hyperemia index (rhi). in addition, we measured established markers and alternative biomarkers potentially indicate vascular diseases such as substrates and products from the no-metabolism l-arginin, asymmetric/symmetric dimethylarginine (adma/sdma), von-willebrand factor (vwf) and sphingosine-1-phosphate (s1p). rhi was able to identify patients with pod. rhi was significant lower in patients with clinical signs and symptoms of pod (p<0.05). among other markers adma was significant higher in pod patients compared to controls and correlates with rhi. the pad technology is a helpful non-invasive functional test to measure ed and seems able in identify patients with vascular disease. in future, a combination of anamnesis, new diagnostic tools and biomarkers may further increase our sensitivity in identifying risk-patients. single-lumen 5fr and triple-lumen 6fr peripherally inserted central catheters (piccs) for cardiac output assessment by transpulmonary thermodilution s d´arrigo 1 achieving effective critical care in low-and middle-income countries is a global health goal [1] , which includes the provision of effective point of care ultrasound [2] . we sought to establish zambia's first focused critical care echocardiography training programme in a 16bedded icu at university teaching hospital, lusaka. the programme was accredited by the uk intensive care society fice programme, with teaching adapted for local disease patterns such as tuberculous pericardial effusions. parasternal, apical and subcostal windows were used to assess ventricular dysfunction, hypovolaemia, pleural effusion, alveolar interstitial syndrome and pneumothorax. zambian doctors working with critically ill patients received an intensive one-day course, followed by mentored scanning at the bedside. teaching was delivered by visiting fellows from the uk who are accredited in echocardiography and experienced ultrasound educators. patients with abnormal mean ci or hr suffer from increased hospital mortality. abnormality of mean svi was not associated with mortality. these data support accurate measurement of ci as a hemodynamic target and the normal range defined for ci. since ci also carries the hr information, ci seems to be the more important target than svi. our data cannot necessarily be interpolated to less invasive and less precise measurements of ci. an evaluative study of the novelty device with the function of auto-aspirating and pressure indicator for safety central venous catheterization ly lin, wf luo, cy tsao national taiwan university hospital, taipei, taiwan critical care 2020, 24(suppl 1):p203 previous studies have shown that 0.8% of cvc attempts resulted in arterial punctures that were not recognized by blood color. to overcome the problem, our team has developed a concept of pressure detecting syringe that can indicate the artery puncture [1] . based on previous research, different springs, the actuator of the design, have been evaluated to optimize the proposed device and reduce the risk of cvc procedure. tested devices -the inner-spring is set between the pressure indicator and plunger (fig. 1a ). three springs are tested. test condition -blood samples were simulated by glucose solution with absolute viscosities of 2 and 6 mpa-s. different blood pressures were applied to simulate the artery and vein (fig. 1b) . the response time (rt) is defined as the time required to show the indicating signal (is) which is the movement of the piston from the position in fig. 1b : a2-1 to a2-2. the rt is strongly influenced by spring (fig. 1b) but every design can show the is when pressure is higher than 50 mmhg, the assumed minimum artery pressure. the rt of s1, the strongest spring design, is about 10s in the 50mmhg-pressure and high viscosity condition. during our tests we found the user can realize the is before the position be fully changed from fig. ib : a2-1 to a2-2. thus, we believe the 10s rt, the worst case, is still acceptable. we also found the weak spring force may lead to difficulty to empty the syringe because the spring must to overcome the blood pressure and the friction between the piston and barrel. as a result, it was difficult for s3 to absolutely empty the syringe even if the blood pressure is only 30 mmhg. the spring will be compressed as fig. 1b : a2-2 and fail to push the piston when pushing the plunger forwardly, which is not acceptable in clinical use. the results indicate the feasibility of using the device to facilitate cvc and we believe the s1 or s2 are more suitable for the future application. introduction: models using standard statistical features of hemodynamic vital sign waveforms (vs) enable rapid detection of covert hemorrhage at a predetermined bleed rate [1] . by featurizing interactions between vs we can train powerful hemorrhage detectors robust to unknown bleed rates. waveforms (arterial, central venous, pulmonary arterial pressures; peripheral and mixed venous oxygen saturation; photoplethysmograph; ecg) of healthy pigs were monitored 20 min prior and during a controlled hemorrhage at 20 ml/min (n=38) and 5 ml/min (n=13). two sets of vs features were extracted: statistical features [1] and maximal pairwise cross correlations between pairs of vs within a 5s lag over various time window sizes (30s, 60s, 180s, 300s); and normalized with pre-bleed data of each given animal. for each feature set, a tree-based (ert) model [2] was trained and tested in a one-animal-out setting to mitigate overfitting on the 20 ml/min cohort, and another trained on the 5 ml/min and tested on the 20 ml/min cohort. we evaluated models with activity monitoring operating characteristics curves [3] that measure false alert rate as a function of time to detect bleeding. models using cross-correlations show no significant deterioration of performance when applied to detect bleeding at different rates than trained for, while standard models require 64s longer on average to detect hemorrhage at 1% false alert rate in the previously unknown setting ( figure 1 ). correlations between vs data encode physiologic responses to hemorrhage in a way independent of the actual bleed rates. this enables training effective hemorrhage detectors using only limited experimental data, and using them in practice to detect bleeding that occurs at rates other than used in training. we validated a dataset of 634 data lines containing hemodynamic variables and treatment options. we selected nine hemodynamic variables as inputs. furthermore, data were collected regarding underlying conditions: heart failure, septic shock, renal failure or respiratory failure or a combination. we applied datastories regression on the dataset (turnhout, belgium, www.datastories.com). six different interventions were analyzed as kpi: administration or removal of fluids, increasing or decreasing inotropes and increasing or decreasing vasopressors. finally, we elaborated and challenged 63537 predictive models to generate a decision algorithm to predict each kpi. we first looked at how each hemodynamic parameter impacts the prediction of each kpi individually and performed a standard correlation analysis as well as a more involved analysis of the mutual information content between each kpi and all other hemodynamic parameters individually. confusion matrix and variable importance was obtained for each kpi. the baseline hemodynamic parameters were: gedvi 738±218 ml/m2, evwli 11.2±5.5 ml/kg pbw, svv 14.8±8 %, mbp 77.8±16.5 mmhg, hr 94.2±23.5 bpm, ci 3.3±1.2 l/min.m2. the results of the regression analysis identified the different variables of importance for each of the different interventions ( fig 1a) . based on these results the hemodynamic variables (hr, mbp, gedvi, elwi, ci, svv) were used to develop the final hemoguide prediction model ( fig 1b) . the hemoguide app can be used to advise physicians with respect to basic therapeutic decisions at the bedside or as an educational tool for students. with the collection of new data, the accuracy of the system may grow over time. the next step of the project is to develop a more-sophisticated suite: the icu cockpit. feedback function contributes to accurate measurement of capillary refill time r kawaguchi 1 , ta nakada 2 , m shinozaki 2 , t nakaguchi 2 , h haneishi 2 , s oda 2 1 chiba university, department of emergency and critical care medicine, chiba, japan; 2 chiba university, chiba, japan critical care 2020, 24(suppl 1):p206 capillary refill time (crt) is well known as an indicator of peripheral perfusion. however, it has been reported to have an intra-observer variance, partly because of manual compression and naked-eye measurement of the nailbed color change. we hypothesized that a we developed a novel portable crt measurement device with an oled display that feedbacks weather the strength of the nailbed compression is enough and counts the time. we settled the target strength and time as 5n and 5seconds according to the study we reported before [1] . 20 examiners measured crt with and without the feedback function. the pressing strength and time during the measurement were evaluated. there was a significant difference among the pressing strength and time between the crt measurement using the device with and without the feedback function (strength: p<0.001; time: p<0.001). furthermore, intra-examiner variance was significantly reduced with the feedback function (strength: p<0.001; time: p<0.001). in all measurements without the feedback function, 41% was outside the optimal strength while the measurements with the feedback function 100% achieved the targeted range. without the feedback function, 12% could not reach the optimal time, while 100% with the feedback function did. in total, 49% of the measurements could not achieve the optimal pressing strength and time. the feedback function for crt measurements, guiding examiners to an optimal pressing strength and time, fulfilled the required measurement conditions and reduced intra-examiner variance. our novel portable device would assist an accurate crt measurement regardless of personal work experience. introduction: the aim of the study was to detect the difference of conjunctival microcirculation between septic patients and healthy subjects and evaluate the course of conjunctival microcirculatory changes in survivors and non-survivors over a 24 hours period of time. this single-centre prospective observational study was performed in mixed icu in a tertiary teaching hospital. we included patients with sepsis or septic shock within the first 24 hours after icu admission. conjunctival imaging using idf videomicroscope as well as systemic hemodynamic measurements were performed at three time points: at baseline, 6 hours and 24 hours later. baseline conjunctival microcirculatory parameters were compared with healthy control. a total of 48 patients were included in the final assessment and analysis. median apache ii and sofa scores were 16 (12-21) and 10 (7-12) respectively. 44 (92%) were in septic shock, 48 (100%) required mechanical ventilation. 19 patients were discharged alive from the intensive care unit. we found significant reductions in all microcirculatory parameters in the conjunctiva when comparing septic and healthy subjects. we found a significant lower proportion of perfused vessels and microvascular flow index (mfi) of small vessels during all three time points in non-survivors compared with survivors. in nonsurvivors we observed no significant changes in conjunctival microcirculatory parameters over time. however, survivors had significantly improved mfi of small vessels at second and third time points compared to first time point. microcirculatory perfusion in conjunctiva was altered in septic patients. over 24 hours evaluation survivors in comparison with nonsurvivors had better microcirculatory flow with incremental improvement of microvascular flow index. 16 healthy pigs were centrally cannulated for veno-arterial ecmo and precision flow probes were placed on the pulmonary artery main trunk for reference. 10ml boluses of iced 0.9% saline chloride solution were injected into the ecmo circuit and right atrium at different ecmo flow settings (4, 3, 2, 1 l/min). rapid response thermistors of standard pa-catheters in the ecmo circuit and pulmonary artery recorded the temperature change. after calibration of the catheter constants for different injection volumes in the ecmo circuit, the distribution of injection volumes passing each circuit was assessed and enabled calculation of pulmonary blood flow. analysis of the exponential decay of the signals allowed assessment of right ventricular function. calculated blood flow correlated well with true blood flow (r 2 = 0.74, p < 0.001, figure 1 panel a, individual measurements organ congestion is susceptible to be a mediator of adverse outcomes in critically ill patients. point-of-care ultrasound (pocus) is widely available and could enable clinicians to detect signs of venous congestion at the bedside. the aim of this study was to develop prototypes of congestion scores and to determine their respective ability to predict acute kidney injury (aki) after cardiac surgery. this is a post-hoc analysis of a prospective study in 145 patients for which repeated daily measurements of hepatic, portal, intra-renal vein doppler and inferior vena cava (ivc) ultrasound were performed before surgery and during the first 72 hours after cardiac surgery [1] . five prototypes of venous excess ultrasound (vexus) scores combining multiple ultrasound markers were developed (figure 1 ). the association between each score and aki was assessed using timedependant cox models as well as conventional performance measures of diagnostic testing. a total of 706 ultrasound assessments were analyzed. we found that defining severe congestion as the presence of severe flow abnormalities in multiple doppler patterns with a dilated ivc (>2cm), corresponding to grade 3 of the vexus c score, showed the strongest association with the development of subsequent aki compared with other combinations of ultrasonographic features (hr: 3. there is an increasing awareness on the consequences of fluid administration in patients leading to the development of methods that evaluate the effects of fluids loading on the cardiocirculatory system. however, most of methods used in the clinical practice investigate the effects of fluids on the cardiac function, instead of investigating those on the determinants of venous return. besides volume of fluids, the determinants of fluid loading are the blood volume distribution and the availability of vascular bed. in this study we aimed to test non-invasively the effects of fluids administration on the venular compartment in the skeletal muscle. in addition to the mean systemic filling pressure (msfp), we calculated changes in the stressed and unstressed volumes (vs, vu) and the venular bed availability. we enrolled 10 critically ill patients in our intensive care unit. we assessed volumes and pressures by the near infra-red spectroscopy on the forearm using graded venous occlusions in steps of 5mmhg from 50 to 0 mmhg. the msfp, vu and vs were measured as previously reported (microcirculation 2014; 21:606-614). the vascular bed availability was measured by changes in the volume recruited from the occlusion maneuvers. all the measures were done at baseline and after a fluid load ranging from 250 to 500 ml. values were expressed as median and interquartile range. wilcoxon test was used to compare data and a p< 0.05 was considered as significant. introduction: hypotension is a common side effect of general anesthesia (ga) and is associated with organ hypoperfusion and poor perioperative outcome [1] . post-induction hypotension (pih) is caused by the depressant cardiovascular effect of anesthetic drugs and could be amplified by hypovolemia. the aim of this study was to assess the ability of two echocardiographic fluid responsiveness markers to predict pih: the inferior vena cava collapsibility index (ivc-ci) and the velocity time integral change (δvti) after passive leg raising. sixty patients > 50 years of age and scheduled for elective surgery were included. ivc-ci and δvti were measured before ga induction. anesthesia protocol, fluid infusion and vasopressor administration were standardized in all patients. pih was defined as a mean arterial pressure (map) <65 mmhg or a relative decline from pre-induction value of at least 30% within 12 minutes of ga induction. receiver operating characteristic (roc) curve analysis was used. the optimal cutoff was selected to maximize the youden index (sensitivity + specificity − 1). the measurement of ivc-ci and/or δvti were unsuccessful in seven patients (11.6%). pih occurred in 32 patients (incidence 53 %). the areas under the roc curves ( figure 1) preload responsiveness might be detected by the changes of cardiac index (δcimini) induced by a "mini-fluid challenge" (mini-fc) of 100 ml or even by the changes (δcimicro) in response to a "micro-fluid challenge" (micro-fc) of 50 ml. however, the smaller the fluid challenge, the larger the "grey zone" of diagnostic uncertainty. we tested whether (1) micro-and mini-fc monitored by calibrated pulse contour analysis detect preload responsiveness and (2) adding 50 ml when the result of a micro-fc is within the grey zone improves diagnostic accuracy. in 30 patients with circulatory failure, we infused 50 ml saline over 30s followed by 50 ml over 60s. we measured δcimicro and δcimini by the pulse contour analysis (picco2). preload responsiveness was defined by an increase in ci (δciplr) during a passive leg raising test ≥10%. diagnostic uncertainty was described by calculating the grey zone after bootstrapping. δcimicro were larger in responders than in non-responders (5. for the micro-fc, the area under the receiver operating characteristic curve was 0.975±0.03 (threshold 1%), while it was 0.955±0.03 for the mini-fc (threshold 4%). for the micro-fc, the grey zone ranged from 0.82% to 3.47% and included 9 (30%) patients. for the mini-fc, it ranged from 2.8% to 6.8% and included 9 (33)% patients, among which 6 were already in the grey zone of the micro-fc. when evaluated by pulse contour analysis, micro-and mini-fc reliably detect preload responsiveness but with a large diagnostic uncertainty. it seems that adding 50ml more fluid to a micro-fc when its result is within the grey zone does not improve the diagnostic accuracy. the study is ongoing. the starling-sv bioreactance device (cheetah medical) reliably detects passive leg raising (plr)-induced changes in cardiac index (δci). we tested whether it can also track the small and short-time δci induced by the end-expiratory occlusion (eexpo) test, and whether shortening the time over which it averages cardiac output (24 s in the commercial version) improves the detection. in 42 mechanically ventilated patients, during a 15-sec eexpo, we measured δci (in absolute value and in percentage) through calibrated pulse contour analysis (ci pulse , picco2 device) and starling-sv. for the latter, we considered both ci starling-24 provided by the commercial version and ci starling-8 obtained by averaging the raw data over 8 s. we calculated the correlation between δci pulse and both δci starling-24 and δci starling-8 , and the area under the receiver operating characteristic curve (auroc) to detect preload responsiveness, defined by a plr test. when considering absolute values, the correlation coefficient r between δci pulse and δci starling-24 was 0.362 (p=0.02), which was lower than the one between δci pulse and δci starling-8 (rr comparison). when considering percentage changes, no correlation was observed between δci pulse and δci starling-24 . conversely, the correlation coefficient between δci pulse and δci starling-8 was 0.402 (p=0.01), but it was lower than the one obtained for absolute values (p=0.04 for r comparison). eexpo-induced δci starling-8 , both in absolute values and in percentage, detected preload responsiveness with aurocs of 0.90 (sensitivity 83%, specificity 87%) and 0.89 (sensitivity 83%, specificity 79%), respectively. shortening the averaging time of the bioreactance signal increases the reliability of the starling-sv device to detect eexpo-induced δci. moreover, the accuracy of the method is increased when absolute rather than percentage changes of ci are considered. fluids are among the most prescribed drug in intensive care, particularly among patient with circulatory failure. yet, very little is known about their pharmacodynamic properties and this topic has been left largely unexplored. there is a lack of strong scientific evidence in current guidelines for fluid administration in shock. several factors may impact the hemodynamic efficacy of fluids among which the infusion rate. the aim of this study was to study the influence of fluids administration rate on their pharmacodynamics in particular by studying mean systemic pressure (p ms ). we conducted a prospective observational study in 17 patients with circulatory failure to compare two volume expansion strategies. when a patient required a fluid bolus, 500 ml of normal saline were administered and several hemodynamic parameters were recorded continuously: cardiac output (co), arterial pressure (ap), mean systemic pressure (p ms ). infusion rate was let to the discretion of the attending physician and a "slow" and a "fast" group were determined based on the median of the infusion time. fluids effect was measured by the area under the curve (auc), maximal effect (e max ) and time to maximal effect (t max ) for each hemodynamic variable. results: p ms auc was higher in the "fast" group compared to the "slow" group (p=0.043). we observed a shorter t max and a higher e max for p ms in the "fast" group compared to the "slow" group (p=0.039 and 0.02 respectively). regarding co, t max was also shorter in the "fast" group (p=0.041). auc and e max were similar between the two groups. fluid effect dissipated within 60 minutes following the end of fluid infusion for every patient in both groups. the decreasing slope from maximal effect was comparable in the groups, for p ms and co alike. the effect of a 500 ml fluid bolus in septic shock patients vanished within one hour. a faster infusion rate increased maximal effect and shortened the delay to reach it. study is ongoing. fluid management in the control arm of sepsis trials aa anparasan, ac gordon, mk komorowski imperial college london, department of surgery and cancer, london, united kingdom critical care 2020, 24(suppl 1):p219 in the past, high-volume intravenous fluid resuscitation in severe sepsis and septic shock was common. more recently, concerns over the harmful effects of this practice have led some clinicians to adopt less liberal fluid strategies. we sought to analyse temporal trends in fluid administration in the control arms of recent adult sepsis trials and assess any correlation with patient severity and mortality. a literature search was conducted to identify relevant randomized controlled trials that reported fluid administration published post 2000. we recorded 4 outcomes: total amount of iv fluid administered in the control arms of these trials between hospital admission and hour 6 and hour 72 following trial enrolment, mortality rates at the latest reported time point and apache-ii score at admission. we computed the pearson correlation coefficient and linear regression between study dates and the 4 outcomes. we identified 9 relevant trials [1] [2] [3] [4] [5] [6] [7] [8] [9] , which recruited a total of 2,444 patients in their control arms, from 1997 to 2018. the temporal analysis revealed no obvious trend in the in the total volume of iv fluid given by hour 6 following trial enrolment (correlation p=0.94) ( figure 1 ). however, the total volume of fluid given by hour 72 decreased significantly over the period of interest (r=-0.78, p=0.02). in parallel, we observed a decrease in mortality (r=-0.6, p=0.08) but there was no evidence of decrease in illness severity over time (p=0.84). we found that in published rcts over the last two decades, the amount of intravenous fluid given to patients with sepsis in the initial 6 hours did not appear to change, however less intravenous fluid was given over the first three days. upcoming large rcts will test the safety and efficacy of restrictive fluid administration approaches in sepsis. clinical practice guidelines recommend prompt intravenous (iv) fluid resuscitation for pediatric sepsis, including an initial fluid bolus of 20 ml/kg [1] . however, recent evidence is conflicting as to the effectiveness, volume, and consequences of aggressive fluid resuscitation in septic children. therefore, we sought to determine the epidemiology of early iv fluid resuscitation in an integrated health system, specifically at community hospital emergency departments (ed). we studied a retrospective cohort of pediatric patients (ages > 1 month to < 18 years) with sepsis identified in electronic health record data at 11 community eds in southwestern pennsylvania from 2010 to 2014. sepsis was defined as 1) suspected infection (combination of fluid culture collection and administration of antibiotics and 2) organ dysfunction (pediatric sofa score ≥ 1) within 24 hours of suspected infection. fluid bolus therapy was defined as electronic documentation of administration of 0.9% normal saline iv bolus within 1 hour of the time of sepsis onset. results: among 1,247 patients with pediatric sepsis, 513 (41%) received iv fluid bolus therapy within 1 hour of time of sepsis onset. the volume of fluid administered ranged from 2 ml/kg to 67 ml/kg (figure 1 , panel a), corresponding to a median volume of 20 ml/kg (iqr 17-22 ml/kg). patients who received ≥ 20 ml/kg of fluids (n = 258, 50%) were younger (mean age 5 years, sd 5 vs. 9 years, sd 6; p<0.001), more often had blood cultures collected during evaluation (86% vs. 76%, p=0.003), and were more often transferred to another facility (48% vs. 33%, p<0.001) when compared to patients who received < 20 ml/kg of fluids (n = 255, 50%). mean fluid bolus volume within 1 hour of time of sepsis onset by hospital ranged from 12 ml/kg to 24 ml/kg (figure 1, panel b) . in a cohort of community emergency departments, 41% of septic children received intravenous fluid boluses within one hour, and of those, only one half received volumes concordant with guidelines. (figure 1 ). a wide range of fluid balance exists in septic shock patients cared for in icu. trends of serum albumin in septic and non-septic critically ill introduction: the link between hypoalbuminaemia and poor outcomes in critical care is well established [1] . limited data are available on serum albumin trends during critical illness [2] . in this study we assessed trends in serum albumin for up to 7 days in both septic and non-septic critically ill patients. we retrospectively examined the records of 1107 adult patients admitted to critical care at the royal liverpool university hospital between 2008 and 2014. we then excluded patients who did not have albumin data available for the first 7 days, leaving us with 758 patients. 506 patients (66.8%) had sepsis, and of these patients 116 had died by day 28. of the 252 non-septic patients (33.2%), 40 patients had died by day 28. albumin levels were collected for 7 days from admission to critical care, in addition to other demographic and biochemical data. statistical analysis was performed using repeated measures analysis. septic patients had lower serum albumin than non-septic patients throughout the 7 day period (p<0.001). we observed a decrease in albumin by day 2 in all groups, with levels increasing over the subsequent days. there was no difference in daily serum albumin between non-septic patients who survived or died. this is the first study, to our knowledge, to compare albumin trends in septic and non-septic critically ill patients over 7 days. further research is needed to elucidate the optimal recipients and timing of albumin therapy. introduction: burn injury is characterized by marked inflammation, capillary leakage, and profound hemodynamic alterations. early albumin resuscitation is avoided fearing a paradoxical fluid escape into the interstitium. on the other hand, administration of crystalloids in massive amounts causes tissue edema and fluid extravasation, which deteriorates tissue perfusion by increasing oxygen diffusion distance. albumin administration could reduce the amount required to maintain hemodynamic stability in this population. we investigated whether albumin improves tissue perfusion and microcirculation by reducing tissue edema. this is an observational study conducted in the burn unit of maasstad hospital, rotterdam. patients with burns higher than 15% of total body surface area (tbsa) were included in the study. sublingual microcirculation was measured at admission (t0), 4(t4), and 12(t12) hours after burn injury. total vessel density (tvd) and functional capillary density (fcd) were analyzed. fluid management was calculated according to the modified parkland formula. albumin (20%) infusion was started 12 hours after the burn insult. a total of nine patients were recruited between january and december 2019. patients were included in the study after 5.7±2.3 hours of the insult with a mean tbsa of 36±22%. the amount of crystalloid infusion was 2718±3348 ml and 8501±5230 ml at t0 and t12,respectively. within the first 12h (t12) 502±386 ml albumin was given. tvd decreased from 23.6±2.2 at t0 to 20±1.3 at t4 (p<0.05) (figure 1) introduction: spontaneous bacterial peritonitis (sbp) accounts for ≥24% of the bacterial infections that occur in patients with cirrhosis, and sbp has a high mortality rate (20% to 50%). albumin infusion has been shown to improve the outcome of sbp. the aim of this study is to examine the impact of albumin infusion on hospital length of stay (los) for cirrhotic patients with sbp. we utilized a nationwide electronic health record data set (cerner health facts®) to extract real-world data on adult patients (≥18 years old) with cirrhosis and sbp who received antibiotics and admitted between january 1, 2009, and april 30, 2018. international classification of diseases (icd-9/10) codes were used to identify cirrhosis and sbp. we used laboratory data for calculation of the model for endstage liver disease sodium (meld-na) score and vital signs data for calculation of the quick sepsis related organ failure assessment (qsofa) score at baseline for each encounter. a generalized linear model was used to assess the relationship between albumin infusion and hospital los. results: there were 2,131 encounters that identified patients with sbp and cirrhosis, of which 1,661 survived hospitalization. albumin was infused within 24 hours of admission ('early albumin') in 43% (n=718), after 24 hours in 31% ('late albumin', n=517), and not administered in 26% ('no albumin', n=426). meld-na was higher at presentation in early albumin cases versus late-or no-albumin cases (mean 24.0 and 19.5). unadjusted los was lower in patients receiving early albumin (8.7 days versus 10.4 days). risk-adjusted analysis demonstrated that early albumin led to a 17.5% reduction in los (95% ci 12.6%-22.2%, p = <0.0001). in these real-world data, albumin infusion within 24 hours of admission in patients with cirrhosis and sbp was associated with a shorter hospital stay despite more severe illness. early albumin may not only improve clinical outcomes but may also reduce the costs of hospitalization in cirrhotic patients with sbp. early albumin use in patients with septic shock is associated with a shorter hospital stay: real-world evidence in the united states introduction: septic shock is among the most common critical care illnesses and incidence is rising, with mortality in excess of 35%. septic shock predisposes patients to multiple organ failure. while albumin is effective in management of circulatory dysfunction in septic shock, its utilization in this population is understudied in the us. we evaluated the impact of albumin utilization on hospital length of stay (los) among septic shock patients. we used a nationwide electronic health record data set (cerner health facts®) to extract real-world data on adult patients (≥18 years old) with severe sepsis or septic shock, admitted between january 1, 2013, and april 30, 2018, identified by international classification of disease (icd-9/10) codes, and receipt of antibiotics and vasopressors. we calculated the charlson comorbidity index (cci) and the acute physiology score (aps) at baseline. a generalized linear model was used to examine the association between albumin and hospital los, especially accounting for the timing of albumin infusion. we identified 3,156 unique visits for septic shock patients that survived to discharge. albumin was infused within 24 hours of admission ('early albumin') in 15%, after 24 hours ('late albumin') in 20%, and not administered in 65%. both cci and aps were higher, at presentation, in early albumin cases than late-or no-albumin cases (mean: 7.49 and 7.17, and 51.50 and 43.23, respectively). unadjusted los was slightly lower in patients receiving early albumin (11.81 days versus 11.84 days). a risk-adjusted analysis demonstrated that early albumin was associated with 4.92% shorter los (95% ci 0.43%-9.22%, p = 0.0322). albumin infusion within 24 hours of admission was associated with a shorter length of hospital stay. early albumin infusion may lead to better outcomes and reduced costs in patients with septic shock. further research is being conducted to assess other potential benefits of early albumin administration in this patient population. every new septic event follows by hemodynamic instability may lead sequentially to decreased organ perfusion, multiple organ failure. acute renal failure is recognized clinical feature during sepsis (up to 40-50% in all cases). furthermore, urine output close monitoring is a cornerstone diagnostic clinical tool in each septic critically ill patient. in present study, we analyzed the dynamic minute-to-minute changes in the urine flow rate (ufr) and also the changes in its minute-to-minute variability (ufrv) during new septic event in critically ill patients. demographic and clinical data were extracted from the of 50 critically ill patients who were admitted to the icu and developed new septic event (followed by fever and leukocytosis) and analyzed. a foley catheter was inserted into the urinary bladder of each study patient. the catheter was then connected to electronic urinometer, a collecting and measurement system which employs an optical drop detector to measure urine flow. the urine flow rate variability (ufrv) is defined and calculated as the change in ufr from minute to minute. results: ufr and ufrv both decreased significantly immediate after new septic episode until beginning fluid resuscitation (ppvalues <0.001) (figure 1) . statistical analysis by the pearson method demonstrated a strong direct correlation between the decrease in ufr, ufrv and the decrease in the map (r=0.03, p=0.003; r=0.03, p=0.004) ( figure 1 ), and heart rate (r=0.12,p=<0.001) since systemic pressure starts to drop. ufrv and ufr demonstrated good clinical response to fluid administration despite the fact that systemic blood pressure did not improve (figure 1) . we consider that dynamic changes in ufrv and ufr could potentially serve as a more sensitive signals ofclinicaldeterioration during the new septic event in critically ill patients.we also suggest that those parameters mightbeable to identify the optimal end-point of fluid resuscitative measures in septic critically ill patients. diminished urinary output (uo) is largely used as marker of acute kidney injury (aki) in critically ill patients. we aimed to explore the role of urinary output on incidence and mortality of aki developed during icu admission. the study population consists of all patients admitted between 2007 and 2018 to one of the dutch icus included in the nice database with an icu length of stay of at least 48 hours, having daily measurement of creatinine and uo. only patients without renal replacement therapy that have a serum creatinine lower than 1.1 mg/dl (97.5 μmol/l) or a uo above 0.5 ml/kg/h on the day of the index icu admission were considered at risk for aki. patients were followed during their icu stay and classified according to the highest kdigo criteria reached based on creatinine alone (model 1) and creatinine plus uo (model 2) using icu admission serum creatinine as baseline. in both models, patients were classified as: no aki, renal impairment at the first day of icu admission, aki stage 1, aki stage 2, and aki stage 3. we identified 52,863 patients (60% male, mean age 63 years, median icu-los 4 days). of those, 51.2% of patients had renal impairment at the first day of icu admission. among the remaining patients, 44.4% in model 1 and 29.9% in model 2 were classified as having no aki, 2.6% and 1.4% as aki stage 1, 0.7% and 9.3% as aki stage 2, and 1.1% and 8.2% as aki stage 3, respectively. survival at 30-day markedly differed according to the aki classification model used (figure) . similarly, adjusted hrs for 30-day mortality differed among patients with and without aki compared to patients with renal impairment at the first day of icu admission ( figure 1) . among patients admitted to the icu 50% had renal impairment at the first day of icu admission. our findings suggested that uo plays an important role both on aki incidence and mortality and should be carefully interpret in the clinical setting especially in aki stage 2 classification. introduction: acute kidney injury (aki) mostly attributed to renal tubular damage, has a high morbidity and mortality outcome [1] , so a sensitive tool to assess the degree of tubular affection is needed for early detection and management of this condition. we investigated the ability of furosemide stress test (fst) (one-time bolus dose of 1mg/kg or 1.5 mg/kg if on prior furosemide-intake) to predict progression to akin stage-iii in critically ill subjects with early aki. we studied 80 subjects; 40 consecutive patients in group i receiving fst and 40 consecutive patients in group ii receiving standard medical management for aki;15 patients (37.5%) and 20 patients (50%) met the primary endpoint of progression to akin-iii in groups i and ii respectively. patients with progressive aki had significantly lower urine output following fst in the first 6 hours (p<0.033). the area under the roc curves for the total urine output over the first 2 hours following fst to predict progression to akin-iii was 0.87 (p = 0.001). the ideal-cutoff for predicting aki progression during the first 2 fig. 1 (abstract p227) . thirty-day survival according to aki classification model 1 and model 2. hazard ratios (hrs) for 30-day mortality adjusted by sex, age, type of admission, apache iv score, sofa score at day of admission (excluded renal sofa score) for patients with aki classified with model 1 and model 2 fig. 1 (abstract p226) . clinical correlation between urine flow rate variability (ufrv) and ufr and mean arterial blood pressure over new septic event (black arrows) and and after initial fluid resuscitation (red arrows). note: the ufrv and ufr decreased progressively in parallel with the falling mean arterial blood pressure and, than, rose again after the administration of fluids hours was a urine volume of less than 325 milliliters with a sensitivity of 87.1% and specificity 84.1% group receiving fst. on the other hand, statistically significant hypotension, hypo-(kalemia, phosphatemia and magnesemia) occurred in group i. the fst in patients with early aki could predict liability for progression of aki, however it should be performed under adequate monitoring. introduction: ischemia-reperfusion (ir) causes renal dysfunction and damage. ir induces renal tubular injury triggered by hypoxia and hyperoxia, mediated by oxidative stress and inflammation. furosemide inhibits na + -k + -2clcotransporter in the thick ascending limb of the renal medulla to decrease na + reabsorption, reducing oxygen consumption. we investigated if furosemide could improve renal oxygenation, function and damage by reducing o 2 consumption and oxidative stress after ir. methods: 24 wistar albino rats were divided into 4 groups, with 6 in each group; sham-operated control (c), control + furosemide (c+f), ir and ir+f. after anaesthesia (bl), 45 min supra-aortic occlusion was applied to ir and ir+f groups followed by 15 min (t1) and 2 hours of reperfusion (t2). furosemide 50μg/kg/h infusion was simultaneously administered to c+f and ir+f after ischemia. systemic hemodynamic, renal blood flow (rbf), renal vascular resistance (rvr), renal oxygen delivery (do 2ren ), renal oxygen consumption (vo 2ren ), creatinine clearance (ccr), sodium handling, urine output (uo), cortical (cμo2) and medullar (mμo2) microvascular oxygenation were measured. results: rbf was reduced in ir (2.1±1) and ir+f (2.3±1) at t1 (p<0.05) but it was further reduced in ir+f (1.9±1) (p<0.05) at t2 compared to c and c+f. rvr was increased in ir (5338±2860) and ir+f (5123±2517) at t1 compared to c. rvr was normalized in ir (2198±879) but not in ir+f (4232±2636) at t2 compared to c (p<0.05). cμo 2 and mμo 2 did not differ between groups after ir insults (figure 1 ). tissue o 2 was reduced at the medulla, but not at the cortex in ir+f group compared to ir. do 2ren and vo 2ren were reduced in ir (56±17 and 26±12 ml/ min) and ir+f (34±20 and 21±14) at t2 (p<0.05). pc was higher in ir+f (37.33±4.27) compared to ir 29.67±3.39 (p<0.05). vo 2 / tna + was increased in ir+f compared to ir. no change in ccr and uo was observed. furosemide after ir causes further impairment of renal perfusion, energy utilization and renal oxygenation resulting in renal damage. acute renal failure induced by hypoxemia: incidence and correlation study a trifi 1 , h fazzeni 2 , a mehdi 2 , c abdennebi 2 , f daly 2 , y touil 2 , s abdellatif 2 , s ben lakhal 2 1 la rabta hopital, medical intensive care unit., tunis, tunisia; 2 la rabta hopital, tunis, tunisia critical care 2020, 24(suppl 1):p230 introduction: acute renal failure (arr) is a common complication in icus and usually caused by hypoperfusion. arf induced by hypoxemia is a concept rarely reported in icu. its incidence and pathogenesis are not well understood. we aimed to study the relationship between hypoxemia and the occurrence of arf. retrospective cohort study including patients with hypoxemia whatever its etiology between january 2016 and august 2019. patients with chronic renal failure were excluded. arf was defined and ranked according to the kdigo criteria 2012. arterial blood gas, urea, creatinine and clearance were reordered on the first, third and seventh days of evolution. results: 50 patients were included and 2 groups were obtained: group of hypoxemic patients with arf (arf+, n=30): versus group of hypoxemic patients without arf (arf-, n= 20). the incidence of hypoxemie-induced arf was therefore 60%. clinical characteristics were comparable in both groups with a mean age of 47 ± 16 and a sex ratio of 1.77. the comparative study showed in arf+ group: a lower ph (7. .25], p = 0.023). the most significant correlation was showed with mdrd clearance at day 3 and p/f ratio at day 1 (rho = 0.338, p = 0.038). multivariate analysis found that septic shock and non invasive ventilation in hypoxemic patients were the factors related to arf with respectively or=11.08, 95% ci=1.56-83.84, p=0.016 and or=6.18, 95% ci=1.16-34.07, p=0.033. overall mortality was 68% (n=34) and arf was an independent factor of mortality: or=6, and 95% ci=1.35-26.64, p = 0.017. hypoxemia-induced arf is a common complication associated with excess mortality. our study suggests that renal function is correlated with the degree of hypoxemia and that this correlation is rather distinct 48 hours from hypoxemia. in preclinical models of sepsis, we have previously demonstrated that activation of amp activated protein kinase (ampk) using metformin, improves survival and organ function. thus, ampk activation is a potential therapeutic target in sepsis, and we hypothesize that exposure to metformin during sepsis is associated with decreased aki and mortality methods: retrospective analysis of a 13-hospital cohort of adult icu patients with type 2 diabetes mellitus (t2dm) who presented sepsis. we investigated if exposure to metformin during the hospitalization was associated with reduced 90-day mortality and aki. we used 1:4 propensity score matching (psm), propensity score stratification (pss) and propensity score weighting (psw) based on the probability to be exposed to metformin using 55 covariates. for psm an exact match for insulin, amputation, cardiovascular diseases, retinopathy, charlson index, egfr, hba1c, and apache iii, were used. sepsis was defined using sepsis 3 criteria, and aki as kdigo stage 2 or 3. from 164,910 patients, we found 673 diabetic adults exposed to metformin during hospitalization and 14,174 who were not. metformin exposure during hospitalization is associated with decreased 90-day mortality and aki in septic adult patients with t2dm. these findings suggest that metformin may constitute a potential therapeutic strategy in sepsis, and the potential role of ampk activation as a protective mechanism. however, studies are needed to confirm this association and the specific mechanisms of action. introduction: acute kidney injury (aki) may occur up to 50% in the intensive care unit (icu). predicting aki recovery may allow for risk stratification of patients, patient and family counseling, and early post-discharge renal care planning. however, predicting aki recovery at an early stage remains a challenge. methods: this is a retrospective study of the epanic multicenter randomized controlled trial database [1] , which was split into development (n=2194) and validation (n=2446) cohorts, and patients experiencing aki stage 3 and/or renal replacement therapy (rrt) in the icu were included [2] . aki recovery was defined as being alive, without any stage of aki, and without need of rrt at hospital discharge. a logistic regression model with backward feature elimination was developed. the model performance was assessed by discrimination, calibration, and net benefit analysis, and internally validated with ten-fold cross validation. only the results in the development cohort are reported. of the 229 patients who developed aki3, 86 patients (37.55%) recovered from aki. the multivariable model selected age, bilirubin, heart rate, mean arterial blood pressure, surgical diagnostic group on icu admission, mechanical hemodynamic support on icu admission, suspected sepsis on icu admission as aki recovery predictors. the model had a mean area under the receiver operating characteristic curve (auroc) of 0.75 (standard deviation (sd) 0.01), mean calibration slope of 1.02 (sd 0.04), and mean calibration-inthe-large of <0.01 (sd 0.01) (figure 1 ). at the classification threshold that maximized sensitivity and specificity, mean net benefit with respect to treat-none was 0.16 (sd 0.01) and mean net benefit with respect to treat-all was 0.11 (sd 0.01). by using the routinely collected clinical data, the developed prediction model can fairly identify patients with a higher chance of aki recovery at hospital discharge. introduction: acute kidney injury (aki) is a frequent complication in critically ill patients and is associated with increased morbidity and mortality. sepsis is one of the most common cause of aki. a prospective study was conducted over 6 months (january 01-june 30, 2018).we included patients with septic shock at admission or at any time during hospitalization.the aki staging was based on kdigo criteria.patients were divided into two groups, a group with aki (aki+) and a group without aki (aki-).then we compared the baseline characteristics, laboratory and physiologic data. patients with aki (aki+) were subdivided according to their prognosis. were enrolled 75 patients. the mean (sd) age was 56.43(±18) years.sex ratio was 1.91. fifty-two (70%) patients developed aki.sapsii and sofa score in admission were higher in patients with kidney injury [59 vs 44 points (p= 0.002), 6.5 vs 4 points ;(p=0.003)] respectively.the serum lactate level was significantly higher in (aki +) group patients during the first day of septic shock [6.12± 1.38 mmol/l (aki+)vs 4.11± 0.79 mmol/l(aki-);(p=0.002) ] and its clearance was lower [(32±10.99% (aki +)vs 61±13%(aki-);(p=0.001)]. a significant difference was observed in c reactive protein level [224±114 mg/l (aki +) vs 124±77 mg/l (aki-) ; (p=0.004)].among (aki+) patients, kadigo iii was observed in 59.6% of cases.nineteen (36.5%) patients received hemodialysis.a normal kidney function was recovered in 40.4% of cases.aki+ patients had a higher occurrence in disseminated intravascular coagulation (32 vs 3 patients, p=0.002),acute respiratory distress syndrome (18 vs 2 patients; p=0.023) and cardiac dysfunction (20 vs 1 patient, p= 0.001).mortality was higher in aki group (67% vs 9%; p=0.001). the development of septic aki was associated with poor outcomes and prognosis.a better understanding of sepsis induced aki pathway will enable us to develop targeted therapeutic protocols.newer tools,permitting aki early detection, may make these therapies more fruitful. this study aims to show that contrast procedures do not significantly increase the risk of renal injury and should not be deferred. traditionally ciaki is the most important cause of in-hospital renal failure after nephrotoxic drugs and shock. problem is also the non-uniform definition of ciaki proposed by three different initiatives (akin, esur and kdigo). akin, being the most rigorous, defines ciaki as an increase in serum creatinine >0.3 mg/dl or >50% of baseline within 48hours. a retrospective observational single-centre cohort study analyzed 82 patients who underwent a contrast procedure with iomeron 350. the first group underwent a ct pulmonary angiography (ctpa), and the fig. 1 (abstract p232 ). internally validated model performance: (top row) roc curve; (middle row) calibration curve; (bottom row) decision curve second a coronary angiography with pci. no patient was previously prepared (raas blockade removal, crystalloid administration etc). we studied demographics, history of ckd and comorbidities and their impact on the ciaki by the akin criteria. a total of 82 patients were divided into two groups (ctpa and pci). ctpa group (20m, 21f) all had acute pe and the pci group (28m, 13f) were treated for acs. the mean age was 69 and 65 years respectively. ckd was more prevalent in the pci group (8pt vs. 3pt) possibly explained by the more advanced atherosclerotic disease. advanced chd (nyha iii/iv) was found in 3pt (pci) vs. 2pt (ctpa) while diabetes and shock were equally distributed (11pt and 5pt) in both groups. the mean amount of contrast was significantly higher in the pci group (242.3ml vs. 60ml). the mean creatinine/egfr measured before and after contrast in the ctpa group was 87. the goal of this study was to determine whether changing the body mass (bm) with fat-free mass (ffm) in cockcroft-gault (cg) formula could provide a more accurate prediction of aki in obese patients undergoing cardiac surgery. in this retrospective study, we reviewed institutional data of patients who underwent elective cardiac surgery in a tertiary referral university hospital. baseline patient creatinine value was collected and gfr was estimated using the mdrd, ckd-epi and cg formulas. cg formula was further modified by replacing the bm with ffm derived from the bioelectrical impedance analysis. postoperative aki was defined by kdigo creatinine change definitions. accuracy of the egfr values to predict the aki was calculated with roc-auc analysis. all the calculations were performed in different categories of bmi. figure 1 ). the egfr is a poor predictor of aki in obese patients undergoing cardiac surgery. the ffm modified cauckraft-gault formula yield more accuracy in this specific group. retroaki: a ten-year retrospective study of acute kidney injury in intensive and progressive care units introduction: acute kidney injury (aki) is a frequent condition in intensive care units (icu) and progressive care units (pcu), affecting 15% to 70% of the patients, depending on the studied population and aki definition. aki has been identified as an independent risk factor of icu mortality and development of chronic kidney desease. the objective of this study was to describe the incidence of each aki stages as defined by kdigo definition (with evaluation of urine output, serum creatinine and initiation of renal replacement therapy (rrt)), in a mixed medical and surgical population of patients hospitalized in icu and pcu over a 10-year period (2008-2018). we included all patients who stayed more than 12 hours in icu or pcu of edouard herriot hospital from may 2008 to january 2019. data used to classify the patients were the urine output over a sixhour period, serum creatinine and the need for rrt, according to kdigo classification results: 18,882 hospital stays were analyzed. median icu/pcu length of stay was 3 days [iqr: 1.5-6.6]. among icu patients, 74% had at least one aki episode graded 1, 2 or 3 and 49% had at least one severe episode (stage 2 or 3). among pcu patients, 44% had at least one episode of aki and 20% a severe episode of aki. patients had an average of 1.9 episodes of aki per stay. table 1 represents the incidence of maximal aki stage during one stay. we found that urine output was the more frequent criteria to make diagnosis of aki stage 1 or 2 whereas rrt was more frequent for aki stage 3. this retrospective study reports a more important aki incidence in our icu/pcu than in previous studies. the difference could be fig. 1 (abstract p236) . when comparing auc in different categories of bmi, the mcg appeared to be the only statistically accurate formula in patients with bmi 30-34.9 explained by the difficulty to collect urine output from conventional database. serum creatinine and the use of rrt are often the only two criteria used to define and classify aki. these results confirm the high incidence of aki in icu and pcu and the importance to make an early aki screening of patients for whom preventive nephroprotective actions are needed. introduction: icu-patients with acute kidney injury (aki) requiring renal replacement therapy (rrt) are at risk for infections [1, 2] . in this study we evaluated the incidence of infection in icu patients with and without less severe aki. finally, impact on outcomes was explored. this is a retrospective study on the pdms (protection data management system) of the 4 adult icus of a university hospital. aki was assessed on kdigo criteria (creatinine (scr) and urine output), during the first 7-d of icu stay. infection was validated in the pdms by a team of icu specialists. results: during a 4-year period, a total of 7485 subjects were enrolled. aki was diagnosed in 64.7% of patients during icu stay. aki patients were older (63 vs. 59 y, p=0.001), had higher saps 2 (57 vs. 41, p< 0.001), and had more urgent icu admission (64% vs. 48%, p<0.001). more aki patients had mechanical ventilation (55% vs. 41%, p<0.001) and vasopressors on d-1 (47% vs. 23%, p<0.001). aki stage 1, 2, and 3 was present in 25.5%, 28.0% and 11.1% of patients. more aki patients had infection (57% vs. 28%, p<0.001) and increasing aki stages were associated with higher infection rates (aki-0: 28%; aki-1: 55%, aki-2: 55%, aki-3: 69%, p<0.001) (figure 1 ). we observed 2-3 times higher mortality in aki patients with infection, and a stepwise increase of mortality with increasing aki stages. after correction for infection and other confounders we found that all aki stages were associated with in-hospital mortality (ors aki-1: 1.7, aki-2: 2.0, aki-3: 3.6, all p< 0.001). over half of aki patients experienced an episode of infection and increasing aki severity was associated with higher infection rate. aki patients with infection had marked higher mortality, suggesting that infection was an important driver of outcome. however, after adjustment, aki stages had strong association with hospital mortality. several new biomarkers have been introduced to improve early diagnosis of acute kidney injury (aki). "nephrocheck" (nc; astute medical, usa) is a bedside test calculating "akirisk" (product of urinary concentration of the cell cycle arrest-markers timp-2 and igfbp7). several studies suggest the usefulness of nc in selected populations. however, the value of early routine measurement of nc is unclear. methods: therefore, we compared the prediction of a combined endpoint (cep: death <60 days and/or requirement of renal replacement therapy rrt) by nc within 12h of icu admission (nc1) and 24h later (nc2) with admission values of serum-creatinine, bun, cystatin c, urinary ngal, apache ii and sofa (roc-analysis). as a secondary endpoint we investigated the additional value of pathological measurements of nc1≥0. 3 critically ill patients showed increased relative uce in the first days of icu admission, which may be attributed to higher protein catabolism. increased relative uce was associated with arc and both had no effect on 90-day mortality. introduction: this study compared epidemiology, short-and long-term outcomes for patients with community-acquired (ca) and hospital-acquired (ha) acute kidney injury (aki). we retrospectively analyzed all episodes of aki over a period of 3.5 years (2014-2017) on the basis of routinely obtained serum creatinine measurements in 103,161 patients whose creatinine had been measured at least twice and who had been in the hospital for at least two days. we used the "kidney disease: improving global outcomes" (kdigo) criteria for aki and analyzed the first hospital admission. a total of 103161 were admitted in hospital and fulfilled the inclusion criteria. average observation period per patient was 248 days. the incidence of ca-aki among included hospital admissions was 9.7% compared with an incidence of 8.6% of ha-aki, giving an overall aki incidence of 18.3%. patients with ca-aki were younger than patients with ha-aki (64 vs 66.2y) and had significantly less comorbidities, including preexisting cardiac failure, ischemic heart disease, hypertension, diabetes. patients with ca-aki were more likely to have stage 1 aki (69,3 vs 58,4%, p<0.001) and had significantly shorter lengths of hospital stay than patients with ha-aki (14 vs 24d, p< 0.001). those with ca-aki had better survival than patients with ha-aki (figure 1; p<0 the evidence base for management of fluid removal during renal replacement therapy (rrt) is limited. a recent international survey revealed the extent of practice variation worldwide [1] . our aim was to summarise the responses from europe-based healthcare professionals who participated in the survey. the international self-administered, cross-sectional, internet-assisted, open survey was disseminated between january 2018 and january 2019 via website links and emails to members of different critical care societies. results: 485 participants from 31 european countries completed the survey of whom 365 (75%) were intensivists and 306 (63%) worked in university-based hospitals. persistent oliguria / anuria was the most common indication for fluid removal (51% responders). the parameters which guided fluid removal included hemodynamic status (47% responders), cumulative fluid balance since admission (23% responders), and 24-hour fluid balance (17% responders). 90% of participants reported using crrt with a median net ultrafiltration rate 98 ml/hr (iqr 51-108ml/hr) for hemodynamically unstable and a rate of 300 ml/hr (iqr, 201-352ml/hr) for hemodynamically stable patients. only 26% of practitioners checked net fluid balance hourly (70% nurses, 16% physicians). new hemodynamic instability, defined as new onset or worsening tachycardia, hypotension, or need to start or increase the dose of vasopressors was reported to occur in 20% fig. 1 (abstract p242 ). long-term survival patients (iqr 10.0-30.0). different strategies to re-gain hemodynamic stability were used. (figure 1 ) main barriers to fluid removal were patient intolerance (72% physicians, 85% nurses) and interruptions in fluid removal (43% physicians, 64% nurses). the majority of participants agreed that guidelines and protocols would be beneficial. the practice of fluid removal during rrt is very variable across european countries. nurses and doctors identified a need for evidencebased protocols and clear guidelines. introduction: kidney disease improving global outcomes (kdigo) guidelines suggest the use of anticoagulation in continuous renal replacement therapy (crrt) [1] . the effectiveness of the anticoagulation is important because replacing the hemofilter and tube interrupts crrt and increases total therapy time. regional citrate anticoagulation (rca) and unfractionated heparin (ufh) are most commonly using methods for crrt anticoagulation [2] . the aim of this study was to investigate the efficacy, safety and metabolic differences of the patients in icu who underwent crrt and anticoagulation method changed from ufh to rca for different reasons. after ethics committee approval (2019-14/9) 100 patients who underwent crrt between 2018-2019 at bursa uludag university hospital icu have been investigated and 11 patients who underwent crrt by both rca and ufh included in the study. we divided patients in two groups (rca, ufh), demographic data (sex, age), sofa score, creatinine, urea, mean filter life time (flt) and ultrafiltration flow (uf), platelets, electrolytes (na, k, ca, mg), lactate, nahco3 and ph of groups at beginning and ending of first rca and ufh hemodialysis collected. we used t-test and 1000 bootstraps statistic tests. in agreement with other studies [3, 4] , flt and uf was statistically significant lower in ufh group (table 1) . there was no statistically significant difference in efficiency (urea and creatinine decrease), ph, lactate, nahco3 level, platelets count and electrolytes between two groups. to our knowledge, there are no studies comparing these two anticoagulation methods in the same patients. small number of patients and retrospective evaluation are limitations of the study. our results suggest that the implementation of rca method is safe and effective as ufh method with longer flt and uf. regional citrate anticoagulation during crrt in liver failure mj jain, pk kumar g, dg govil, jk kn, sp patel, ms shafi, rh harne, dp pal, sm monanga medanta the medicity, critical care, gurugram, india critical care 2020, 24(suppl 1):p245 continuous renal replacement therapy (crrt) with regional citrate anti-coagulation (rca) is increasingly being used as a treatment modality in critically ill patients. there is limited experience of use of citrate anticoagulation patients with acute liver failure and acute on chronic liver failure who pose a tough challenge of being at a higher risk for bleeding. an institutional protocol was formulated for use of commercially available citrate solutions and the same was studied to assess filter life and safety of citrate in liver disease. the primary objective was to assess safety of citrate anticoagulation in liver disease. this study was a single centre, prospective, non-randomized, single arm, observational study. all adult patients, with acute liver failure and acute on chronic liver failure requiring crrt were included. blood ionized calcium levels of 0.9 to 1.1mmol/l was targeted throughout the therapy and total to ionized calcium ratio of less than 2.4 was maintained. rca was stopped if the ratio was more than 2.4 for 2 consecutive assessments. incidence of citrate accumulation and toxicity were assessed. average filter life was also assessed. metabolic parameters, electrolytes and strong ion gap were followed till 24 hours after completion on crrt. a total of 25 patients were included in the study. nineteen patients of acute on chronic liver failure and 6 patients of acute liver failure underwent crrt with rca. baseline average serum bilirubin, lactate and inr were 11.8 mg/dl, 6.4 mmol/l and 2.1 respectively. the average filter life was 50 hours 3 minutes. citrate accumulation took place in (n=13) patients and rca had to be stopped for ( n=6) patients due to the same. none of the patients had evidence of citrate toxicity. citrate anticoagulation was well tolerated in patients with acute liver failure in patients with or without pre-existing chronic liver disease on crrt. introduction: the intention of this study is to highlight the levels of citrate load for the general population that increases the risk of citrate complications (insufficient trisodium citrate delivery; net citrate overload and citrate accumulation) [1] . this was a prospective data collection between february and march 2019 in a fourteen bedded critical care unit. eleven consecutive episodes of crrt were collected (a new episode characterized if crrt was discontinued for 48 hours and above). one episode was excluded due to short duration (less than 4 hours). patients undergoing rca-crrt received either a fixed 25 or 35 ml/kg/h effluent dose protocol. median patient age was 59, male 100%. average time on crrt was 4.1 days (2-9). 70% of the patients had complications, although 60% were minor ( figure 1 ). all of the patients with net citrate overload had citrate loads of 13.8mmol/h or above. the main risk factors were found to be shock and liver impairment which occurred in 60% of cases of which 40% developed complications. a fixed dose effluent protocol to standardise practice can potentially lead to a higher risk of minor complications. in our experience this is likely due to a lack of appropriate monitoring for rca-crrt complications. despite this, our complication rate of citrate accumulation is in line with that reported in literature. citrate loads in our 25 ml/kg/ hr protocol were 22.6% higher than our 35 ml/kg/hr protocol and strongly related to higher complication rate that worsened in patients with risk factors for poor citrate metabolism. introduction: there is no optimal timing of continuous renal replacement therapy (crrt) in acute kidney injury (aki); however, it is based on volume overload, azotemia, hyperkalemia and severe metabolic acidosis [1] . an important reason for metabolic acidosis in aki is increased unmeasured anions (ua) [2] . delta-ph-ua (δph ua ) detects the degree of metabolic acidosis caused by ua and is calculated by using 'the partitioned ph model' [3] . in this study, we investigated whether δph ua was a predictor to start crrt in patients with aki. the study was designed as a multicentric, prospective, observational study in 2019. patients who were ≥18 years old and diagnosed with aki [1] were included. the moment aki was diagnosed, arterial blood gas, albumin, magnesium, inorganic phosphorus, urea, creatinine and δph ua values were recorded. all patients were divided into two groups as crrt(-) and crrt(+) which consists of patients performed crrt due to traditional criteria. fig. 1 (abstract p246) . incidence of complications introduction: continuous renal replacement therapy (crrt) is labor intensive and requires advanced nursing knowledge and skills. however, 40% of registered nurses (rn) are less than 2-year post-registration experiences in our unit. also there is an increasing demand of crrt from 185 crrt days in 2017 to 248 crrt days in 2018. the obstacles for crrt in our department, includes variation of regimen, complicated workflow and insufficient training of nurses. a continuous quality improvement project is carried out to standardize the regimen, enhance workflow and provide structured training to nurses in the intensive care unit, to enhance nursing competence. methods: introduction: sepsis and septic shock is a leading cause of mortality in the intensive care unit. we tried to evaluate a novel hemoperfusion cartridge through a retrospective evaluation of patient's data in our centre. we used it as an adjuvant therapy in our patients with sepsis and septic shock due to varied causes. the aim of this study was to evaluate the efficacy of therapeutic hemoperfusion cartridge (hc-foshan biosun medical ® ) in the management of patients with sepsis. we retrospectively analysed data of group 1 (n=30 sepsis) and group 2 (n=30 sepsis+hemoperfusison; sepsis treated with hemoperfusion cartridge) admitted between 2015 to 2018. group 2 had received hemoperfusion cartridge as adjuvant therapy along with standard of care. demographic data, procalcitonin [1] and leukocyte levels before and after therapeutic cytokine removal and duration of hc were recorded. while the mean duration of cvvhdf was 96.4 hours, the duration of hemoperfusion cartridge (application was 32.1±16.4 hours). among 30 patients who survived 25 patients were administered hemoperfusion cartridge within 12 hours of icu admission. there was a significant reduction in scores like apache and sofa score post hemoperfusion cartridge therapy procalcitonin and leucocyte levels after therapeutic hemoperfusion cartridge were found significantly lower than the pretreatment values (respectively p=0.001, p=0.001). retrospective analysis showed significant reduction of vasopressors, and improvement in map in group2. therapeutic hemoperfusion cartridge with cytokine removal applied with cvvhdf in septic patients have positive contributions to provide survival advantage. removal of activated leukocytes and endotoxin from the blood is a complex therapeutic effect of the device for removing endotoxin. in the main group (16 patients with abdominal septic shock) after surgery, the traditional treatment was supplemented with two sessions of endotoxin removal (2 hours each with an interval of 24 hours) using "alteco lps adsorber" (sweden). the control group consisted of 8 patients with a similar diagnosis and only traditional treatment. results: 28% of white blood cells were adsorbed in lps adsorber. among them, granulocytes (35%) were maximally extracted, then cd14 + monocytes (cd14 + mo) (33%), hla-dr + mononuclear cells (6%), monocytes (2%). il-6, il-10, procalcitonin (pct) were not adsorbed. the 28-day mortality rate in the main group was 50% and was lower compared to the control group -75%. during monitoring, in the main group 24 hours after the first removal of endotoxin, a decrease in the initially increased amount of activated cd14 + mo by 2.2 times, as well as functionally mature defensin + granulocytes (def + gran) by 1.6 times was observed. il-6, il-10, and pct decreased by 1.9; 17.8; and 1.2 times, respectively. during this period, the control group showed an increase in cd14 + mo and def + gran, while il-6, il-10 did not change, and pct increased 1.9 times. a day after the second removal of endotoxin and then 5 days later, the main group of il-6, il-10, and pct continued to decline. in the control group, only il-10 decreased after 3 days, the rest continued to grow. the cellular adsorption of endotoxin-bound cd14 + mo and mature def + gran is an important part of the mechanism of action of the endotoxin removal device. does the endotoxin adsorption of pmx column saturate in 2 hours? preliminary study c yamashita 1 in the euphrates trial, the polymyxin b-immobilized fiber column (pmx) hemoperfusion (hp) had no significant effect on 28-day mortality. endotoxin (lps) burden by endotoxin activity assay >0.90 may exceed 50 μg [1] , so the dose and duration of pmx-hp could be insufficient to lower the lps burden. to confirm this issue, we experimented in a closed-circuit with 24 h continuous lps addition, and pmx can adsorb > 50μg [2] . further, lps concentration became constant within 2 h in the single lps spike test for determining pmx-hp duration [3] . to prove our hypothesis that the single lps spike test reflects the adsorption equilibrium, and not saturation, we added lps intermittently to reaction. methods: lps (10 ng/ml) was mixed with 125 ml deactivated fetal calf serum as a reflux solution, as previously described [2] ; this concentration is much higher than that observed in septic patients. we created a closed circuit that incorporates pmx-01r at 1/14 th the amount of an adult pmx and performed pmx-hp at 10 ml/min for 5 h. lps was added in two shots (post 2 h: 1250 ng, 10 ng/ml; post 4 h: 3750 ng, 30 ng/ml). lps was measured using the limulus amebocyte lysate test at 0, 0.5, 1, 2, 3, 4 and 5 hr. after an initial decrease between 0 and 1 h, lps concentration did not decrease between 1 and 2 h after pmx-hp initiation. post lps pulse addition at 2 h, it increased and then decreased till 3 h. futher, it did not decrease between 3 and 4 h, but it increased and then decreased again after lps pulse addition post 4 h (figure 1 ). lps adsorption rates were 76.2, 43.4, and 40.7% at 2, 4, and 5 h, respectively. conclusions: lps adsorption capacity of pmx-01r was maintained even after two additional shots of lps, suggesting that the constant lps concentration in the previously reported lps spike test might be indicative of adsorption equilibrium rather than saturation. a coohort study included 65 patients admitted to three intensive care with sepsis / septic shock ( sepsis 3 criteria ) and aki ( akin score). all patients were submitted to cvvhdf with the oxiris filter (baxter, usa) . the main clinical data, il 6, procalcitonin, endotoxin ( eaa ) and sofa score were evaluated at basal time ( t0 ) and at the end of the treatment ( t1 ). all data are expressed as mean ± sd or median and iqr . anova test was used to compare the changes in the time. results: 60 patients were submitted to rrt with the oxiris filter for 46 ± 12 hours . 21 patients had aki 3 stage , 13 patients aki 2 stage and 25 patients had aki 1 stage. at t0 all groups had an high vasopressor fig. 1 (abstract 251) . lps concentration in lps pulse addition test support to maintain map ≥ 70 mmhg. il6, procalcitonin eaa and sofa total were also elevated with no difference between the groups. at t1 creatinine improved better in aki 2 ( p< 0.001 vs. t0 ) and in aki 1 ( p< 0.0001 vs t0) then in aki 3 group. map increased in aki 2 ( p< 0.01 vs t0) and aki 1 ( p < 0.01 vs t0) , but not in aki 3 group. il6, procalcitonin decreased more in aki 1 ( p < 0.0001 vs t0) then aki 3 . at t 2 sofa total was higher in aki 3 then aki 1 ( p< 0.001 ) and aki 2 ( p< 0.01 ). conclusions: aki 2 and aki 1 stage patients submitted to bp with the filter oxiris respond better then aki 3 stage patients . 2 -this transalte in a better clinical course. 3-crrt with oxiris filter is useful in septic patients with aki, but aki 3 stage septic patients represent an high risk group. a non-interventional, multicenter, non-randomized patient registry for multiple organ dialysis with the advos system multiple organ failure is a challenging problem in the icu. as an advanced dialysis system, the advos procedure can eliminate watersoluble and protein-bound substances, regulate the acid-base balance as well as fluid and temperature. in 2017, a national registry was established to collect data under "real-life" conditions of patients treated with advos without any trial-specific interventions (drks id: drks00017068). methods: data from 01/2017 to 02/2019 from 4 german hospitals (university hospitals in hamburg-eppendorf, mainz, essen, and klinikum weiden) were analyzed. clinical parameters, treatment settings and adverse events were documented. the 28-and 90-day mortality rates were compared with extrapolated rates based on the sofa score. results: 118 patients with a median age of 60 years (iqr 45-69), of whom 70 (59%) were male, were evaluated. patients had a median sofa score of 14 (iqr: 11-17) before the 1st advos treatment, which is associated with an expected mortality of 80%. the number of failing organs was 3 (iqr 2-4): cardiovascular (74%), lungs (57%), liver (47%), kidneys (74%), coagulation (69%) and cns (29%). 429 treatments with a median duration of 16 (iqr: 10-20) hours were evaluated. 87 were discontinued, of which 25 (6%) were due to a device error. 79 adverse events were documented, 13 were related to the device (all due to clotting and recovered without sequelae). significant removal of protein-bound (bilirubin: 11.2 vs 9.2 mg/dl) and water-soluble toxins (bun 32 vs 20 and creatinine 1.9 vs 1.4 mg/dl). in addition, improvement in acid-base balance was observed: ph (7.33 vs. 7.40), bicarbonate (21.3 vs. 25.5 mmol/l) and base excess (-4.5 vs. 1.0 mmol/l) ( table 1) . 28-and 90-day mortality rates were 60% and 65%, respectively. in a cohort of patients with multiple organ failure, we observed an improvement in the expected mortality rate, especially if the advos procedure was applied early. adverse events are comparable to other dialysis therapies in intensive care patients. introduction: acute kidney injury (aki) due to ischemia-reperfusion affects onethird of the patients in cardiac surgery. we investigated the potential role of cyclosporine (csa) to prevent postoperative aki and mitigate inflammatory response to extracorporeal circulation (ecc). methods: double-blind, randomized, placebo-controlled single-center study. patients (n=67) scheduled for elective cardiac surgery were randomized to 2,5 mg/kg csa or placebo before the surgery. the primary objective was to assess the role of csa to reduce the incidence of postoperative aki. the secondary objective was to study csa induced changes in the inflammatory response to ecc. results: all enrolled patients were analyzed. postoperative aki was more pronounced in the cyclosporine group compared to placebo. or=5.03 (1.76-15.74), 95% ci. the cytokine production in response to ecc was not affected by cyclosporine (figure 1) . in patients undergoing cardiac surgery, a single preoperative dose of csa does not prevent the postoperative decrease in renal function. csa does not alter cytokine release in response to extracorporeal circulation. elevated post-ecc levels of pro-inflammatory cytokine il-6 are associated with kidney dysfunction and may be predictive. new generation adsorbent such as oxiris r was introduced as novel technique in renal support for critically ill patients [1] . septic shock patients require decatecholaminization strategies emphasizing blood purification to remove catecholamine-producing mediators and evacuate overload fluid in interstitials. our 64-year-old female patient, admitted to icu after surgery with history of ovarium cancer. her septic shock was worsened with ards, hypercoagulable state and aki. vasopressors were set. patient was controlled with mode simv16,ps12,tv350 ml,peep7,fio270%. renal support was implemented by diuretic and cvvh started on the second day. at first,regular adsorbent was used, post-filter mode was set, and periodic fluid removal target was 50 ml/h. but after 24hours, no significant changes observed. oxiris r added and after 12 hours passed, requirements of vasopressors reduced, tidal volume increased, hemodynamic parameters stabilized, urine production increased. it was continued for 2 days and patient was recovered. our patient had fallen into inadequate cars stage in which not able to counter septic effects on vital organs (figure 1 ). renal would be primary target for filtration and monitoring tool. adsorbent consisted of an69 and polyethyleneimine was useful to purify blood from endotoxins conjoined with slower filtration. continuous yet cautious process in cvvh evacuate fluid and mediators while maintain steady hemodynamics. biomarkers could not be evaluated due to limited resources, but improving parameters could be signs that showed recovery process had already took place. advanced hemofiltration is a privilege. implementing and enhancing it with new generation adsorbent would increase survivors by extracting unnecessary fluids and eliminating catastrophic endotoxins and mediators. consent to publish: written informed consent for publication was obtained from the patient. analysis of retrospective cohort study data of 120 patients (pt) treated for dka at icu of kaunas clinics during 2014 -2019 has been carried out. serum kalemia, glycemia; hypokalemia, hypoglycemia episodes; rate of insulin interruption for hypo-and normoglycemia during ketoacidosis; use of nah 2 co 3 for ketoacidosis, and los in icu were analysed. spss 23.0 was used for statistic calculations. traits evaluated as significant at p < 0.05. at the beginning of dka treatment in totally hypokalemia (3.1 ± 0.3 mmol/l) was recorded in 64/120 pt (53.3 %). due to ignoring of blood ph (6.8 -7.3 (7.0 ± 0.1) kalemia was falsely misinterpreted as "normo-" or "hyper-" 3.5 -7.1 (5.1 ± 0.9 mmol/l) in 49/68 pt (72.1 %), thus disregarded so complicated by obvious hypokalemia additionally in 26/49 pt (53.1 %). in hypokalemia los in icu was 52.9 ± 29.7 vs 32.8 ± 18.6 h, p < 0.05. insulin use has caused hypoglycemia (1.2 -3.3 (2.5 ± 0.7 mmol/l)) in 22/120 pt (18.3 %), los in icu 63.2 ± 38.5 vs 38.9 ± 21.2 h, p < 0.05.insulin use was interrupted in case of normoand hypoglycemia with still persisting ketoacidosis in 39/120 pt (32.5 %), los in icu was found to be 56.5 ± 30.7 vs 37.0 ± 22.5 hr, p < 0.05. nah 2 co 3 was given for symptomatic treatment of ketoacidosis during first 10 h of dka in 33/120 pt (27.5 %) with stable hemodynamic: hco -3 buffer has increased (4.8 ± 3.3 -7.9 ± 3.1 mmol/l), p < 0.05, but it didn't control ketoacidosis, and los in icu was 55.2 ± 27.5.2 vs 39.1 ± 25.6 h, p < 0.05. hypokalemia, hypoglycemia, precocious interruption of insulin use were recorded as complications of dka treatment. all of them have prolonged los in icu. symptomatic treatment of ketoacidosis with nah 2 co 3 had no effect on it, and prolonged los in icu as well. a growing interest exists about co 2 derived parameters in shock management. central venous-arterial pco 2 difference (p cv-a co 2 ) is strictly related to cardiac output; central venous-arterial pco 2 difference to arterial-central venous o 2 content difference ratio, p cv-a co 2 / c a-cv o 2 , has been proposed as anaerobic metabolism when it's >1.4 mmhg/ml [1] . to evaluate p cv-a co 2 /c a-cv o 2 reliability in detecting anaerobic metabolism, we analyzed it in 7 consecutive patients affected by mala admitted to our icu, considering these patients as a prevalent anaerobic metabolism model. we calculated, by douglas formula, central venous-arterial co 2 content difference to arterial-central venous o 2 content difference ratio, c cv-ca co 2 /c a-ccv o 2 , as a respiratory quotient surrogate. we performed arterial and central venous blood gas analysis simultaneously at admission, we calculated p cv-a co 2 , p cv-a co 2 /c a-cv o 2 and c cv-a co 2 /c a-cv o 2 and we recorded scvo 2 . we verified relationship between p cv-a co 2 /c a-cv o 2 and scvo 2 and arterial ph, arterial lactates, sofa score at admission and c cv-a co 2 /c a-cv o 2 by linear regression analysis. pcv-aco2/ca-cvo2 greatly increases in mala (2.16 ± 0.84). pcv-aco2/ ca-cvo2 (fig.1) shows significant co-variation with ph (r2=0.618; p= 0.003) and sofa score at admission (r2=0.628; p=0.003). pcv-aco2/ ca-cvo2 has poor agreement with ccv-aco2/ca-cvo2 (r2=0.008) and disagrees with it in identifying anaerobic metabolism, in our series, in fact, ccv-aco2/ca-cvo2 is, in 3 patients, < 1 like an aerobic rq value. pcv-aco2/ca-cvo2 shows better agreement with ph, sofa score and lactate level than scvo2. in our series, p cv-a co 2 /c a-cv o 2 is good illness and acidosis severity marker, but it seems to be affected by ph value in accord with haldane effect [2] . p cv-a co 2 /c a-cv o 2 , in our study, doesn't seem to be a reliable anaerobic metabolism marker nor a rq surrogate. it is thought that early administration of basal insulin to patients with diabetic ketoacidosis (dka) may improve outcomes. small studies have shown trends towards decreases in time to closure of anion gap (tcag), rates of rebound hyperglycemia following discontinuation of intravenous (iv) insulin, rates of hypoglycemia, intensive care unit (icu) length of stay (los), and hospital los [1] [2] [3] [4] . this was a single-center, retrospective chart review of our institution's dka protocol between january 2010 and august 2019. patients that received early basal insulin within 24 hours of initiation of iv insulin and before closure of the anion gap (ag) were compared to those that did not receive early basal insulin. the primary outcome was median tcag. secondary efficacy outcomes include: time on iv insulin infusion, time to de-escalation of level of care, hospital los, and re-elevation of ag. secondary safety outcomes included incidences of hyperglycemia, hypoglycemia, and hypokalemia. a total of 334 patients were identified meeting inclusion and exclusion criteria. median tcag was longer in the experimental group (9 vs. 6 hours, p <0.01). incidence of re-elevation of ag and incidence of hyperglycemia were lower in the experimental group. other outcomes were similar (figure 1 ). early administration of basal insulin to patients with dka resulted in a longer tcag with a lower incidence of re-elevation of ag and hyperglycemia. early administration of basal insulin appears to be safe with respect to hypoglycemia and hypokalemia. glycaemic control continues to be a challenge in critically ill patients. stress induced hyperglycaemia has been associated with increased morbidity and mortality [1] . conversely, patients receiving intensive glucose control have a higher risk of death [2] . a quality improvement project was designed to develop a comprehensive insulin protocol that recognized pre-existing diabetes and reduced hypoglycaemia. data was collected prospectively in all adult patients admitted to the rah intensive care unit (icu) between october 2018 and august 2019 from the national icu audit database and electronic patient records. daily figures were collected for numbers of hypoglycaemic episodes (<4mmol/l), "in range" (4-10mmol/l) blood sugar measurements and patients with a pre-existing diagnosis of diabetes. data was collected and analysed using microsoft excel. results: 307 patients were identified; 56 patients (18.2%) had pre-existing diabetes. a total of 6908 blood sugar measurements were reviewed; 5268 (76.3%) were "in range" and 126 hypoglycaemic episodes (1.8%) occurred. there was no significant correlation between number of diabetic patients and measurements within range. of note, there was an increase in number of measurements per patient in the second half of the time period (11 vs 32). the development of this protocol has improved glycaemic control in our icu. there are considerably fewer episodes of hypoglycaemia and a large proportion of blood sugar measurements are in range. we hope to continue data collection and interrogate the prevalence of pre-existing diabetes further to reduce glycaemic variability. the optimal management of blood glucose levels for critically ill patients remains unclear. hypoglycemia, hyperglycemia and glycemic variability are associated with mortality. the time in targeted blood glucose range (tir) has been suggested to correlate with mortality depending on the status of antecedent glycemic control, but it has not been verified optimal tir and whether there is an optimal disease-specific tir. a retrospective observational study was performed at a single center. in the present study, we enrolled all critically ill patients admitted in intensive care unit from 1 january 2016 to 31 october. patients with diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome and patients who had < 10 blood glucose readings were excluded. gathered information included, in part, demographics, comorbidities, severity of illness scores, diagnosis at admission, length of icu stay and hospital discharge status. the primary outcome was 28-day mortality. we analyzed to find the optimal tir for critically ill patients. several tirs were each tested for correlation with mortality. a total of 1,523 patients, 51.8% of whom had diabetes, were studied. tir 70 to 139 mg/dl (or, 0.33; 95%ci, 0.18-0.58), tir 70 to 179 mg/ dl (or, 0.33; 95%ci, 0.23-0.47) and tir 110 to 179 mg/dl (or, 0.28; 95%ci, 0.17-0.44) > 80 % was independently associated with mortality in critically ill patients respectively. the optimal tir did not differ depending on diagnosis at admission. in this retrospective evaluation, tir 110 to 179 mg/dl > 80 % was independently associated with mortality in critically ill patients, especially those with good antecedent glucose control. these findings have implications for the design of future trials of intensive insulin therapy. the prevalence of chronic dysglycemia (diabetes and prediabetes) in patients admitted to swedish intensive care units (icus) is unknown. we aimed to determine the prevalence of such chronic dysglycemia and asses its impact on blood glucose control and patient-centred outcomes in critically ill patients. in this retrospective, observational study, we obtained routine glycated hemoglobin a1c (hba1c) measured in patients admitted to four tertiary icus in sweden between march and august 2016. based on previous diabetes history and hba1c we determined the prevalence of chronic dysglycemia (prediabetes, undiagnosed diabetes and known diabetes). we compared indices of acute glycemic control in the icu and explored the association between chronic dysglycemia and icu-associated infections, mechanical ventilation, renal replacement therapy, vasopressor therapy, and mortality within 90 days. of 943 patients, 312 (33%) had chronic dysglycemia. of these 312 patients, 127 (41%) had prediabetes or undiagnosed diabetes and fig. 1 (abstract p259) . results 185 (59%) had a known diabetes diagnosis. during icu stay, patients with chronic dysglycemia had higher average blood glucose, spent less time in target glucose range, had greater glucose variability, and were more likely to develop hypoglycemia than patients without chronic dysglycemia. chronic dysglycemia was associated with greater need for renal replacement therapy (odds ratio 2.10, 95% ci 1.35-3.27) and increased 90-day mortality (hazard ratio 1.33, 95% ci 1.01-1.77) after adjustment for simplified acute physiology score 3. in contrast, chronic dysglycemia was not associated with mechanical ventilation, vasopressor therapy, or icu-associated infections. in four tertiary swedish icus, measurement of hba1c showed that 1/ 3 of patients had chronic dysglycemia (prediabetes or diabetes). chronic dysglycemia was associated with marked derangements in glycemic control during icu stay, greater need for renal replacement therapy and with increased mortality at 90 days. case report: modern antidiabetic therapie causes ketoacidosis am heiden, m emmerich krankenhaus bad oeynhausen, institut für anästhesie, bad oeynhausen, germany critical care 2020, 24(suppl 1):p263 the modern antidiabetic class of sglt2-inhibitors, that are known to reduce the risk for cardiac events [1] , are increasingly used in the last few years. a 68-year old male patient with diabetes mellitus suffered 10 days after colectomy surgery from abdominal pain and nausea. the patient had an antidiabetic therapy with empaglifozin that was paused until day 5 after surgery (nutrition start on day 5, weaning on day 6). methods: this is a case report of one male patient seen in the icu setting. daily blood values including arterial blood gases, vital parameters and clinical status of the patient were observed and evaluated. the blood gases showed this metabolic acidosis: ph 7.38; pco2 20.3 mmhg, bicarbonate 12 mmol/l, be -11.63 mmol/l, lactate 1.6 mmol/l, glucose 7 mmol/l. a ketonuria despite normal blood glucose values was noticed, so that the diagnosis of ketoacidosis was clear. after analyzing the possible causes we found out, that empaglifozin in times of catabolism and fasting can cause this severe symptomatic. we terminated the therapie with empaglifozin and under the treatment with insulin the symptoms disappeared within 3 days and the patient could be discharged from the icu on day 17 after surgery. after one episode of ketoacidosis the therapy with sglt2-inhibitors should lifelong never be started again. we recommend that intensivists should be aware of the modern sglt2-inhibitors because of the shown severe complications and the increased use of this medication. consent to publish: written informed consent for publication was obtained from the patient. while obesity confers an increased risk of death in the general population, numerous studies have reported an association between obesity and improved survival among critically ill patients. this contrary finding has been referred to as the obesity paradox. this retrospective study uses two causal inference approaches to address whether the survival of non-obese critically ill patients would have been improved if they had been obese. the study cohort comprises 6,557 adult critically ill patients hospitalized at the intensive care unit of the ghent university hospital between 2015 and 2017. obesity is defined as a body mass index of ≥30 kg/m 2 . two causal inference approaches are used to estimate the average treatment effect in the untreated (atu): a naive approach that uses traditional regression adjustment for confounding and that assumes missingness completely at random, and a robust approach that uses super learning within the targeted maximum likelihood estimation framework and that uses multivariate imputation of missing values under the assumption of missingness at random. obesity is present in 18.9% of patients. the in-hospital mortality is 14.6% in non-obese patients and 13.5% in obese patients. the marginal associational risk difference for in-hospital mortality between obese and non-obese patients is -1.06% (95% confidence interval (ci) -3.23% to 1.11%, p=0.337). the naive approach results in an atu of -2.48% (95% ci -4.80% to -0.15%, p=0.037), whereas the robust approach yields an atu of -0.59% (95% ci -2.77% to 1.60%, p=0.599). a robust causal inference approach that may handle confounding bias due to model misspecification and selection bias due to missing data mitigates the obesity paradox, whereas a naive approach results in even more paradoxical findings. the robust approach does not provide evidence that the survival of non-obese critically ill patients would have been improved if they had been obese. bowel management within an icu environment is often difficult. recent data collection from an intensive care unit at the rvi identified either loose stool or constipation on > 50% of patient days. it was postulated this could be improved with a more tightly controlled bowel management regimen. to test this hypothesis a step-wise bowel protocol was created and introduced. data was collected in the 4 month period following its implementation with the following aims: 1) assess effectiveness of the protocol 2) further observe the reasons for loose or constipated stool on an diarrhea is an important problem in each critically ill pateints [1] . we aimed to investigate the frequency and management of diarrhea in our icu. in this study 47 patient retrospectively reviewed, in our icu between 01.01.2017-03.01.2018. patients were divided into two group as diarrhea "positive" and "negative". patients with diarrhea had fluid or loose stools 3 or more times a day. each diarrhea period of the patients with diarrhea was examined separately and compared with the group without diarrhea. nutritional status, enteral product formulation, leukocyte, neutrophil, albumin values, gastric sparing, antibacterial and antimycotic use, los in hospital and in icu were compared. in diarrhea positive group, on the day of hospitalization, laxative and/or enema administration, toxin a in stool, nitrogen balance before and after diarrhea, enteral product change in diarrhea, probiotic, metronidazole or oral vancomycin use were examined. the incidence of diarrhea was 68.3%. the most common diagnosis of icu admision was respiratory failure (60-85%) in both groups. diarrhea occurred in two days after laxative and/or enema treatment. enteral nutrition was higher in both groups (≥90%). nasogastric tube feeding was significantly higher in the diarrhea group (p=0.041). there was no difference between nutritional product formulation and diarrhea development (p>0,1). antibacterial use was high in both groups (75%); however, teicoplanin use was significantly higher in the group diarrhea negative group (p=0.028). the los in icu, and hospital was higher in diarrhea group (p<0.001). no difference in mortality rates (p>0.5). many factors may cause diarrhea in icu, and diarrhea may adversely affect patient treatment and increase morbidity. we think that preventive methods are as important as the treatment of diarrhea. the use of parenteral glutamine is studied in number of rcts and systemic reviews (heyland d 2013, wischmeyer p 2014), while there is a lack of data about the use of enteral glutamine. the aim of our study was to determine the effect of enteral glutamine supplementation on the incidence of hospital infections and death. design: retrospective cohort study. inclusion criteria: males and females > 18 years of age, tbsa burned 20%-80%, nasogastric intubation.patients were divided in two groups: glutamine group (n=25) and control group (n=17). in the study group enteral glutamine was administered to the patients for 5 days after admission to the icu. baseline characteristics were well balanced between groups. no significant difference was found between groups on patients' age, sex, tbsa, need for mechanical ventilation and rate of inhalation injury. primary outcome was all-cause mortality. secondary outcome was rate of nosocomial infections (skin and skin structure infections (sssi), lower respiratory tract infections, urinary tract infections, bacteremia, sepsis). mortality rate was 6 (24%) and 7 (41%) in the glutamine group and the control group, respectively, p=0.40. rate of nosocomial infections was 14 (56%) in the glutamine group and 11 (65%) in the control group, respectively, р=0.81. rates of sssi, lower respiratory tract infections, urinary tract infections and sepsis did not differ significantly between the groups: 11 (44%) and 6 (35%), p=0.81; 6 (24%) and 7 (41%), р=0.40; 1 (4%) and 1 (6%), р=1.00; 6(24%) and 5 (29%), р= 0.97, respectively. rate of bacteremia was significantly different between the groups: 1 (4%) in the glutamine group and 5 (29%) in the control group, p=0.03. retrospective design is a significant limitation of our study. enteral glutamine supplementation may reduce the incidence of bacteremia in burn patients, but has no influence on the incidence of other nosocomial infections and mortality. further large clinical trials are needed. with outcomes were assessed with multivariable logistic regression and cox proportional hazard analyses, adjusted for baseline risk factors and randomization. in sensitivity analyses, models were further adjusted for key regulators of ketogenesis to assess whether any effect was direct or indirect. late pn increased plasma 3hb as compared with early pn, with maximal effect on day 2 (p<0.0001 for day 1 to 5 and for the "maximal effect" day in the 1142 patients). adjusted for baseline risk and randomization, plasma 3hb associated with a higher likelihood of earlier live weaning from mechanical ventilation (p=0.0002) and of earlier live picu discharge (p=0.004). as plasma 3hb replaced the effect of the randomization, the 3hb effect statistically explained these benefits of the randomization. further adjustment for key regulators of ketogenesis did not alter these findings. plasma 3hb did not independently associate with the risk of infections and mortality. withholding early pn increased ketogenesis in critically ill children, an effect that statistically mediated part of its clinical benefits. critical care patients are prone to frequent feeding interruptions for various reasons including feeding intolerance. these interruptions can lead to adverse outcomes. the aim of the study was to determine the reasons for and the duration of interruptions of enteral nutrition (en). single-center observational, cross-sectional study in a 19-bed mixed icu of a tertiary hospital. duration: 6 months. 50 patients, aged 65.4 years old (±14.6), that stayed in the icu > 48 hrs and were fed with en were included. anthropometric data, bmi, time of initiation of prescribed en, type of en formula, daily calories delivered were recorded. energy intake was calculated according to espen guidelines (25 kcal/ kg bw/day). the causes for and duration of interruption were reviewed from the patient's chart. apache ii and mnutric score was calculated for all patients. mnutric score ≤5 was used to diagnose malnutrition. all patients included in the study were endotracheally intubated. apache ii was 22.4 ±5.6. 58% of patients had increased risk of malnutrition. icu stay was 24.4 (8.0±32.0) days, and the in-hospital mortality was 24%. there were 318 episodes of en interruptions over a median icu stay of 24.4 days. median 2.5 interruptions/patient. the most common reason for en interruption was gastric residual volume monitoring followed by diagnostic and therapeutic procedures (figure 1 ). other reasons include surgery, intolerance and/or delayed feeding and extubation. the median lost feeding time was 5.4 hours/ day (3.7-7.4) for all causes, while the mean loss of total energy intake was 790 kcal/day (±321)/day. average body weight of the patients was 78 kg (±12). caloric deficit was calculated at 1950 kcal/day or 40% of the prescribed caloric goal. the results of this study showed that interruptions can lead to substantial caloric deficit, malnutrition and adverse events. an interruptionminimizing protocol could be useful in order to reduce the missing hours and to improve the clinical outcomes. relationship of goal-directed nutritional adequacy with clinical outcomes in critically ill patients pc tah there are controversies surrounding the effects of optimal nutritional intake on clinical outcomes in critically ill patients. this study aimed at investigating the relationship of goal-directed energy and protein adequacy on clinical outcomes which includes mortality, intensive care unit(icu) and hospital length of stay (los), and length of mechanical ventilation (lomv). this was a single centre prospective observational study. nutritional requirements were guided by indirect calorimetry and 24-h urinary urea.nutritional intake was recorded daily until death, discharge, or until day 14 of icu stay. clinical outcomes were collected from patient's hospital record. the relationship between the two groups (< 80% and ≥80% of overall nutritional requirement) with mortality outcomes was examined by using logistic regression with adjustment for potential confounders. terlipressin, despite being one of the main treatments for acute variceal bleeding, may lead to severe hyponatremia due to its antidiuretic activity.we aimed to identify risk factors for development of hyponatremia during terlipressin treatment. retrospective study of patients admitted to acute intermediate care unit for hypertensive upper gastrointestinal bleeding due to chronic liver disease who received terlipressin(december2011-decem-ber2018).hyponatremia was defined as a decrease in na serum levels ≥5meq and severe hyponatremia as >10meq within 3 days of treatment. we studied 191 patients, 84.3% male, mean age of 58.6 years (sd 10.8). alcohol-related liver disease was the most frequent etiology. hyponatremia occurred in 53 patients (27.7%). serum na δbetween -5 and -10meq and serum na δ>-10meq occurred in 20.4 and 7.3%, respectively (table 1) . severe hyponatremia occurred in 11 patients (5.8%) and symptoms were reported in two cases (status epilepticus and altered mental status). patients with higher baseline levels of na were more susceptible to terlipressin-induced hyponatremia and a longer length of stay was observed in patients with serum naδ>-10 meq (6.3 vs 4.4 days, p<0.022). the prevalence of hyponatremia in our study was lower than previously reported.higher serum na at admission and aih as etiology of cirrhosis were predictors of terlipressin-induced hyponatremia. neither the cumulative dose of terlipressin nor the duration of treatment appear to be related to the development of hyponatremia a δ48h-[na] >5 mmol/l was associated with larger hazards of mortality ( figure 1 ). an increase in serum sodium in the first 48 hours of icu admission is independently associated with a higher mortality in patients admitted with mild hyponatremia, normonatremia, and hypernatremia. based on our findings, it is possible that mild hyponatremia may be a protective mechanism in critical illness, which questions common practice of routinely correcting serum sodium when it is too low. introduction: acute liver failure (alf) represents a life-threatening organ dysfunction associated with increased mortality and liver transplantation represents the only definitive treatment. the aim of this study was to assess the effects of renal replacement therapy in combination with hemoadsorption in alf patients. twenty-nine patients with alf admitted to the intensive care unit (icu) of fundeni clinical institute were included in the study. after icu admission, 3 consecutive session of hemoadsorption in combination with continuous veno-venous hemodiafiltration were applied. number of organ dysfunctions and sirs criteria were recorded at icu admission. the following data were recorded before and after the 3 hemoadsorption therapies: glasgow coma scale, pao2/fio2, creatinine, 24-hours urine output, bilirubin, leucocyte and platelet count, heart rate, mean arterial pressure and vasopressor support, c-reactive protein and procalcitonine. clif-sofa score was calculated before and after the therapy. icu length of stay and 28-days outcome were noted. the mean age in the study group was 34±14 years. the median number of sirs criteria was 3 [2, 4] and the median number of organ dysfunctions was 3 [1, 6] . the use of hemoadsorption was associated with a decrease in creatinine (from 1.9±1.4 to 1.2±0.8 mg/dl, p= 0.02), bilirubin (from 14.2±12.6 to 9.2±9.1 mg/dl, p=0.05) and platelet count (96482±70913 / ul to 51275±24393 /ul, p=0.01). we also observed a decrease in clif-sofa score from 12.0±2.1 to 10.0±2.6 (p= 0.05). overall mortality was 37.9% (n=11). six patients (20.7%) underwent liver transplantation with 100% 28-days survival. the use of hemoadsorption in patients with alf is associated with improvement in liver and kidney functional tests and may represent a new therapy in bridging these patients to liver transplantation. introduction: impairment of intestinal mucosal barrier function is the initiating factor of sepsis. in order to explore the effect of lactic acid bacteria on intestinal barrier function impaired by sepsis, it is necessary to establish sepsis and lactic acid bacteria ecological models. however, how to construct these models is still unclear. co-cultures with a gradient of lactic acid bacteria and caco-2 cells were constructed. the symbiotic state was observed under an inverted microscope and lactate dehydrogenase (ldh) toxicity tests, transepithelial electrical resistance(teer) tests and western blots were used to determine effective concentrations of lactic acid bacteria in monolayer cell models. lipopolysaccharide (lps) was used to treat cells, and cell counting kit-8, quantitative reverse transcription pcr(rt-qpcr) and enzyme linked immunosorbent assays (elisa) were used to determine the appropriate concentration for sepsis models. the number of living cells decreased significantly when the moi(number of lactic acid bacteria/cell number) reached 8 ( figure 1 , panels 1a, b). the release of ldh indicated that damage to cells began to increase when the moi exceeded 10 (panels 2a, b). at an moi of 0.5, resistance values began to increase over time, whereas resistance values began to decrease when the moi reached 10 (panel 3). as the number of lactobacilli increased, the expression of tight junction protein increased and then decreased (panel 4a, b, c). in sepsis model experiments, the cell survival rate began to decrease once the concentration of lps exceeded 10^4 ng/ml (panel 5). rt-qpcr results showed that 10 2 ng/ml lps significantly increased inflammatory cytokines (panel 6), and elisa results consistently showed that tnf-α and il-6 increased significantly when lps concentrations reached 10 2 ng/ml (panel 7a, b). it is feasible to construct a cell monolayer model of lactic acid bacteria and lps. the appropriate moi of lactic acid bacteria is 0.5 and the optimal concentration of lps is 10 2 ng/ml. introduction: sepsis is associated with high mortality and morbidity. as the severity increases, physiological parameters such as ph changes are one of the most notable features in metabolic acidosis secondary to high lactate. currently there is no point of care test other than blood gas measurement that could detect these ph changes. this is challenging especially in prehospital environment. the aim of this study is to develop a novel rapid point of care testing using a sensor to detect ph change in blood. sensors were produced by screen printing graphene and silver electrodes and functionalizing the graphene working electrode with an active layer of melanin. a preclinical sensor model was produced by adding lactic acid to a citrated plasma sample thus altering its ph over a clinically relevant range. the ph sensors were exposed to modified plasma, recording any changes in the voltage. the relationship between the voltage potential and plasma ph was established using weighted least squares regression. a ph dependent change in the measured voltage, with respect to the ph of the solution, was observed with a sensitivity of -111.27 mv/ph +/-15.95 over a physiologically relevant ph range between ph7.1 and ph7.6. in this first phase proof of concept study a low cost, ph sensor was fabricated and demonstrated to be effective in measuring the ph of the plasma. this is the first time that such a sensor has been demonstrated and validated to work in this preclinical model of acidosis. the technology demonstrated here is a promising candidate for a point of care test whereby abnormal blood ph levels can be detected and monitored outside of a laboratory environment in a rapid manner. further studies are now underway to detect this change in whole blood. (figure 1) . over one year only a small proportion of patients (n=7, 4%) were classified as 'intermediate high' risk and potential candidates for reperfusion therapies. the revised national early warning score (news) with modified glasgow prognostic score (mgps) is superior to the news for predicting in-hospital mortality in elderly emergency patients t mitsunaga jikei university school of medicine, emergency medicine, tokyo, japan critical care 2020, 24(suppl 1):p286 the national early warning score (news) was developed in the ukto identify the risk of death. the previous study showed that the modified glasgow prognostic score (mgps) correlate with frailty in elderly patients [1] . the aim of this study is to evaluate the predict value of the revised news with mgps for in-hospital mortality (in 28 days) in elderly emergency patients. this study is secondary analysis and was carried out in jikei university kashiwa hospital, in japan, from 1 april 2017 to 31 march 2018. the acute medical patients aged 65 and older were included. the news was derived from seven physiological vital signs. the mgps was derived from c-reactive protein (crp) and albumin. discrimination was assessed by plotting the receiver operating characteristics (roc) curve and calculating the area under the roc curve (auc). the aucs for predicting in 28 days in-hospital mortality were 0.818 for revised news with mgps and 0.797 for the original news. the auc of the revised news with mgps was significantly higher than that of the original news for predicting in-hospital mortality (p < 0.001) (figure 1) . our single-centred study has demonstrated the utility of the revised news with mgps as a high predictor of acute phase in-hospital mortality in elderly emergency patients. the diagnostic performance of the five main emergency department (ed) triage systems has been shown to be poor in distinguishing acute coronary syndromes (acs) from mild severity diseases in chest pain patients. these ed triage systems are either clinically-based, being more sensitive or ecg-based, more specific [1] . the goal of the study was to evaluate if incorporation of cardiovascular risk factors (cvrf) into ecgbased triage could increase his diagnostic performance. cecidoc is a prospective, observational, single-center study in an academic hospital. all consecutive adult patients admitted for acute chest pain were included. we compared the ecg-based french triage system [2] to a modified system upgrading patients with a normal ecg but significant cardiovascular risk from a low acuity triage score (waiting period before medical assessment of max. 60 min.) to a high acuity triage score (waiting period before medical assessment of max. 20 min.). the final diagnosis was determined after a 30-day follow-up. we predefined as being adequate a high-acuity triage score (level 1 or 2) for acs and a low-acuity score (level 3, 4 or 5) for mild severity diseases. a total of 190 patients was enrolled over a 5-month period (age 56.8 ± 16.4; m/f ratio 1.7). triage scores of 35 patients (18.4%) with acs were compared to 103 patients (54.2%) with mild severity diseases. taking into account cvrf, the sensitivity of the triage system increased from 60 to 80% whereas the specificity decreased from 74 to 61%. area under the roc curve (auc) went from 0.69 to 0.72 (fig. 1) . for chest pain triage at ed, addition of cardiovascular risk factors into ecg-based triage increases his diagnostic performance. approximately 20% of patients presenting to hospital with an intentional overdose require admission to an intensive care unit (icu) [1] . there are currently no uk guidelines regarding the optimal use of ct head scans (cth) in this patient cohort [2, 3] . this study aims to determine whether we should be performing ct head scans in obtunded patients with suspected overdose requiring admission to intensive care. we performed a retrospective search of the icnarc database for plymouth university hospital trust, looking for patients admitted to the icu with overdose or self-poisoning as a primary diagnosis. 146 patients were identified and 86 of these patients required intubation due to obtundation(gcs<8). there were 59 males and 27 females with an average age of 38 years old. the median length of stay on the unit was 1 day. 52 of the patients has a past medical history of mental illness, and 53 overdosed on prescribed medications. the average gcs recorded on admission was 5. 52 of the 86 (64%) patients had a cth on admission, of which 5 were part of a trauma scan. 11 were known overdoses and 7 were suspected overdose as per the cth request form. the main rationale behind those requests were to exclude additional intracranial injury. none of those cth showed any signs of acute pathology (figure 1) . in this retrospective study, obtunded patients with suspected or known overdose with no history of apparent trauma or injury do not benefit from cth. in the absence of a history of trauma or focal neurological signs our conclusions are that cth provides limited value in the management of these patients. the audit was carried out to objectively investigate the problems associated with technique of folley catheterization in emergency department and 3 indoor units of internal medicine wards [1] . introduction: cellular and molecular mechanisms, epigenetic aspects of acute clozapine poisoning are studied insufficiently. the aim of this study was to identify morphological and epigenetic alteratons in brain neurons during acute exposure to clozapine combined wit ethanol. the experiments were carried out on male wistar rats weighting 200-250g (n=21). group i (control) received 0.9% nacl solution enterally; group iiclozapine 150 mg/kg in 0.9% nacl solution; group iiiclozapine 150 mg/kg in 40% ethyl alcohol. after 4 hours euthanasia was performed. autopsy included withdrawal of brain samples for histological examination (n = 21) and for determination of global dna methylation level (n = 21). the global dna methylation level (5-mc%) was determinated by fluorimetric method. inter-group comparisons were made by kruskal-wallis test. histological examination of paraffin sections of brains stained with hematoxylin and eosin was performed by light microscopy. in acute сlozapine poisoning and its combination with ethanol morphological changes in neurons of the cerebral cortex were detected. in acute сlozapine with alcohol poisoning an increase of global dna methylation level was observed. probably the identified changes have a common pathogenesis which will be clarified in our further studies. there is limited information available regarding the prevalence of adder bites and the complications of envenomation. nhs data suggests there are 100 adder bites annually in the uk with the last fatality in 1975 [1] . we performed an audit into adder bites in south west wales to identify the number attending our emergency departments, their management and clinical course as well as any environmental factors that predict increased likelihood of being bitten or the severity of the bite. a retrospective study of adder bites attending emergency departments in south west wales was undertaken (jan 2014 to aug 2019). measurements included were patient demographics, clinical presentation, type of treatment (conservative vs anti-venom) and outcome. results: 31 patients were included, age range 2-72 years ( figure 1 ). the majority of bites occurred in sand dunes (41.9%) and all bites were on extremities. anti-venom was administered to 45.2% (14/31) of patients. there was a significant positive association between the use of anti-venom and the length of hospital stay (r = 0.520; p=0.003) and a significant negative correlation between the anti-venom use and both diastolic and systolic blood pressure (p= 0.501 and 0.487 respectively p=0.01). all patients fully recovered. in this study, we demonstrated that with a full clinical assessment on presentation it is safe to decide whether anti-venom is required. the current guidelines are safe and effective in the treatment of adder bites. 98μmol/l, for pao2 < 9.9kpa and > 12.3 kpa, platelets < 165*10^9/l and > 327*10^9/l, and bilirubin > 12μmol/l. in our population of adult ed patients, the thresholds of vital values associated with increased 7-day mortality were very close to routinely used values, and most of the thresholds were included in the lowest urgency level in triage and risk-stratification scoring systems. the workload in the emergency room: direct assessment by the therapeutic intervention scoring system-76 and indirect assessment by the nasa task introduction: the number of emergency room admissions continues to increase each year, which increases the care workload of the emergency department staff, who should to use its theoretical and practical knowledge in order to provide quality care in difficult working conditions. the aim of our study was to assess the emergency room staff workload its impact on health workers and patients and to suggest an improvement strategy to decrease this workload. a prospective, monocentric cohort study with descriptive and analytic approach over one month (december 2018) conducted at the emergency department of an academic hospital. the workload endured by the emergency room staff was evaluated by the nasa task load index and on patients by the therapeutic intervention scoring system-76. there were 286 cumulative days of hospitalization in 67 consecutive patients admitted to the emergency room. the average age was 61 ±15 years. the average length of stay at the emergency room was about 103 ±48h. the average tiss-76 score was 31.7 ±14.9. factors associated with important care workload were: age ≥ 65 years, diabetes, more than 3 comorbidities, the use of intravenous antibiotics; the use of vasoactive drugs and the use of mechanical ventilation; a high tiss score was predictive of emergency room mortality. in the indirect assessment of the care workload, 41 medical and paramedical staff were interviewed, 73% of them were under 40 years old with a sex ratio of 0.58. a high level of mental and physical workload was expressed by ed staff with considerable level of frustration; the ed staff suggested mainly to improve the working conditions, communication and to redefine tasks "who does what". our study had shown a significant workload in the emergency room, a process to reduce this workload is being implemented medical simulation is a modern teaching tool increasingly used in specialties such as anesthesia, emergency medicine and obstetrics. however, it's not widely used in specialties like cardiology, althought cardiovascular emergencies are very frequent. the purpose of our study was to assess the effectiveness of simulation-based medical education in the management of cardiovascular emergencies among moroccan graduate students. we conducted a prospective, observational, multi-centrer study including the students of three moroccan universities from the 5 th to the 7 th year of medicine who underwent 6 phases: first a pre-test, then a theoretical and practical training on cardiovascular emergencies after which the students were separated in two groups, one undergoing the medical simulation training (group 1) and one who didn't (group 2), followed by a theoretical then a practical post-test on resusci anne and simman®. at last, the students were asked to answer a satisfaction survey. the reform procedure in the tunisian army consists in repairing the physical damage and deciding on the applicant's ability to continue working. terrorism increases the impact of the co-morbidity generated and the socio-economic consequences that result from it. the purpose of this work was to study the epidemiological, clinical and evolutionary profile of terrorist injuries, to specify the rates of consequent partial permanent disability (ppi) and the possibilities of returning to work. descriptive retrospective cross-sectional study of 177 reform files on military personnel injured during anti-terrorist operations from fig. 1 (abstract 296) . changes in total bcpr rate in family-and friends-witnessed ohca cases with dispatcher-assisted instruction during 20-week period after the day of disaster during three years january 2013 to september 2019. the data collection was carried out on the basis of a collection form. our 177 wounded were male, 96% of whom belonged to the army. the average age was 36 years and 3 months ± 8.869. half of our wounded were troopers. infantry and special forces were the most exposed military units. half of the accidents were recorded in the kasserine region (88 cases). chronic post-traumatic stress disorder (cptss) was found in 130 injured, followed by amputations in 18 injured. the after-effects were psychological in 32%, physical in 26% and mixed in 39% of our injured. the ppi rate ranged from 36% to 75% in 23.7% of injuries.. more than half of the injured had returned to their professional activity, 33% were put on reform for health reasons. our results showed that the esptc was the most recorded sequel, and that the ppi rate was significant in a quarter of our injuries. in our series, a third of our wounded were put on reform for health reasons. to state the importance of initial care and adequate and rigorous follow-up to recover a greater number of war wounded. introduction: the rapid response system (rrs) has been shown to decrease hospital mortality [1] . the japanese coalition for patient safety has set a major goal for hospitals to more widely implement the rrs. however, prevalence and actual circumstances of use in acute care hospitals (including small scale hospitals) in japan are as yet not well-known. web-based questionnaires were sent to acute care hospitals (of scale 75 beds-or-larger) of 17 prefectures in western japan. each participant hospital selected a certain department which answered the questionnaire. the rrs included the medical emergency team (met), the rapid response team (rrt), and the critical care outreach team (ccot). we investigated the presence and circumstances of in-hospital emergency calls, rrs and other systems, and then illuminated issues to be solved. our study suggests that delays in patient transfer to the icu after rrt activation in the wards were associated with slower physiological improvement.these findings support further and larger studies. blood and blood products use in intensive care unit m akcivan, s bozbay, o demirkiran istanbul university cerrahpasa, anesthesiology and intensive care, istanbul, turkey critical care 2020, 24(suppl 1):p304 blood and blood product (bp) transfusions are frequently used in intensive care units (icu) [1] . it is important to know transfusion epidemiology and the effect of adverse transfusion reactions and their effect on mortality and morbidity.we aimed to investigate the blood and bp transfusions in the icu. blood and bp transfusions in icu, between 2013-2017 were reviewed retrospectively. we evaluated each transfusion as a data and examined the pre-and post-transfusion laboratory values, demographic data, cause of icu admission and comorbidities. results: 284 patients who underwent transfusion in the icu, and 2188 transfusion data from these patients were included. the most frequent cause of hospitalizations were respiratory failure and sepsis. the rate of patients transfused in the five-year period decreased from 73.9% to 36.67%. the hemoglobin threshold before transfusion decreased from 8.34 g / dl to 7.91 g / dl. a total of 148 transfusion reactions were observed and the most common transfusion reaction was febrile non-hemolytic reaction. the most commonly transfused product was red blood cell suspension. transfusion reactions were found to be slightly higher in men than women in young age group(<65y) (p = 0.44 and p=0.021, respectively). transfusion reactions were found to be more frequent in emergency transfusions (p <0.01). the number of transfusions was significantly lower in patients with apache ii score <20 (p <0.01). the need for transfusion was found to be higher in patients with hematological malignancy (p <0.01). it was observed that as the mean number of transfusions increased the mortality is also increased (p <0.01). transfusion therapies are the treatments that are vital but have a serious mortality and morbidity risk. in particular, intensive care patients should be considered in detail because of their specific features. restrictive transfusion practices have positive results. association between anemia or red blood cell transfusion and outcome in oncologic surgical patients. figure 1a) . the association between rbc transfusion and adverse events also remained after adjustment (or 4.3 [2.2 -8.8] ; p < 0.001) ( figure 1b) . in oncologic surgical critically ill patients, there was an independent association between anemia (even moderate anemia) or rbc transfusion and patient outcomes. our findings highlight the need for further research to determine the optimal transfusion strategy in surgical oncologic patients. transfusion impaired skin blood flow when initially high e cavalcante dos santos, w mongkolpun, p bakos, al alves da cunha, c woitexen campos, jl vincent, j creteur, fs taccone erasme hospital, intensive care department, brussels, belgium critical care 2020, 24(suppl 1):p306 red blood cell transfusion (rbct) increases global oxygen delivery (do 2 ) and may improve microcirculation. however, the effects on blood flow have been found to be conflicting. we studied icu patients with stable hemodynamic status (mean arterial pressure (map) ≥ 65 mmhg for at least 6 hours) and without active bleeding, who received a rbct. skin blood flow (sbf) was determined (periflux system 5000, perimed, index finger; perfusion unit, pu) together with map, heart rate (hr), hemoglobin (hb), lactate levels and scvo 2 before and after rbct. sbf was measured before rbct (t0) and after (t1) for each 3 min. according to previous data indicating the lowest sbf value found in noninfected icu patients was 151 pu, all patients were analyzed according to the baseline sbf (i.e. <151 pu -low sbf vs. ≥151 puhigh sbf). the relative change of sbf (δsbf) was calculated after rbct and the responders were defined by the function of >10%. results: 63 icu patients were studied. rbct was associated with increases in map and scvo 2 but no change in sbf. at baseline, scvo 2 was lower in the responders than in the non-responders (p=0.04) and lower in patients with low sbf than in the high sbf (p=0.04). there was no difference in hb, map, and lactate, between the patients with low and high sbf. after rbct, map rose in the responders (p<0.01) and in the non-responders (p=0.03), sbf (p<0.01) rose in patients with low sbf, and sbf (p=0.02) decreased in patients with high sbf. there was a negative correlation between baseline scvo 2 (r= -0.363, p<0.01) or baseline sbf (r= -0.560, p<0.01) and the relative increase in sbf after rbct. rbct increases skin blood flow only when it is impaired at baseline. severe immune dysregulation is associated with adverse outcomes and is common in intensive care unit (icu) patients [1] . erythropoietin-stimulating agents (esas) have both anti-apoptotic and immune-modulating properties [2] . despite potential benefit, both the safety and efficacy of these agents remains unclear [3] . here we evaluate the impact of esas on morality at hospital discharge in critically unwell adult patients admitted to the icu. we conducted our search strategy in accordance with a predetermined protocol. the use of ffp is associated with an increased incidence of complications such as acute respiratory distress and infections, and the rate of complications increased with the quantities of ffp transfused [1] . pcc contain several important coagulation factors and it has been suggested that they could replace ffp. this has been shown mainly in case reports or series in which coagulation factor deficit was detected by using poc viscoelastic tests in trauma [2] or traditional hemostatic tests in obstetric patients [3] . multicenter observational study of the safety and efficacy of the prothrombin complex concentrate. a survey of anesthetists was conducted in 19 maternity hospitals at various levels of care in the russian federation. data has been collected and processed. as a result, 251 patients were analyzed. pph was determined as a volume of blood loss more than 500 ml during vaginal delivery or cs. the most significant risk factors for pph were: preeclampsia or arterial hypertension and a history of postpartum hemorrhage. 32.3% had no risk factors for pph. it was determined that the use of prothromplex 600 iu decreased the number of patients with transfusion ffp 12-15 ml/kg by 27.8% and increased the number of patients without transfusion by 25.9%, compared with patients without use of prothromplex 600 iu (figure 1 ). no complications were detected. the use of pcc safety and efficacy reduce use of ffp during pph. the full analysis included 45 patients on either hfc (n=22) or cryoprecipitate (n=23). the intraoperative and postoperative changes in etp and fibrinogen concentration are shown in table 1 . for fibtem a20 (intraoperatively) and fibrinogen concentration (intraoperatively and postoperatively), the mean numerical values appeared higher with hfc than cryoprecipitate. fxiii (hfc: 121.86%, 66.85%; cryoprecipitate: 115.55%, 68.68%, at baseline and 4hr after surgery start), fviii and vwf were maintained throughout surgery in both treatment groups. this was also the case for laboratory tests activated partial thromboplastin time, prothrombin time and platelet count. the forma-05 coagulation parameters analyses showed broad overlaps between hfc and cryoprecipitate, with satisfactory maintenance of the clot quality parameters, fxiii concentrations and thrombin generation parameters. the study group includes 118 men and 40 women with a mean age of 43,008 vs. 40.32 years (p=0.639) admitted with the diagnosis of multiple trauma. we found a directly proportional and highly significant statistical correlation between base excess and fibrinogen level diagnosed using the mcf/fibtem parameter(r=0.6382, p<0.0001)and an inverse proportional correlation between lactate level and fibrinogen level (r= -0.2164, p=0.0065). in the roc analysis that uses as a variable the level of base excess and as a criterion of classification the fibrinogen deficit (mcf/fibtem<12 mm) it can be observed that at a value of be<-7 mmol/l, we can diagnose a fibrinogen deficit with a sensitivity of 88.2% and a specificity of 80.6% (auc= 0.872,p< 0.0001). lactate appears to be inferior to the excess base (figure 1) , but still has a good diagnostic power, a value of 2.6 mmol/l has a sensitivity of 67.1% and a specificity of 75% (auc= 0.754,p<0.0001). the difference between the two roc curves (0.118) is statistically significant (p = 0.0028). both base excess and serum lactate can be used to diagnose fibrinogen deficiency with the mention that base excess appears to have a higher sensibility and specificity ability. based goal-directed algorithm. this approach requires further clinical validation. we conducted a retrospective study comparing transfusion strategies in patients with major trauma between 2013 and 2018. we retrieved demographic data and blood products administered from patients with at least one red-blood cell (rbc) transfusion. primary outcome was a reduction of rbc administration. secondary outcomes were mortality, icu length of stay and acute kidney injury. we included 141 patients admitted in the icu due to severe trauma (sapsii:41.5 ±21.9), and mainly after emergent surgery (68.8%). they featured a mean age of 45.3±19.3y, were predominantly male (76.6%) and 73% were in shock. in the first 24 hours of hospital admission a mean of 3.6±4.5 rbc units were administered. most patients received a fibrinogen-based protocol (fbp) (78%), with an average of 5±3g of fibrinogen and 1±3 fresh-frozen plasma (ffp) units, versus 3±4 g of fibrinogen and 6±4 ffp units in the ffp group. the fbp was associated with a decrease administration of rbcs in the first 24 hours (r = -2.6; p < 0.004), even after adjustment for severity (p=0.003) and for tranexamic acid use (p = 0.003). it was associated also with a decrease of platelet transfusion (p=0.004). fibrinogen-based protocol was not associated with a decrease in mortality, acute kidney injury or noradrenaline dose. treatment of tic in past years has progressively changed to a goaldirected fibrinogen-based approach. in our population, the use of fbp lead to a reduction of rbc administration in severe trauma patients. prospective, multicenter, randomized study comparing administration of clotting factor concentrates with a standard massive hemorrhage protocol in severely bleeding trauma patients the objective of this study was to assess the ability of the quantra® qstat® system (hemosonics) to detect coagulopathies in trauma patients. many level 1 trauma centers have adopted whole blood viscoelastic testing, such as rotational thromboelastometry (rotem®, fig. 1 (abstract 315) . study treatment plan instrumentation lab) for directing transfusion therapy in bleeding patients. the quantra qstat system is a cartridge-based point-of-care (poc) device that uses ultrasound to measure viscoelastic properties of whole blood. and provides measures of clot time, clot stiffness and a test of fibrinolytic function. methods: adult subjects were enrolled at two level 1 trauma centers which use a rotem based protocol to guide transfusion decisions. study protocols were approved by the site's ethics committee. for each subject, whole blood samples were drawn upon arrival to the emergency department and again, in some cases, after administration of blood products or antifibrinolytics. samples were analyzed on the quantra (at poc) in parallel to rotem delta (in lab). a total of 54 patients were analyzed. approximately 42% of samples had a low clot stiffness (cs) values suggestive of an hypocoagulable state. the low stiffness values could be attributed to either low platelet contribution (pcs), low fibrinogen contribution (fcs), or a combination ( figure 1) . additionally, 12% of samples showed evidence of hyperfibrinolysis based on the quantra clot stability to lysis parameter. samples analyzed on standard rotem assays showed a lower prevalence of low clot stiffness and fibrinolysis based on extem, fib-tem results. the correlation of cs and fcs vs equivalent rotem parameters was strong with r-values of 0.83 and 0.78, respectively. this first clinical experience with the quantra in trauma patients showed that the qstat cartridge detected coagulopathies associated with critical bleeding and may be useful for directing blood product transfusions in these patients. ability to perform testing at poc may provide additional clinical advantage. the objective of the study was to describe the conditions of use of fibryga® 1g, a new, highly purified, human fibrinogen (hf) recently granted a temporary import authorization for use in congenital and acquired fibrinogen deficiencies in france. observational, non-interventional, non-comparative, retrospective study conducted in 5 french hospital centres using fibryga®. data from patients with fibrinogen deficiency having received fibryga® from december 2017 to july 2019 were retrieved from their medical files. indications, modalities, efficacy and safety outcomes were recorded. indications encompassed non-surgical bleeding (nsb) either spontaneous or traumatic, including post-partum hemorrhage (pph), bleeding during surgery (sb) or administration to prevent bleeding during planned surgery. treatment success was defined as control of the bleeding or hemoglobin loss <20% for bleeding treatment and as absence of major perioperative hemorrhage for pre-surgical prevention. this analysis included 110 patients aged 56,7 ± 17.7 years and 60% were male. all presented an acquired fibrinogen deficiency requiring administration of hf. indications were nsb (n=45, 40.9%) including 15 (13.6%) pph, sb (n=31, 28.2%), and prevention of sb (n=34; 30,9%). cardiac surgeries were the main procedures associated with treatment and prevention of sb. mean total doses of fc were 2.95± 1.66g, 2.00±1.37g and 2.21±1.23g for nsb, sb and prevention of sb. success rates were 88.4% (95%ci 78.8-98.0%), 96.8% (95%ci 90.6-100%) and 91.2% (95%ci 81.6-100%) respectively. for pph, mean dose of hf was 2.53±0.74g with a success rate of 86.7% (95%ci 69.5-100%). overall, tolerance was good. fibrinogen concentrate fibryga® is mostly used for bleeding control. in one third of patients, hf was administered preventively to avoid bleeding during surgery. use of fibryga® was associated with favourable efficacy outcomes. functional testing for tranexamic acid effect duration using modified viscoelastometry t kammerer 1 , p groene 2 , s sappel 2 , p scheiermann 2 , st schaefer 2 1 ruhr-university bochum, institute of anaesthesiology, heart and diabetes center nrw, bad oeynhausen, germany; 2 ludwig-maximilans university, department of anaesthesiology, munich, germany critical care 2020, 24(suppl 1):p318 tranexamic acid (txa) is the gold standard to prevent or treat hyperfibrinolysis [1] . effective plasma concentrations are still under discussion [2] . in this prospective, observational trial using modified viscoelastometry we evaluated the time-course of the antifibrinolytic activity of txa in patients undergoing cardiac surgery. methods: 25 patients were included. modified viscoelastometry (tpa-test) was performed and txa-plasma-concentration, plasminogen-activatorinhibitor-1 (pai-1) and pai-antigen-plasma-concentrations were measured over 96h. additionally, in vitro dose-effect-curves from blood of healthy volunteers were performed. data presented as median with interquartile range (q1/q3). results: txa plasma-concentration was increased compared to baseline (t1:0 μg ml -1 ) at every time-point with a peak concentration 30min (t2) after application (p<0.0001; see fig.1a ). lysis was inhibited from 30min (lysistime tpa-test : p<0.01; lysisonsettime tpa-test :p<0.0001). maximumlysis tpa-test was decreased at t2 (t1:97% (96/97) vs. t2: 9% (6/11); p<0.0001). of note, after 24h some patients (n=17) had normalized lysis whereas others (n=8) had strong lysis inhibition (ml< 30%;p<0.05) up to 96h. high and low lysis groups differed regarding kidney function (cystatin c:1.64mg l -1 (1.42/2.02) vs. 1.28mg l -1 (1.01/ 1.52);p=0.002) and active pai-1 (93.05ng ml -1 (33.15/9100.0) vs. 16.13ng ml -1 (6.62/79.98);p=0.047). in-vitro, txa concentrations >10μg ml -1 were effective to inhibit fibrinolysis. in our trial, after 24h there was still completely blocked lysis in patients with moderate renal impairment. this could be critical with respect to postoperative thromboembolic events [3] . here modified viscoelastometry could be helpful to detect the individual fibrinolytic capacity. introduction: peri-operative coagulopathy correction based on viscoelastic hemostatic assays (vhas) and single-factor coagulation products has changed the paradigm of bleeding management in cardiac surgery [1] . in a retrospective study, we analysed patients with emergency surgery for thoracic acute aortic dissection (taad), before and after the introduction of fibrinogen concentrate in clinical practice. data were collected from paper and electronic records. the study was approved by the institutional ethical committee. 60 patients were included in the analysis, 19 operated in 2012, before fibrinogen concentrate was approved for human use, and 41 in 2018-2019. therapy was guided by a rotational thrombo-elastometry (rotem) algorithm. exclusion criteria were non-compliance with the institutional protocol and intra-operative death. we investigated allogeneic blood transfusion (abt), fibrinogen use, peri-operative bleeding (pob), surgical reexploration and post-operative complications (poc). the groups were similar in gender, age, body weight, additive euro-score and aortic cross-clamp time. fresh frozen plasma, cryoprecipitate and red blood cell transfusion were lower in the fibrinogen group, but not platelet transfusion (table). 48,7% of patients in the study group received fibrinogen concentrate and median dose was 2 g (iqr 2-3). day 1 postoperative chest tube drainage and surgical reexploration were significantly lower. there were no differences in stroke, renal replacement therapy, mechanical ventilation time and icu stay. in patients with taad surgery, rotem-guided algorithms which include fibrinogen concentrate are associated with less (pob), surgical re-exploration and abt. further research is needed to document the role of vhas and concentrated factors in reducing (poc). andexanet alfa (aa, portola pharmaceuticals, san francisco, ca) represents a modified factor xa agent which is approved antidote for apixaban and rivaroxaban. andexanet alfa may also neutralize the anti-xa effects of betrixaban and edoxaban. this study aims to compare the relative neutralization of these four anti-xa agents by andexanet alfa in different matrices. andexanet alfa was diluted at 10 mg/ml. apixaban (a), betrixaban (b), edoxaban (e) and rivaroxaban (r) were diluted in ph 8.4, 0.5 m tris buffer (tb), blood bank plasma (bbp) and in 5% albuminated buffer (ab) at 0.062 -1.0 ug/ml. anti-xa activities of all four agents were measured in three systems and the reversibility indices of aa were profiled. the reversibility index (ri 50 ) of anti-xa effects by aa was determined at 25 -100 ug/ml. each of the four agents produced varying degrees of inhibition of anti-xa at 0.062 -1.0 ug/ml, the ic 50 ranged 0.61 -1.53 ug/ml in bbp, 0.47 -1.28 ug/ml in ab and 0.49 -1.4 ug/ml in tb. andexanet alfa produced a concentration dependent reversal of all four anti-xa agents. in the bbp, the ri 50 values for a (192 ug/ml), b (32 ug/ml), e (152 ug/ml) and r (85 ug/ml). in the ab, the ri 50 values for a (140 ug/ml), b (46 ug/ml), e (176 ug/ml) and r (58 ug/ml). in the tb, the ri 50 values for a (154 ug/ml), b (79 ug/ml), e (>400 ug/ml) and r (110 ug/ml). each of the four anti-xa agents exhibit varying degrees of matrix independent anti-xa potencies in different systems, the collective order follows edoxaban > apixaban > betrixaban > rivaroxaban. andexanet alfa produced matrix dependent differential neutralization of the anti-xa effects of these agents. individualized dosing of andexanet alfa may be required to obtain desirable clinical results. the diagnostic and prognostic value of thromboelastogram (teg) in sepsis has not been determined. this study aimed to assess whether teg is an early predictor of coagulopathy [1, 2] and is associated with mortality in patients with sepsis. in total, 518 patients with sepsis on intensive care unit admission were prospectively evaluated. we measured teg and conventional coagulation tests(ccts)on preadmission and observed for development of 1, 3 days and 1, 3, 7days respectively. multivariable logistic regression was utilized to determine odds of icu/hospital mortality. the parameter of teg (maximum amplitude, reaction time; ma/r ratio) was calculated to evaluate sepsis-induced coagulopathy. the admission patients were divided into three groupsma/r0 group(ma/r= 5-14mm/min); ma/r1group(ma/r>14 mm/min)and ma/r2 group(ma/r<5mm/min). in our cohort of patients with severe sepsis, coagulopathy defined by ma/r ratio was associated with increased risk of icu/hospital mortality. introduction: blood sampling for coagulation assessment is often carried out in either arterial or venous samples in the intensive care unit (icu). there is controversy as to the accuracy of this method due to the inherent differences in physicochemical properties as well as the underlying effects of individual diseases in arterial and venous blood. clot microstructure has shown to be a new biomarker (fractal dimension-d f ) which encompasses the effects of diseases in all aspects of the coagulation system [1, 2] . in this study, we compared the effect of all these factors in venous and arterial blood to see if there is a difference in the clot microstructure and quality. 45 patients admitted to a tertiary intensive care unit and busy teaching hospital were recruited. arterial and venous blood was sampled from an arterial line and central venous catheter in situ from the same patient. standard markers of coagulation (pt, aptt, fibrinogen, full blood count), rotational thromboelastometry (rotem), whole blood impedance aggregometry and measured clot microstructure (d f ) were measured on both arterial and venous samples. no significant difference was observed in standard laboratory markers, rotem and platelet aggregation between arterial and venous blood. there were no differences in the fractal dimension (d f ) between the arterial and venous blood samples (d f 1.658 ± 0.10 vs 1.654 ± 0.08 respectively, p=0.830). samples from patients with critical illness give comparable results from either arterial or venous blood despite their underlying pathophysiological process or treatment. this confirms blood for coagulation testing can be taken from arterial or venous blood. clinicians in the emergency setting use a wide range of hemostatic markers to diagnose and monitor disease and treatment. current methods rely on the anticoagulant effect of citrate on whole blood prior to laboratory analysis. despite the well-recognized modulatory effects of citrate on hemostasis, the use of anticoagulated blood has clear analytical advantages, including repeat sampling and storage. however by altering the physiological state of the blood reproducibility and accuracy of the test is affected. recent studies have shown the potential of a novel functional biomarker of clot formation: fractal dimension (d f ), that may give an improved diagnostic accuracy. in this study we assessed the potential of this new biomarker in scientifically measuring the effects of recalcification of citrated samples. methods: 35 healthy volunteers were included. unadulterated and sodium citrate samples of blood were taken from each volunteer. citrated samples were recalcified using (1m cacl 2 ). in the study we compared unadulterated whole blood d f results to citrated d f results and repeated the citrated d f experiments 5 times for each sample over a 2 hour period to ascertain reproducibility. the d f of citrated blood was significantly lower than that of unadulterated blood (1.57±0.04 vs 1.69±0.04, p<0.001). the results of the citrate samples when tested 5 times over 2 hrs gave a coefficient of variation of 1.16%. for the first time we show that a functional biomarker of clot microstructure, d f , can precisely quantify and measure accurately the direct effect that the addition of the anticoagulant sodium citrate has on whole blood clot microstructure. the study also shows that the test is reproducible and has potential utility as a biomarker of acute disease in the emergency setting in citrated blood. this procedure now needs to be evaluated in a group of acute disease states. in this study, we analyzed the hematological abnormalities of dengue patients by thromboelastography (teg) at initial and 1-hour of fluid resuscitation. methods: this is a cross-sectional study evaluating teg readings of dengue patients with different severities presenting to the emergency department. laboratory confirmed dengue patient (positive ns1 antigen or igg/igm) was consecutively sampled. teg readings were taken at presentation and after 1-hour of fluid resuscitation. twenty dengue patients with varying severity had a median reaction time (r), α -angle, k time, maximum amplitude (ma) and lysis 30% (ly30) of 0.495 min, 68.74 ο , 3.58 min, 44.64 mm and 0.54% respectively. mean fibrinogen was normal before and after fluid infusion. there is a non-significant reduction in ma with prolongation of other teg parameters between different dengue severities. there is a statistically significant reduction of α-angle and ma between pre and post 1-hour fluid resuscitation (p=0.019 and p=0.040). normal fibrinogen with low ma, which signifies a weak clot strength, may indicate either a platelet reduction, platelet dysfunction or both. reduction in ma and α-angle post fluid resuscitation is an alarming finding. this is in contrast with previous teg studies although none of it used normal saline exclusively, studied initial fluid resuscitation in emergency department settings or studied a subject with dengue. a bigger study, especially in severe dengue is needed to validate our findings. agreement between the thromboelastography reaction time parameter using fresh and citrated whole blood during extracorporeal membrane oxygenation with teg®5000 and teg®6s m panigada, s de falco, n bottino, p properzi, g grasselli, a pesenti fondazione irccs ca´granda ospedale maggiore policlinico, intensive care unit, milano, italy critical care 2020, 24(suppl 1):p327 the r (reaction time) parameter of kaolin-activated thromboelastography (teg) may be used to assess the degree of heparinization of blood during ecmo. a teg analysis is usually performed on two types of samples: fresh (f) or citrated-recalcified (c) whole blood. teg®5000 can perform the analysis on c and f whole blood, the new teg®6s (haemonetics corp., ma, usa) only on c whole blood. aim of the study was to compare the response of r to heparin using the two types of samples and two teg devices methods: during a three months period at fondazione irccs ca' granda -policlinico of milan, teg was performed (using teg5000® and teg 6s® with and without heparinase, an enzyme that degrades heparin) on 13 consecutive ecmo patients (as part of the gatra study, nct03208270) and in 8 consecutive non-ecmo patients in whom a teg was requested for clinical purposes. bland altman analysis and lin's concordance correlation coefficient were used to assess agreement results: a total of 84 paired samples were taken (74 in-ecmo and 10 off-ecmo). ecmo patients received 19.2 (12.6-25.8) iu/kg/h of heparin. among non-ecmo patients, 5 of them did not receive any dose of heparin, two of them a very low prophylactic dose (1.6 and 2.9 iu/ kg/h, respectively), and one of them 13.1 iu/kg/h of heparin. using teg®5000, r was -21.0 (-65.5; 23.4) min shorter on c compared to f blood in patients receiving heparin (this difference disappeared using heparinase) and only -1.58 (-8.70; 5.54) min shorter in patients notreceiving heparin. r was -26.6 (-77.3; 24.2) min shorter using teg®6s (which performs the analysis only on c blood) than teg®5000 on f blood (figure 1) . when evaluating the effect of heparin using teg, clinicians should be aware that results obtained using citrated-recalcified or fresh whole blood are not interchangeable. using citrated-recalcified blood to perform teg might lead to underestimation of the effect of heparin trauma patients are at high risk for venous thromboembolism (vte). the 2002 east guidelines recommend low molecular weight heparin (lmwh) for vte prevention and antixa monitoring after initiation of the medication or after adjusting doses in certain populations [1] . studies have shown standard enoxaparin dosing of 30 mg every 12 hours may result in low antixa levels [2] . this study aims to evaluate the efficacy of a pharmacist-lead protocol for adjusting enoxaparin dosing based on antixa levels in trauma patients. this single center retrospective chart review included adult trauma patients admitted from 3/1/2018 to 9/20/2019. per protocol, patients with body mass index (bmi) ≤40 kg/m 2 were initiated on enoxaparin 30 mg twice daily, and patients with bmi > 40 kg/m 2 were initiated on enoxaparin 40 mg twice daily. peak antixa levels were drawn 4 to 6 hours after at least the third dose of enoxaparin with a goal therapeutic range of 0.2-0.4 iu/ml. the primary objective was time in days to goal peak antixa level. secondary objectives include vte occurrence, bleeding attributed to lmwh, and dosing regimens utilized. subgroups were analyzed based on body mass index (bmi). of 511 patients identified, 375 patients met inclusion criteria. median time to therapeutic antixa level was 3 days (iqr 2-6). of 337 patients fig. 1 (abstract 327) . agreement between teg®6s and r teg®5000 on citrated recalcified and fresh whole blood with bmi ≤ 40 kg/m 2 , 319 patients (94.7%) were dosed initially per protocol and 153/319 patients (48.0%) met goal antixa level at first check (table 1) . of 38 patients with bmi > 40 kg/m 2 , 24 patients (63.1%) were dosed initially per protocol and 8/24 patients (33.3%) met goal antixa level at first check. our results indicate the protocol is safe due to lack of bleeding attributed to enoxaparin, but less than 50% of patients achieved goal antixa level at first check. however, despite low rates of achieving goal antixa level, vte rates also remained low. introduction: most patients in the icu are given prophylactic anticoagulation with a fixed dose of 40 mg once daily of enoxaparin (clexane) if cct is normal and 20 mg if cct is low. studies on non icu patients have shown that afxa is below desired range for venous thromboembolism (vte) prevention. in the icu, many factors might influence afxa levels including weight, creatinine clearance (cct), shock and other medication. atxa activity was not yet reported in a big mixed icu population with variable morbidity. our study hypothesis is that enoxaparin is underdosed in most cases and routine afxa activity should be monitored in all icu patients. preventive enoxaparin (40 mg qd) was given to all patients unless therapeutic dose was needed or contraindication existed. levels of afxa activity were taken 4 hours after the 3 rd dose. therapeutic vte preventive effect was defined as afxa activity of 0.2-0.5. patient data was collected from medical files. the study is still ongoing, preliminary results were analyzed for 31 patients. 14 of 31 patients (45%) had afxa activity below normal (subtherapeutic). weight and cct were negatively correlated with afxa activity (figure 1 ). mean weight in the subtherapeutic afxa was significantly higher than the therapeutic group (83.2 vs. 72.6 respectively, p=0.031). cct in the subtherapeutic afxa was significantly higher than the therapeutic group (95.1 vs. 60.4 respectively, p= 0.003). the normal cct group (>50) had significantly more patients with subtherapeutic afxa (13 vs 8, p=0.017). in our icu, 45% of the patients receive insufficient vte prophylaxis. overweight patients and patients with normal cct should probably receive higher enoxaprin dose. afxa activity should be routinely monitored in icu patients. in this study we use a new bedside biomarker to test its ability to measure anticoagulation effects on patients who present with acute first time deep vein thrombosis (dvt). dvt requires oral anticoagulants to prevent progression to potentially fatal pulmonary embolism and recurrence. therapeutic efficacy monitoring of direct oral anticoagulants (doac) including rivaroxaban is problematic as no reliable test is currently available. advances in hemorheological techniques have created a functional coagulation biomarker at the gel point (gp) which allows quantitative assessment of: time to the gel point (t gp ), fractal dimension (d f ) and elasticity (g') [1, 2] . the prospective observational cohort study measured t gp , d f , g', standard coagulation and cellular markers in first time dvt patients at three sample points: pre-treatment and approximately 20 and 60 days following 15mg bd and 20mg od rivaroxaban respectively. strict inclusion and exclusion criteria applied. results: 40 dvt patients (mean age 64 years [sd±14.8]; 23 male, 17 female) and 177 non-dvt patients were well matched for age, gender and co-morbidities. mean t gp on admission was 267s (sd±63.3s) and 262.9s (sd±73.5s) for dvt and non-dvt respectively. doac therapy significantly increased t gp to 392.3s (sd±135.7s) after 20 days, and subsequently increased to 395.5s (sd±194.2s) at 60 days as shown in table 1 . d f , g' and standard hemostatic markers all remain within the normal range. conclusions: t gp demonstrates its utility in determining the anticoagulant effect of rivaroxaban. the significant difference in t gp between males and females needs further exploration. localized stasis as a result of transient provoking factors appears not to generate a systemic strength fig. 1 (abstract p329) . correlation of anti factor xa activity with patient cct and weight. anti fxa activity value below 0.2 (red line), was considered "non-effective prevention" introduction: trauma remains the leading cause of death all over the world. to better exploit the trauma care system, precise diagnosis of the injury site and prompt control of bleeding are essential. here, we created a nursing protocol for initial medical care for trauma. the aim of this study was to evaluate the impact of protocoled nursing care for trauma on measures of quality performance. this was a retrospective historical control study, consisted of consecutive severe trauma patients (injury severity score >16). people were divided into two groups: protocoled group (from april 2017 to march 2019) and control group (from april 2014 to march 2017). we set the primary endpoint as mortality for bleeding. the secondary endpoints included time allotted from arrival to start of ct scan and surgery, administration rate of several drugs (sedations, painkillers, preoperative antibiotics, and tranexamic acid). for the statistical analysis, continuous variables were expressed as median (interquartile range) and were compared by wilcoxon rank sum tests given a nonnormal distribution of the data. we included 152 patients in the study: 84 in the control group before the introduction of the protocol, 68 in the protocoled group. as a primary endpoint, the mortality for bleeding was similar between two groups (5% in the control group and 5% in the protocoled group). as a secondary endpoint, the time to ct initiation [group a 11 (7-16) min vs group b 7 (5-10) min; p <0.001], and emergency procedure [group a 41 (33-56) min vs group b (29-43); p <0.001] were shortened by the protocol introduction. furthermore, the administration rates of sedations, painkillers, preoperative antibiotics, and tranexamic acid were increased in the protocoled group compared with the control group. although the mortality as a patient-oriented outcome was not affected, improved quality of medical care by nursing protocol introduction may be suggested in this analysis. this single-institutional prospective study included 72 patients with uprf who were admitted to the trauma surgical intensive care unit (tsicu) and survived until discharge to home between 2012 and 2017. we evaluated the activities of daily living after the discharge using physical and mental component scores of sf-36® and defined physical dysfunction (pd) as physical function (pf-n) score of 40 or less. we divided the patients in the pd (n=34) and control (without pd, n=38) groups and compared the groups. the patients had experienced blunt injuries, including falls (38%) and pedestrian injuries (33%). the mean age was 59.9 years (men: 65.3%); the median injury severity score was 22 (interquartile range: 13-29); and the mean length of tsicu stay was 3.3 days. the average period from the injury until the survey was 34.1 months. there was no difference between the pd group and the control group in the patient characteristics, fracture type, pelvic fixation, and complications. at the time of the survey, the pd group had significantly more painful complaints than the control group (pd: 67.6%, c: 23.6%, p <0.01), and had more physical and mental problems. the sf-36®subscale score showed a significant positive correlation between physical function and body pain, mental health respectively. the percentage of those who were able to return to work was not different in both groups (pd:26.5%, c:47.4%). in the multivariate analysis of pd, only age (odds ratio: 1.039, 95% ci: 1.00-1.07, p = 0.03) was relevant. long-term pd was observed in 47% of patients with uprf. the elderly were particularly prominent, and there was an association between pain and mental health. cells (rbc) this can lead to inhibition of oxygen transport function and development of hypoxia. currently used methods for analyzing the state of rbc either do not have sufficient accuracy or require lengthy analysis and expensive equipment. the use of a simpler and more informative electrochemical approach to assessing the state of rbc is very promising. electrochemical measurements in rbc suspensions (~5 • 109 cells / l) were carried out in a special electrochemical cell [1] in the potentiodynamic mode in the potential range from -0.5 to +1.2 v using the ipc pro mf potentiostat (kronas, russia); optical measurements were performed using an eclipse ts100 inverted microscope (nikon, japan), a cfi s plan fluor elwd 60x / 0.70 lens (nikon, japan); rbc morphology was recorded in real time using a ds-fi1 digital camera (nikon, japan). when examining rbc of patients with severe multiple trauma a decrease in the ability of rbc to change their shape during electrochemical exposure was observed, indicating a decrease in deformability, which can lead to a disruption in the oxygen supply to tissues. at the same time, with the stabilization of the patient's condition a restoration of the ability of rbc to change morphology was detected which in turn could have a positive effect on the rheological characteristics of the blood (fig. 1) . the results of the analysis of red blood cells using electrochemical changes in their morphology can be used as an additional method for the diagnosis of critical conditions. severe trauma should be treated immediately. whole-body ct (wbct) is widely accepted to improve the accuracy of detecting injuries. however, it remains the problem of time-consuming. therefore, we focused on the scout image taken in advance of wbct. detecting major traumatic injuries from a single scout image would reduce the time to start treatment. a previous study suggested that even specialists could not easily find chest and pelvic injuries using wbct scout image alone. in this study, we aimed to develop and validate deep neural network (dnn) models detecting pneumo/hemothorax and pelvic fracture from wbct scouts. we retrospectively collected 2088 anonymous wbct scouts together with their clinical reports at the osaka general medical center between january 1, 2013, and december 31, 2017. we excluded incomplete, younger than 7 years old, postoperative, and poorly depicted images. the part of this dataset from january 1, 2017, until december 31, 2017, was used for validation and the rest for training dnn models. pneumo/hemothorax detection model and pelvic fracture detection model were trained respectively. accuracy, and areas under the receiver operating characteristic curves (aucs) were used to assess the models. the training dataset for pneumo/hemothorax contained 984 images (mean age 48 years; 30% female patients), and for pelvic fracture consisted of 783 images (48 years; 28%). the validation dataset for the former contained 258 images (54 years; 30%), and for the latter consisted of 186 images (55 years; 24%). the models achieved 59% accuracy and an auc of 0.57 for detecting pneumo/hemothorax, 72% and 0.62 for pelvic fracture. our results show that dnn models can potentially identify pneumo/ hemothorax and pelvic fracture from wbct scouts. increasing the number of samples, dnn model could accurately detect severe trauma injuries using wbct scout image. clinical information system (cis) is a computer system used in collecting, processing, and presenting data for patient care. it can reduce staff workload and errors; help in monitoring quality of care; track staff's compliance to care bundles; and provide data for research purpose. however, the transition from paper record format to electronic record involves changes in all kind of workflow in icu. therefore, an effective, efficient and evaluative rollout plan was required to minimize the risk that might arise from the new practice. methods: 1. small groups training were provided. a working station with different case scenarios were set up for practices. 2. individual tutorials were conducted to clarify questions. emphasis on patient care was always top priority. 3. contingency plans were available in case of server breakdown and power failure. downtime drills were conducted to prepare the staff in emergency situations. 4. step-by-step transition from paper record to electronic format was gradually carried out. a plan was discussed among cis team with clear dates and goals. 5. new items in cis were first reviewed and amended in team meeting until consensus was made; then were promulgated to all staffs during handover before implementation. fig. 1 (abstract p333) . the effect of therapy on the electrochemically induced change in the morphology of red blood cells in patients with combined trauma 6. staff compliance and outcomes were then monitored; further review and amendment would be possible if necessary. cis roll-out plan was smooth. all staffs were able to integrate cis into the daily routine. the contingency plans were well acknowledged. new items were followed as planned. ongoing enhancement in cis was put forward on nursing orders, handover summary, and integration with inpatient medication order entry (ipmoe) system. with emerging benefits cis brings along, our staff has more time to devote to direct patient care. human input in data interpretation and clinical judgment on top of cis play an irreplaceable role in patient care. the daily request for laboratory tests in intensive care units is a common practice. although common, this strategy is not supported, since more than 50% of the exams requested with this rationale may be within the normal range [1] . misconduct based on misleading results, anemia, delirium and unnecessary increase in costs may happen [2] . we have developed a strategy to reduce laboratory tests without clinical rationale. observational retrospective study, from july 2018 to june 2019. the number and type of laboratory orders requested, the epidemiological profile of hospitalized patients, the use of advanced supports, the average length of icu stay and the impact in outcomes such as mortality and hospital discharge at a private tertiary general hospital in the city of rio de janeiro / rj -brazil were analyzed. a strategy was implemented to reduce the request for exams considered unnecessary. approximately 1,300 patients underwent icu during this period. the epidemiological profile and severity of patients admitted to the unit were similar to those observed historically. there was a significant reduction (> 50%) in the request for laboratory tests and there was no negative impact on outcomes such as mortality, mean length of stay and no greater use of invasive resources. over the period evaluated, the estimated savings from reducing the need for unnecessary exams were approximately $ 150,000 per year. the rational use of resources in the icu should be increasingly prioritized and the request for routine laboratory tests reviewed. a strategy that avoids such waste, when properly implemented, enables proper care, reducing costs and ensuring quality without compromising safety. evaluating the medication reconciliation errors in 2 icus after implementing a hospital-wide integrated electronic health record system a rosillette, r shulman, y jani university college hospital, centre for medicines optimisation research and education, london, united kingdom critical care 2020, 24(suppl 1):p337 introduction: medication errors in intensive care unit (icu) are frequent [1] and can arise from a number of causes including transition of care. our aim was to investigate the impact of an integrated electronic health record system (ehrs) on medication reconciliation (mr) errors occurring at 2 critical steps: during the transition from an icu to the hospital ward and from the ward to hospital discharge. the objective was to examine the influence of icu admission on long-term medication. we performed a monocentric study in 2 icus of a university-affiliated hospital using drug chart and medical notes review to identify mr errors before, during and after icu admission. data were collected retrospectively from ehrs for 50 consecutive patients discharged from the icu between 1 june-31 july 2019, and who were newly initiated on specific drugs of interest. results: 129 drugs of interest were initiated in icu. many of these were continued after hospital discharge as shown in table 1 . there was appropriate discontinuation of all the antipsychotics newly initiated in icu. other than anticoagulants, there was no reason documented for continuation of the initiated drugs. the planned durations were documented more often after hospital discharge than icu discharge for the following drug classes (% of patients with a plan after icu discharge to the ward; % after home discharge): antibiotics (47.6%; 52.6%), and steroids (45.4%; 57.1%), but less so for analgesics (36.3%; 14.3%), insomnia (0.0%; 20.0%), and gastroprotective drugs (0.0%; 20.0%). our study has shown that medications initiated in the icu can be inadvertently continued at icu and hospital discharge due to failure in documenting indication or duration. systems are required to deprescribe icu only drugs at discharge or communicate a plan for ongoing treatment. introduction: the surviving sepsis campaign advocates the use of care bundles to guide the management of sepsis and septic shock [1] . our study aim was to assess compliance with a locally introduced sepsis pathway and to review intensive care unit admission outcomes. we carried out a prospective audit of patients admitted to the icu at royal surrey county hospital with a diagnosis of sepsis between 19/ 3/19 and 19/11/19, assessing compliance with local sepsis bundle delivery, outcome of icu admission and degree of associated organ dysfunction. results: 119 patients were identified, 71 male (59.7%), with a mean age of 65.7 (18-96). mean 1 st 24 hour sofa score on icu was 6.65 (2-15). 81% of patients required vasopressors, with 67% requiring noradrenaline >0.1mcg/kg/min, and 19% requiring an additional vasopressor/ inotrope. 36% required niv, 32% invasive ventilation and 15% rrt. icu mortality was 15%, in-hospital mortality 24%, mean icu stay 8 days (1-49), and mean length of hospital stay 28 days . in the presence of septic shock mortality was 47% with post-resuscitation lactate >4, versus 21% in patients with no vasopressor requirement or lactate <2 (p<0.05). the sepsis bundle was delivered in one hour to 61 patients (51%). where the bundle wasn't completed, antibiotics were delayed in 26% of cases and blood cultures weren't taken in 66%. where the bundle was fully delivered, unit mortality was 12% vs. 21% where it was not (p<0.05), but there was no significant difference in hospital mortality (26% vs. 30%, p>0.5) or rates of vasopressor requirement, niv, ippv or rrt. there is room for improvement in timely delivery of the sepsis bundle in our hospital and various measures are being instituted. though there was no significant difference in hospital mortality, icu mortality was significantly lower in patients when the bundle was fully delivered. surviving sepsis campaign recommends 3h and 6 h sepsis resuscitation bundle for sepsis. the study was done to assess the feasibility of the guideline and the compliance to sepsis-3 recommendations at an emergency department. prospective interventional study was conducted during one year. were involved in the study all sepsis cases with a qsofa ≥ 2. were assessed a composite of six components (measurement of serum lactate, obtaining blood culture before antibiotic administration and provision of broad-spectrum antibiotic before the end of h3 and provision of fluid bolus in hypotension, attainment of target central venous pressure assessed by cardiac ultrasonography, target lactate to normal level before the end of h6). time base line was the first medical contact at triage zone. secondary outcomes of study were the mortality rate and length of stay at intensive care unit (icu). were involved in the study, 128 patients (mean age 54±17 years, sex ration 2,3). pulmonary infections were the main cause of sepsis (37%) and urinary tracts infections (22%). at h3 components were achieved in 79% of cases [lactates (100%), blood culture (82%) and provision of antibiotics (79%)]. at h6 components were executed in 64% of cases (fluid provision achievement in 89%, ultrasonography assessment in 64% and normal lactate target achieved in 71%) (figure 1 ). the reliability-adjusted rate for completion of the 3 hours and 6 hours bundle was at 68%. patients compliant to composite bundle got the mortality benefit (odds ratios = 0.31, 95% [confidence interval, 0.11-0.72]). the study, however, did not show any benefits of mean intensive care unit (icu) length of stay. faisability of 3-6h bundle ratio was at 68%. it has shown a significant improvement in adaptation and mortality benefit without reducing mean hospital/icu length of stay. more adapted procedures are needed to improve results targeting full compliance of patients to the 3-6h bundle sepsis management. patterns and outcome of critical care admissions with sepsis in a resource limited setting m edirisooriya maddumage 1 , y gunasekara 2 , d priyankara 1 1 national hospital of sri lanka, medical intensive care unit, colombo 10, sri lanka; 2 sri jayawardenepura general hospital, department of critical care, nugegoda, sri lanka critical care 2020, 24(suppl 1):p340 introduction: paucity of epidemiological data is a major barrier in expansion of critical care services, especially in resource limited settings. we evaluated the patterns and the outcome of critically ill patients with sepsis admitted to a level 3 medical intensive care unit in sri lanka. a retrospective cohort study was performed to describe the characteristics and outcome of patients with sepsis, admitted to a medical intensive care unit. sepsis is defined according to sepsis 3 definition. we examined 360 critically ill patients admitted over a period of 6 months. sepsis was the commonest presentation, accounted for 63.6 % of all admissions. mean age was 49.2 ± 16.1 years. septic shock was present in 41.4% on admission. pneumonia (35.4%) was the commonest cause, while leptospirosis (17.9%) and meningoencephalitis (12.2%) accounted for fig. 1 (abstract p339) . sepsis 3-6h bundle components (% of goals achievment) second and third commonest causes of sepsis respectively. the sofa score on admission (8.8 ± 5.0 vs 7.5 ± 4.9, p< 0.025), occurrence of aki (62% vs 49.6%, p<0.02) and the length of icu stay (8.8 days vs 6.2 days, p <0.001), were significantly higher in sepsis than in patients without sepsis. icu mortality in sepsis (n=92) did not show a significant difference to nortality (n= 45) in those without sepsis (40% vs 35%, p= 0.5). patients with leptospirosis had a mean sofa score of 13.3, however the mortality (37.5% vs 40%, p = 0.75) was similar to others with sepsis. in contrast, mortality related to sepsis was significantly high ( 60%, p< 0.02) in the packground of immunosuppression (n= 35). respiratory failure secondary to pneumonia was the commonest cause of critical care admission with sepsis. sepsis related icu mortality was high in the background of immunosuppression. introduction: training in placement, and the subsequent safe confirmation of position, of a nasogastric (ng) tube, relies on clinicians completing an e-learning module at our trust. feeding through an incorrectly placed ng tube is a 'never event,' associated with significant morbidity and mortality [1] . analysis of these incidents reveal that the misinterpretation of chest radiographs, by medical staff, who had not received competency-based training, is the most frequent cause [2] . e-learning has revolutionized the delivery of medical education [3] , however, there are barriers to its use [4] . we hypothesized that, by taking e-learning content, and delivering it face-to-face, we would improve training rates, and thus patient safety. a questionnaire was completed by 50 critical care doctors, concerning their knowledge of the existence of the e-learning module, whether they had completed formal training in ng tube placement, and how confident they were, on confirming correct positioning, using a 5 point likert scale. all clinicians underwent training in the interpretation of ng placement, using chest radiographs. after the session they were asked to re-appraise how confident they felt. results were compared using paired t tests. confidence improved in all, rising from a pre-test average score of 3.74 (sd=0.92), to post-session 4.76 (sd=0.48), p=<0.0001. prior to the intervention, 63% of the doctors were aware of the trust guidelines, but only 17% had completed the training. after the session, 100% were aware of the guidelines, and 100% had completed the training (figure 1) . conclusions: e-learning is a useful tool, but has its limitations. by using course content, delivered with more traditional learning methods, we im-proved the number of appropriately trained clinicians, and thus the safe use of ng tubes in our unit. a systematic review of anticoagulation strategies for patients with atrial fibrillation in critical care a nelson, b johnston, a waite, i welters, g lemma university of liverpool, liverpool, united kingdom critical care 2020, 24(suppl 1):p342 there is a paucity of data assessing the impact on clinical outcomes of anticoagulation strategies for atrial fibrillation (af) in the critical care population. this review aims to assess the existing literature to evaluate the effectiveness of anticoagulation strategies used in critical care for atrial fibrillation. only 4 studies contained analysable data. anticoagulated patients had a lower mortality at 30 days and 365 days post admission to critical care, however there was an increased incidence of major bleeding events compared to the non-anticoagulated population. thromboembolic events were comparable in both cohorts. data from current literature is scarce and inferences regarding the effectiveness of anticoagulation in patients in critical care with af requires further investigation and research. every new admission to the icu prompts a handover from the referring department to the icu staff. this step in the patient pathway provides an opportunity for information to be lost and for patient care to be compromised. mortality rates in intensive care have fallen over the last twenty years, however, 20% of patients admitted to an icu will die during their admission [1] . communication errors contribute to approximately two-thirds of notable clinical incidents; over half of these are related to a handover [2] . nice have concluded that structured handovers can result in reduced mortality, reduced length of hospital stay and improvements in senior clinical staff and nurse satisfaction [3] . a checklist was created to review the information shared and to score the handover. this checklist was created with doctors and nurses and is relevant for handovers between all staff members. information was gathered prospectively by directly observing 17 handovers on the icu. there is a notable discrepancy in the quality of handovers of new patients ( figure 1 ). this is true of handovers between doctors, nurses and a combination of the two. it is also true of all staff grades. whilst a doctor may have reviewed the patient prior to their arrival, 41% (n=7) of patients weren't handed over to a doctor. the most commonly missed pieces of information were details of the patient's weight (96%, n=16), their height (100%, n=17), whether the patient has previously been admitted to an icu (78%, n=15) and whether the patient has any allergies (71%, n=12). the handover of new patients to the icu is often unstructured and important information is missed. this can be said for all staff members and grades, and for handovers from all hospital departments. post intensive care syndrome-family (pics-f) describes new or worsening psychological distress in family and caregivers after critical illness but remains poorly studied within specialist groups [1] . we aim to define the degree of pics-f within our tertiary referral cardiothoracic centre and map change over the course of 12 months. caregivers attended a 5-week multi-professional clinic alongside patients. peer support was facilitated through a café area and a caregiver group psychology session was offered with individual appointments if required. caregiver surveys were completed including: caregiver strain index; hospital anxiety and depression scale (hads); and insomnia severity index. patients also completed hads questionnaires. repeat surveys were completed at 3 and 12 months. results: over 5 cohorts, 23 caregivers attended, of which 17 were spouses (74%), 3 children (13%), and 3 others (13%), with 13 caregivers completing surveys at 12 months. patients' median apache 2 score was 17 (iqr 14-18.5) and median icu length of stay was 11 days (iqr 8-23.5). most admissions were from scheduled operations (56%). severe caregiver strain was present in 4/23 (17%) with changes to personal plans (35%) the most common sub category. hads demonstrated 13 caregivers (57%) with anxiety and 8 (35%) with depression. caregiver anxiety exceded that of patients', only reaching fig. 1 (abstract p343) . each handover was scored according to the information accurately given to icu staff similar levels at 12 months, while depression remained static ( figure 1 ). median number of nights with 'bothered' sleep was 5 (iqr 1-6.75) and 77% of caregivers expressed problems with sleep. conclusions: significant psychological morbidity in caregivers from our tertiary cardiothoracic centre is in keeping with the general icu population [2] . caregiver strain was reduced suggesting higher levels of resilience. future work should address mental wellbeing, particularly anxiety, to minimise the effects of pics-f. burnout syndrome is an illness that has increasingly affected health professionals. it is characterized by great emotional stress, physical and mental exhaustion and depersonalization of the individual. more serious cases can lead to job loss or even suicide. the described work identifies the burnout level of the multidisciplinary team through a specific questionnaireburnout syndrome is an illness that has increasingly affected health professionals. it is characterized by great emotional stress, physical and mental exhaustion and depersonalization of the individual. more serious cases can lead to job loss or even suicide. the described work identifies the burnout level of the multidisciplinary team through a specific questionnaire methods: application of a questionnaire suitable for the multidisciplinary group in november 2019. the same was answered by 85 professionals among physicians and nursing team. there was no identification of employees. after analysis of the results it is observed that 50% of the group presents initial burnout, 30% with the syndrome installed and about 5% with characteristics of greater severity. main factors found were: mental and physical exhaustion during the work day, the level of responsibility existing in the activity and the perception of disproportionate remuneration by work performed. all interviewees presented some degree of burnout or high risk to develop it. the most severe cases should be traced through occupational medicine and anti-stress measures with reorganization of work performance should be discussed in order to reduce the prevalence of this syndrome. introduction: burnout affecting the psychological and physical state of healthcare workers is recognized in the last 10 years. burnout has been shown to affect the quality of care. whilst some risk factors have been identified, there are gaps within the literature related to mental health and burnout. the aim of this study is to measure levels of burnout across 3 icu units in the metropolitan setting. to determine the level of burnout we used 2 surveys, the maslach burnout inventory human services survey (mbi-hss) and the centre for epidemiologic studies depression scale (ces-d). with the mbi-hss we analysed 3 different variables of burnout; exhaustion, cynicism and emotional exhaustion. basic demographic data and information regarding workout schedules were collected. we studied prevalence and contributing risk factors using and analysing the outcomes of the 2 self-scoring questionnaires. analysis was performed using descriptive statistical analysis. there were 90 respondents, 36% scored the threshold for depressive symptoms on the ces-d depression scale. interestingly, 40% (ci 25.4-57.7%) of those meeting the score for depressive symptoms identified as having frequent restless sleep compared with 11% (4.6-21.8 %) from those not meeting. gender did not affect depressive symptoms 35% of females and 37% of males met the threshold. with the mbi-hss for exhaustion the mean was 17.16 (sd 4.6) which is a high level of exhaustion, the second variable cynicism the mean score was 14.08 (sd 4.2), which was considered high. the final variable was emotional exhaustion the mean was 25.16 (sd 9.90), this is considered moderate levels of emotional exhaustion. fig. 1 (abstract p344) . hospital anxiety and depression scale (hads) scores for patients and caregivers at baseline, 3 months, and 12 months there was high prevalence of burnout in icu in all different categories as well as depressive symptoms. age and gender had no affect on burnout. interestingly, we identified that sleep and shift variables were linked to increased burnout. following the implementation of a fully integrated ehrs on 31 march 2019 at our university-affiliated hospital we conducted a prospective study in 2 icus by analysing pharmacists' contributions during 4 data collection periods of 5 days at 10, 15, 19 and 21 weeks post implementation. a pharmacists' contribution was defined as contacting the physician to make a recommendation in a change of therapy/ monitoring [1] . the 3 types of contribution were: a medication errorrectification of an error in the medication process; an optimizationproactive contribution that sought to enhance patient care, and a consult -reactive intervention in response to a request. a panel of experts composed of a senior pharmacist, a consultant, a nurse, and a pharmacy student assessed the impact of each contribution, scoring low impact, moderate impact or high impact. there were 160 pharmacist contributions recorded in the 4 periods. of these, 66 (41.2%) were medication errors, 93 (58.1%) were optimizations, and 1 (0.6%) was a consult ( table 1) . 37% of the contributions were assessed as having medium impact, 36% as high impact and 27% as low impact. in general, the consultant assessed fewer contributions as having high impact compared to other members of the panel, with 7 contributions assessed as high impact by the consultant versus 97 by the senior pharmacist. implementing an ehrs in combination with contributions of clinical pharmacists can prevent medication related issues. interestingly the types of incident did not change over time. introduction: most icu's are noisy and may adversely affect patients outcomes and staff performance [1] . who reports that the noise level in hospitals should not exceed 35 db at daylight and 30 db at night. the aim of this study is to evaluate the noise levels in intensive care unit, to apply awareness training to intensive care staff in terms of noise and to compare the noise levels before and after education. noise measurement areas are separated into 17 points including 12 patient bedsides, nurse desk, staff desk, wareroom, corridor and entrance of intensive care unite. measurements were performed 14 times per day. after 10 day, awareness training were given to staff in terms of harmful effects of noise. after the training, noise measurements were repeated during 10 days. after total 20 days the measurements were terminated. noise was measured with incubator analyzer (fluke model: bio-tek serial no:6050274). the mean noise values before and after the training were not statistically different from the mean average noise values (p>0.05). when the time of measurement were compared, the noise levels were higher between 10-16 hours to other measurements before and after the training statistically (p=0.001). seventeen different noise measurement areas were compared in terms of noise level, there was no statistically significant difference (p>0.05). the differences were examined at the same hours between before and after training. contrary to expectations, noise levels were found to be higher after training statistically (p<0.05). all of noise measurements were higher than the threshold values that who recommended. increased noise levels in critical care units may lead to harmful health effects for both patients and staff. our results suggest that much noise in the icu is largely attributable to environmental factors and behavior modifications due to education have not a meaningful effect. critical care medicine has focused on continuous, multidisciplinary care for patients with organ insufficiency in the face of lifethreatening illness. despite significant resource limitation low income countries carry a huge burden of critical illness. available data is insufficient to clearly show the burden and outcomes of intensive care units in these developing countries [1] . the objective of our study is to evaluate the morbidity and outcomes of patients admitted to the intensive care unit of a tertiary university hospital in hawassa, ethiopia. this was a prospective observational study. data was registered and analysed starting from patient admission to discharge during a 12 month period beginning september 2018. data regarding demographics, sources of admission, diagnosis, length-of-stay and outcomes were analysed. the total number of patients admitted to the icu was 218, with 71 patients dying over a one year period. the highest admission was from emergency medical unit, 36% and the lowest source was from pediatrics department, 8%. out of these, 69.8% were males. the mean age was 27 years (2-62). the most frequent aetiologies of morbidity in the admitted patients were traumatic brain injury (24.6%), acute respiratory distress syndrome (22.9%) and seizure disorder (8%). average median length of stay was 3.0 days (interquartile range: 1.0 -27.0). the overall mortality rate was 32.5%. the top four causes of death in the icu were respiratory illness at 24% followed by sepsis with multiorgan failure at 20%, trauma (16%) and central nervous system infection (12%). infection morbidity and mortality remains very high and needs institution of aggressive preventive strategies. the increase in frequency of trauma patients need to receive due attention. sepsis causes a high number of deaths, though overtaken by respiratory illnesses. improving the overall system of icu may achieve better outcomes in resource limited countries. introduction: icu mortality has been widely studied in the literature in relation to outcome index that primarily value organic failure [1] . however, early mortality, in the first 48 hours of admission has been little documented in the literature. the aim of this study is to analyze factors related to early mortality in icu. retrospective study at a second-level hospital. time of study was 12 months. patients who died in icu were included, patients were classified according timing of dead, including those who died within the first 48 hours of icu admission. the variables analyzed were age, sex, comorbidity, charlson index, apache ii, need for supportive treatments, more frequent admission diagnosis, origin and support treatment limitation decisions. the statistical study was carried out using the spss statistical program. 138 patients were included during the study period, 72 (52.2%) died within the first 48 hours of admission. no differences in the needs of support treatments were observed, more than 90% of patients received mechanical ventilation and vasoactive therapies. table 1 shows characteristics of patients. half of icu deaths occur within the first 48 hours of admission. severity at icu admisison was the main factor related with early mortality. severe stroke and coronary disease were the most frequent causes of early deaths in icu. in august 2018 the royal college of anaesthetists published guidelines on care of the critically ill woman in childbirth and enhanced maternal care [1] . approximately 11000 babies are born across the area covered by leicester university hospitals that includes two large maternity units and is part of the uk ecmo network. this audit sets out to assess current practice and form a basis for future planning, which will likely be representative to most major obstetric centres. a retrospective audit of all patients admitted to 'intensive care units' in leicester over a 12 month period following publication of the guidelines. the focus was on patients admitted to general adult intensive care and excludes all patients cared for in 'enhanced obstetric care' units. 9 simple standards were proposed relating to accessibility, resuscitation, follow up and multi-disciplinary learning. in total 49 women were identified with a broad range of diagnosis. the intensive care services are split across 3 hospitals and we found this led to a number of problems. the presence of trained staff to resuscitate a newborn were easily accessible, no steps to provide necessary equipment pre-emptively were present in any centre. none of our critical care units had a plan for perimortem section. on-going reviews by the obstetric and midwifery teams were very variable. contact with the infant and breastfeeding support was also poor. despite the large number of deliveries significant work needs to be done in order to come in line with the new national guidelines for critically ill woman in childbirth. clearly defined pathways around escalation of care, resuscitation of both the mother and baby, integrating care of the mother and the infant in the first few days of life, and multidisciplinary learning events are being produced de novo in response to these guidelines, some of which will be illustrated in the associated poster. interprofessional collaboration scale [3] . data were analyzed with ibm spss 25.0 results: it was found that cooperative attitudes with an average score of 49 to 75 are considered to be of average significance. interprofessional cooperation at an average score of 2,568 states that the level of cooperation is high and the quality of working life averages 125 to 150, suggesting that it is very good. as far as professional satisfaction is concerned, nurses are happy, content and satisfied with their work, despite workload and burnout conclusions: interprofessional cooperation at the icu of the general hospital of larissa is high, but satisfaction from wages, resources, working environment and conditions is low. in addition, the results showed that improvements in hospital communication between staff, has a positive impact on the quality of professional life (table 1) . contrasting with previous reports, decreased admissions per unit population in older and oldest age groups, and those with high comorbidity, suggest resource constraints may have influenced admission discussion and decision-making over the 10-year study period in wales. further investigation is warranted. icu discharge into weekends and public holidays: an observational study of mortality n mawhood, t campbell, s hollis-smith, k rooney bristol royal infirmary, general intensive care unit, bristol, united kingdom critical care 2020, 24(suppl 1):p355 introduction: up to a third of in-hospital deaths in icu patients occurs following ward stepdown [1] . discharge time seems to be associated with in-hospital prognosis, but meta-analyses have not shown a difference in weekday compared to weekend discharge [2, 3] . however, papers that examined discharge 'into' out-of-hours days, particularly on fridays, have found differences [3] . our aim was to assess whether discharge from icu 'into' out-of-hours (ooh -weekends and public holidays) is associated with in-hospital mortality or re-admission to icu, and whether these patients were seen on the wards ooh by medical staff. all adults discharged from the general icu to a ward at the bristol royal infirmary in december 2016-18 were included. in-hospital mortality rates were assessed for each day, with 'into weekdays' defined as sunday to thursday and 'into ooh' friday, saturday and the day before a public holiday. a subset of patients with data on readmission rate to icu was also examined. all available notes from patients discharged into ooh in 2018 were reviewed. the study included 1732 patients with a subset of 443 with readmission data. 117 sets of notes were reviewed from patients discharged into ooh (figure 1 ). the in-hospital mortality was significantly higher in patients discharged into ooh (5.1% vs 7.6%, p=0.012). within the subset, ooh was associated with in-hospital mortality or readmission to icu (6.8% vs 11.9%, p=0.044), though readmission rate alone was not (1.7% vs 2%, p=0.35). of patients discharged into ooh, once on a ward 64% were reviewed by a specialty doctor but 20.5% were not seen. this is the first study to examine icu discharge 'into' ooh days including public holidays. we found increased hospital mortality in ooh, similar to other studies [3] . up to a fifth of high-risk icu stepdown patients were not reviewed by a doctor on ooh days. exploring the experiences of potential donors' family members (fm) in a follow up clinic is crucial to analyze the effects of organ procurement (op) on the bereavement process, to gain insight on the reasons of family refusals (fr), and to improve family care during op. a mixed-method study involving fm at 3 and 12 months after patients' death was developed and approved by local ethics committee. fm of potential donors after brain (dbd) and cardiac death (dcd) treated in careggi teaching hospital, florence (italy) were eligible if adult and consenting. invitation letters were sent to the entitled 2 months after death and those who actively responded were involved in an encounter with a multidisciplinary group including a clinical psychologist, two nurses and two cultural anthropologists with expertise in op. organ replacement procedures such as ecmo (extracorporeal membrane oxygenation), lvad (left ventricular assist device) and dialysis are routinely used to treat multi-organ failure (mov). globally transplantation programs struggle with increasing organ shortage. patients (pts) with mov are a potential source for procurement. however, outcome data after kidney transplantation (ktx) from such donors are sparse. we retrospectively studied the cadaveric ktx at the charité berlin in 2018 and identified donors with ongoing organ replacement procedures. donor and recipient risk factors were assessed. overall patient and graft outcomes were analyzed at 12 months post-transplant. a total of 220 kidneys were transplanted. we identified 11 ktx from 7 donors with mov (6 following cardio-pulmonary resuscitation, 5 with acute renal failure -4 on dialysis) (figure 1 ). in 3 donors, a venoarterial ecmo was implanted during ecls-resuscitation. one donor needed a veno-venous ecmo due to ards, and 1 donor had a lvad implanted due to cardiac failure. the donor age was 41 ± 10.5 years (yrs). in addition, 6 donors had at least one cardiac risk factor. the kidney donor risk index averaged 0.94 (sd ± 0.14) and s-creatinine prior to ktx was 2.41 (sd ± 1.27 one way to expand the potential donor pool is donation after circulatory death (dcd), and a strategy to reduce the complications related to the ischemic time is the use of normothermic regional perfusion (nrp) with extracorporeal membranous oxygenation (ecmo) [1, 2] . we compare the use of standard nrp with an effective adsorption system inflammatory mediators (cytosorb®) in the regional normothermic reperfusion phase via regional ecmo, that involves a reduction in cellular oxidative damage, assessed as a reduction in levels of proinflammatory substances. we report a case series of 9 dcd-maastricht iiia category donors, treated in ecmo with nrp, to maintain circulation before organ retrieval, in association with cytosorb® in 5 patients. during perfusion, from starting nrp (t0), blood samples are collected 3 times, every 60 minutes (t1, t2, t3). during treatment with cytosorb®, lactate levels progressively decrease, ast and alt increase less than without cytosorb®, as sign of improvement in organs perfusion ( figure 1 ). nrp with cytosorb® might help to successfully limit irreversible organ damages and improve transplantation outcome [2] . development and implementation of uniform guidelines will be necessary to guarantee the clinical use of these donor pools. introduction: shock is a common complication of critical illness in patients in intensive care units (icus), who are undergoing major surgery. this condition is the most common cause of death in postsurgical icus. nowadays, there are different icu scoring systems for predicting the likelihood of mortality, such as apache or sofa. nevertheless, they are used rarely because they also depend on the reliability and predictions of physicians. in these sense, gene expression signatures can be used to evaluate the survival of patients with postsurgical shock. methods: mrna levels in the discovery cohort were evaluated by microarray to select the most differentially expressed genes (degs) between groups of those that survived and did not survive 30 days after their operation. selected degs were evaluated by quantitative real time polymerase chain reactions (qpcr) for the validation cohort to determine the reliability of the expression data and compare their predictive capacity to that of established risk scales. introduction: this study evaluates the prognostic ability of frailty and comorbidity scores in patients with septic shock. the 90-day mortality rate of individual medical conditions are also compared. the burden of comorbid illness and frailty is increasing in the critical care patient population [1] . outcomes from septic shock in patients with chronic ill-health is poorly understood. interstitial lung disease is a group of diseases associated with poor prognosis in the intensive care unit despite major improvement in respiratory care in the last decade. the aim of our study is to assess factors associated with hospital mortality in interstitial lung disease patients admitted in the intensive care unit and to investigate the long-term outcome of these patients. we performed a retrospective study in an intensive care unit of teaching hospital highly specialized in interstitial lung disease management between 2000 and 2014. a total of 196 interstitial lung disease patients were admitted in the intensive care unit during the study period. overall hospital mortality was 55%. two years after intensive care unit admission, 70/196 patients were still alive (36%). one hundred eight patients (55%) required invasive mechanical ventilation of whom 80% died in the hospital (figure 1 ). acute exacerbation of interstitial lung disease was associated with hospital mortality (or=5.4 [1.9-15.5] ), especially in case of acute exacerbation of idiopathic pulmonary fibrosis. multiorgan failure (invasive mechanical ventilation with vasopressor infusion and/or renal replacement therapy) was associated with very high hospital mortality (64/66; 97%). survival after intensive care unit stay of patients with interstitial lung disease is good enough for not denying them from invasive mechanical ventilation, except in case of acute exacerbation for idiopathic pulmonary fibrosis patients. if urgent lung transplantation or extracorporeal membrane oxygenation are ruled out, multiorgan failure should lead to consider withholding or withdrawal life support therapies. αgi is a malfunctioning of the gi tract in icu patients associated with prolonged mechanical ventilation, enteral feeding failure and high mortality risk. the wgap of esicm proposed a grading system for agi. four grades of severity were identified: agi grade i, a selflimiting condition; agi grade ii (gi dysfunction), interventions are required to restore gi function; agi grade iii (gi failure); agi grade iv, gi failure that is immediately life threatening. the aim was to evaluate the feasibility of using agi grades i and ii as predictors of malnutrition and 1-year mortality in critically ill patients methods: single-center retrospective cohort study in a tertiary university hospital (2015 -2017). agi grade iii and iv patients were excluded. αnthropometric data, gi symptoms (vomiting,diarrhea), feeding intolerance, gastric residual volumes and abdominal hypertension were recorded. daily prescribed caloric intake was calculated using a standard protocol and daily achievement of caloric intake was recorded. mnutric score was calculated for all patients. a score ≤5 was used to diagnose malnutrition. 200 patients (59% men, mean age 65 years) that stayed in the icu for >48 hours were included in the study. 52% were at high nutritional risk. 1-year mortality was 31%. the prevalence of agi ii was 14%. age, gender, bmi, mortality and energy intake did not differ significantly between patients with agi ii and those with agi i (table 1) . logistic the study aimed to assess the effects of icu admission on frailty and activities of daily living in the ≥80's population at 6-months. a prospective observational study with data used as a subset of the vip-2 trial [1] . research ethics committee approval from the mater misercordiae university hospital (mmuh). inclusion criteria -≥ 80 years of age and acute admission to icu from may to july 2018. data collected on 20 consecutive patients. frailty and activities of daily living (adl) were assessed using the clinical frailty score (cfs) and the katz index of independence in activities of daily living (katz). results: csf pre-admission frailty was present in 60% of patients, increasing to 93% at 6 months ( figure 1 ). 74% of survivors at 6-months had a cfs score increase by ≥ 1 point. pre-frail and frail cfs patients suffered an average 2-point deterioration in their instrumental activities of daily living (iadl). 60% of katz patients were fully functional preadmission, deteriorating to 13% at 6 months. 74% of patients declined by 1 adl at 6 months. 60% of the deceased were deemed fully functional initially. we demonstrate an association between an icu admission event and enduring functional decline at 6 months. icu admission resulted in patients acquiring on average 1.5 new iadl limitations despite their initial cfs. this is echoed in a study by iwasyna et al. who also showed similar deteriorations in iadl and cognitive impairment [2] . katz benefits may be best used in describing functional decline. 74% of patients developed at least one new limitation. however, the cfs takes into account iadl's and thus may be more sensitive in predicting the functional outcomes of an icu event at 6 months. frailty: an independent factor in predicting length of stay for critically ill t chandler, r sarkar, a bowman, p hayden medway maritime hospital, critical care, gillingham, united kingdom critical care 2020, 24(suppl 1):p366 frailty has attracted attention in the healthcare community in recent years, as it is associated with worse outcomes and increased healthcare costs [1] . our objective was to study the impact of frailty as recorded by clinical frailty scale(cfs) to prospectively evaluate the effect of frailty on hospital length of stay (los). a retrospective analysis of consecutively admitted critical care (cc) patients' data (jan'19-oct'19) was performed. electronic health records were used to collect demographics, cfs and clinical outcomes. statistical analysis was performed using stata. students t-test, simple and multiple (adjusted for age, disease severity/icnarc score) linear regression were used for comparison between groups and to see group effect. we excluded extreme outliers (los>50 days; n=13). frailty was defined as cfs>4. out of the 848 patients (male 58%), 554(66%) were emergency admissions, the rest elective (table 1) . 288(40%) were non-frail. the mean los were 15 days (d) ±12 and 10d±9 (p<0.0001) in the frail and non-frail patients respectively. for emergency patients, los were 16d(±12) and 10d(±10) for the groups, (p<0.0001). for elective patients; los were 12d(±10) and los 8d(±7), (p=0.01) for frail and nonfrail respectively. after adjusting, los was significantly higher in frail patients by 5 days (95%ci 3,7; p<0.0001), by 4 days (95%ci 1,6; p= 0.002) and by 5 days (95%ci 4,8; p<0.0001) for total cohort, elective and emergency admissions respectively. the los was 6 days higher in frail than non-frail (p<0.001) for cc survivors. frailty was associated with significantly increased los in this cohort, independent of age and illness severity. hospital capacity planning should take this into consideration when modelling bed allocation fig. 1 (abstract p365) . clinical frailty score 6-month trend robust clinical governance requires analysis of patient outcomes during an icu admission [1] . on one adult icu weekly mortality meetings are used for this purpose and aid multidisciplinary reflections on individual patient deaths. however, such reviews run the risk of being subjective and fail to acknowledge themes which may relate to preceding or subsequent deaths. this paper describes a new mortality review process in which: a) reviews are structured using the structured judgement review (sjr) framework [2] ; and b) themes are generated over an extended period of time to create longitudinal learning from death. the sjr framework has been developed by nhs improvement for the new medical examiner role, looking at inpatient deaths. we adapted this to better suit the icu creating a novel review structure. this involves explicit judgement comments being recorded, and the use of a scoring system to analyse the quality of care during the patient's stay with a focus on elements of care delivered on the icu. tabulation of this information allows analysis over time, identifying trends across all patients, and in specific subgroups. this framework has been rolled out at the st george's cardiothoracic icu weekly mortality meetings. themes that have emerged include parent team ownership, delayed palliative care referrals and inadequate documentation of mental capacity. this will continue as part of a three-month trial and following review of this trial may be extended to other critical care units in the trust. this system allows greater insight into patient deaths in a longitudinal fashion and facilitates local identification of problems at an early stage in a way that is not possible within the traditional mortality review format. the nature of the process means that key areas for change can be identified as a routine part of the clinical week. [1] . in this study, we evaluated three distinct machine-learning methods for predicting possible patient deterioration after surgery. the data was collected retrospectively from the catharina hospital in eindhoven. this dataset contained all the surgeries conducted in the hospital from 2013 up to 2017. the variables in this dataset were tested on their ability to differentiate between patients with a normal recovery versus patients with an unplanned icu admission after being admitted to the ward. the dataset contained 44 variables related to either the preoperative screening, surgery or recovery room. all variables were tested for statistical significance using a univariate logistic regression (lr), from which a subset of 34 statistically significant (p<0.05) variables was created. these variables were used to train three different types of models, namely, the lr, support vector machine (svm) and bayesian network (bn). the network structure of the bn was designed using expert knowledge and the probabilities were inferred using the data. the three models were validated using five-fold cross-validation, resulting in the following areas under the receiver operating characteristic curve: 0.82(0.79-0.86) for lr, 0.82(0.78-0.88) for svm and 0.65(0.63-0.68) for bn (fig. 1) . the results indicate that machine learning is a promising tool for early prediction of patient deterioration. the bn was included because it permits incorporating clinical domain knowledge into the learning process. however, its performance resulted inferior to the lr and svm. in future work, we will investigate alternative domainaware methods, and compare the performance with that of the clinical experts. intensive care unit (icu) admission decisions of patients with a malignancy can be difficult as clinicians have concerns about unfavourable outcomes, such as mortality [1] . a diagnosis of a malignancy is associated with an almost 6-fold increased likelihood of refusal of icu admission [1] . recent large long-term mortality studies of patients with a malignancy admitted to the icu are scarce. therefore, our aim was to compare mortality of patients with either a hematological or a solid malignancy to the general icu population, all with an unplanned icu admission. all adult patients registered in a national intensive care evaluation registry with an unplanned icu admission from 2008 to 2017 were included. subsequently, we divided these patients into 3 cohorts: cohort 1 (all patients with a hematological malignancy), cohort 2 (all patients with a solid malignancy), and cohort 3 (a general icu population without malignancy). as primary outcome, we used 1-year mortality, and as secondary outcome, icu and hospital mortality. we included 10,401 (2.2 %) patients in cohort 1, 35,920 (7.6%) patients in cohort 2 and 423,984 (90.2%) in cohort 3 ( table 1 ). the 1year mortality of patients of cohort 1, 2, and 3 was 60.1%, 46.2% and 28.3%, respectively (p<0.001). age, comorbidities, organ failure, and type of admission (i.e. surgical or medical) were positively associated with 1-year mortality in all cohorts (p <0.05). one-year mortality is higher in both patients with a hematological malignancy and patients with a solid malignancy compared to the general icu population. in addition, several factors were positively associated with 1-year mortality, i.e., age, comorbidities, medical icu admission, and organ failure. future research should focus on predictive modelling in order to identify patients with a malignancy that may benefit from icu admission. introduction: drug abuse is associated with immunosuppression in multiple mechanisms. despite that, the only study retrospectively reviewing drug abusers in the icu demonstrated less infections and better outcomes. we compared matched patient populations in order to fully understand whether drug abuse is a risk factor for infection and a predictor of poorer prognosis as is perceived by most physicians. we hypothesized that the drug abusers admitted to the icu will fare as good as or better than non-abuser icu patient populations. methods: this is a prospective study done between the years 2010-2012 on the entire patient population of the detroit medical center. after the drug abuse population was identified, controls were matched according to age and admission icu units. patients charts were reviewed and data regarding baseline demographics, infectious complication and outcome was extracted. data was retrospectively collected for 323 drug abusers and 305 matched controls. comorbidities and hospital admission diagnosis were significantly different between the two groups. disease severity scores were significantly higher in the drug abuser's patient group (dapg) on admission and during the icu stay. dapg had significantly more organ failure: more need for ventilation (30.5% vs 46.4% in the dapg (p<0.001)), more ards (1% vs 3.7%, p=0.03), more renal failure (33% vs 45.5%, p=0.002) and more need for renal replacement therapy (6.6% vs 11.2%, p<0.05) .they had longer hospital length of stay (los). there was no difference in icu or hospital mortality. multivariable modeling did not find drug abuse to be an independent risk factor for hospital mortality, icu mortality (hosp: or = 1.37, p = 0.3397; icu: or=1.43, pp = 0.07), but was a risk factor for a longer hospital los (me=1.46, p < 0.0001). drug abuse is not an independent risk factor for mortality or icu los. drug abusers should be evaluated like other patients based on baseline comorbidities and disease severity. this is a small audit which although it did not include general icu still reflects the need for encouraging clinicians and patients to speak freely regarding escalation plans. medical decsions is clinician led however this audit was carried by nursing staff as we have a duty to be advocate for our patients involvement in medical care [2] . a retrospective analysis of independent risk factors of late death in septic shock survivors c sivakorn 1 , c permpikul 2 , s tongyoo 2 (fig. 1) . the pap and katz scales seem to be adequate for predicting mortality of critically ill patients admitted to a medical icu. this finding may help in the elaboration of future icu mortality scoring systems, as well as in more rational use of resources. however, further multicenter studies are needed to better elucidate these results. adherence this last group was chosen because of its experience and specific training in the field of bioethics as a control group or reference. a total of 444 respondents participated in the study. 22.2% were emergency physicians, 14.8% intensivists, 11.2% emergency nursing, 6.2% icu nursing, 24.9% resident doctors, 13.8% medical students and 6.9% other professions. we observed variability in the responses observed not only between different groups of professionals but even within the same group reflecting the difficulty in decision making. variability was observed regarding decisions in end of life ethics conflicts. a high degree of similarity with the group of master in bioethics was observed in the responses issued by medicine students. the barriers and facilitators to framing goals of patient care (gopc) and factors motivating decision making is relatively unexplored [1, 2, 3] . a three part survey of physicians at an australian hospital in a culturally and linguistically diverse suburb ( table 1) . identification of levels of confidence and barriers and facilitators to gopc discussion and decision making was the main outcome measure. factors influencing decision-making was analysed through scenarios. results: 22 out of 96 eligible participants responded; 12 female, 10 male, clinical experience 4-31 years. level of confidence was ranked between "somewhat confident and very confident." all but one respondent had six months of icu experience. no differences in the level of confidence among physician groups. 14 barriers and 8 facilitators were identified; poor prognosis and patient or family request were most common facilitators; conflict between treating teams and the patient/surrogate and language barriers were most common barriers. factors driving gopc decision-making included clinical, value judgement, communication, prognostication, justice and avoidance. numerous barriers and facilitators were identified. factors driving decision making did not just consider clinical factors; conflict and we aimed to investigate physician-related factors contributing to individual variability in end-of-life (eol) decision-making in the intensive care unit (icu). qualitative study with semi-structured interviews with 19 specialists in critical care, (experience 2-32 years) from 5 swedish icus. data was analyzed in accordance to principles of thematic analyses. most of the respondents felt that the intensivist's personality played a major role in eol decisions (table 1) . individual variability was considered inevitable. views on acceptable outcome: respondents experienced that the possible outcome for patients was interpreted very differently and subjectively among colleagues, and what seemed an acceptable patient-outcome for one doctor, was not acceptable for another. values: most of the respondents were well aware that they might be affected by their own values and attitudes in the decision-making process. interestingly, several respondents mentioned that they thought that patients that were marginalized by society, especially drug-abusers could be at risk for receiving decisions to limit life sustaining treatments (lst) more often than others. none of the respondents thought that their own religious beliefs played any part in decision making. fear of criticism: among the less experienced respondents there was a clear sense of fear of making a questionable assessment of the patient's medical prognosis. there was a fear for criticism from colleagues that were not directly involved in the decision-making, and may have made another decision. this created a wish among younger respondents to defer or avoid participating in decision-making. physician-related, individual variability in eol decisions primarily consisted of differing views on acceptable outcome, values and fear of criticism. can (figure 1 ). within each quartile of sofa score, mortality was highest in patients with pneumonia and peritonitis and lowest in patients with cellulitis (see figure 1 ). the sepsis-3 consensus definition identified organ dysfunction as the hallmark feature of sepsis [1] . in developing sepsis-3, the sequential organ failure assessment (sofa) score was chosen for its prognostic value and relative ease of implementation clinically [2] . we propose an update based on epidemiologic data from two intensive care databases that more effectively captures organ dysfunction in the context of sepsis-3. using the mimic-iii (exploration) and e-icu (validation) databases, we extracted patients with suspicion of infection to form the study cohort. the predictive power of each sofa component was assessed using the area under the curve (auc) for in-hospital mortality. a logistic model with the lasso penalty was used to find an alternative statistically optimal score. results: by utilising alternate markers of organ dysfunction (e.g. lactate, ph, urea nitrogen) we demonstrated a significant improvement in auc for several versions of the new score, sofa2.0 ( figure 1 ). the sofa score can be updated to reflect current advances in clinical practice. using epidemiologic data, we have shown that substitution of existing components with more powerful measures of organ dysfunction may provide an improved score with greater predictive power. moreover, sofa 2.0 exhibits equivalent ease of implementation, but better reflects organ dysfunction in the context of sepsis-3. introduction: risk of acute organ failure (aof) in cancer patients(pts) on systemic cancer treatment isunknown. however, 5% of non-hematologic and 15% of hematologic cancer pts will need admission to intensive care unit (icu). ipop-sci-2017/01 is a prospective cohort study designed to ascertain the cumulative incidence of aof in adult cancer pts. single centre prospective cohort study with consecutive sampling of adult cancer pts admitted for unscheduled inpatient care while on, or up to 8 weeks after, systemic cancer treatment. primary endpoint was aof as defined by quick sofa. six months accrual expected an accrual of 400 pts to infera population risk aof with a standard error of 1%. between 08/2018 and 02/2019 10392 pts were on systemic anticancer treatment, 358 had unscheduled inpatient care and were eligible for inclusion and 285 were included. median age was 64 years, 51% were male, 52% had adjusted charlson comorbidity index (cci) &gt; 3 and hematologic cancers accounted for 22% of pts. the cumulative risk of aof on hospital admission was 35% (95%ci: 31-39); and of aof during hospital stay was 40% (95%ci: 35-44). aof was associated with older age, cci &gt; 3,hematologic malignancy, shorter median time from diagnosis and &gt; 1 prior line of therapy. on admission, 62% of pts were considered not eligible for artificial organ replacement therapy (noaort) and 34% of pts who developed aof while inhospital were judged noaort. overall, 17 (15%) of aof pts wereadmitted to icu, 31.5% for aort. median follow up 9.5 months (min 6; max 12). inpatient mortalitywas 18%, with icu mortality rate of 59%, with median cohort survival 4.5 months (95%ci: 3.5-5.4). on multivariate analysis, aof was an independent poor prognostic factor (hr 1.6; 95%ci 1.2-2.1). risk of aof in cancer pts admitted for unscheduled inpatient care while on systemictreatment is 35%, and risk of icu is 15%. aof in cancer pts was an independent poor prognostic factor. a severity-of-illness score in patients with tuberculosis requiring intensive care u lalla, e irusen, b allwood, j taljaard, c koegelenberg tygerberg academic hospital, internal medicine, division of pulmonology and icu, cape town, south africa critical care 2020, 24(suppl 1):p383 we previously retrospectively validated a 6-point severity-of-illness score aimed at identifying patients at risk of dying of tuberculosis (tb) in the intensive care unit (icu). parameters included septic shock, human immunodeficiency virus with cd 4 <200/mm 3 , renal dysfunction, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (pao 2 :fio 2 ) <200mmhg, diffuse parenchymal infiltrates and no tb treatment on admission. the aim of this study was to validate and refine the severity-of-illness score in patients with tuberculosis requiring intensive care. we performed a prospective observational study with a planned post-hoc retrospective analysis, enrolling all adult patients with confirmed tb admitted to the medical intensive care unit from 1 february 2015 to 31 july 2018. descriptive statistics and chi-square or fisher's exact tests were performed on dichotomous categorical variables, and t-tests on continuous data. patients were categorized as hospital survivors or non-survivors. the 6-point score and the refined 4-point score were calculated from data obtained on icu admission. results: forty-one of 78 patients (52.6%) died. the 6-point scores of nonsurvivors were higher (3.5+/-1.3 vs 2.7+/-1.2; p=0.01). a score ≥3 vs. <3 was associated with increased mortality (64.0% vs. 32.1%; or 3.75; 95%ci, 1.25-10.01; p=0.01)( table 1) . post-hoc, a pao 2 :fio 2 < 200mmhg and no tb treatment on admission failed to predict mortality whereas any immunosuppression did. a revised 4-point score (septic shock, any immunosuppression, acute kidney injury and lack of lobar consolidation) demonstrated higher scores in non-survivors (2.8+/-1.1 vs. 1.6+/-1.1; p<0.001). a score ≥3 vs. ≤2 was associated with a higher mortality (78.4% vs. 29.3%; or 8.76; 95%ci, 3.12-24.59; p<0.001) ( table 1) . the 6-point severity-of-illness score identified patients at higher risk of death. we were able to derive and retrospectively validate a simplified 4-point score with a superior predictive power. chronic critical illness remains a scientific challenge, from its conceptualization to its impact on patient prognosis [1] . we evaluated the long-term evolution of icu survivors by identifying the real burden of prolonged critical illness on survival, quality of life and hospital readmissions. we conducted a prospective cohort in 16 brazilian hospitals including 1616 icu survivors with an icu stay > 72h. we compared the patients diagnosed with chronic critical illness with the other patients. telephone follow-up at 3 and 6 months. quality of life was measured by the sf-12 questionnaire. it was observed that 38% of patients had some definition of chronic critical illness. chronic critically ill patients had higher mortality at 6 months (p=0.012). this difference is mainly due to higher intrahospital mortality (p=0.0001). mortality after hospital discharge was similar between groups. there was no difference in hospital readmission rate at 6 months. various scores are developed to predict pulmonary complications such as ariscat for patients at-risk of postoperative pulmonary complication [1] and lips for patients at-risk of lung injury [2] . the aim of this study was to compare these scores with ours for predicting pulmonary complications in mechanically ventilated patients in sicu. this prospective observational study was conducted in sicu at a university hospital. adult patients admitted to sicu and required mechanical ventilation >24 hours were included. primary endpoint was the composite of pulmonary complications including pneumonia, ards, atelectasis, reintubation, and tracheostomy. multivariate analysis was performed to identify risk factors of pulmonary complications and the predictive score was developed. the roc analysis was performed to compare power of ariscat, lips and our newly developed score for predicting pulmonary complications. outcomes in intensive care units have been reported to be better in higher-volume units [1, 2] . we compared outcomes for high-risk patients between low and higher volume units. audit data from irish icus is analysed and reported by the intensive care national audit & research centre (icnarc) in london. icnarc report risk-adjusted mortality rates in all patients and in low-risk patients(predicted mortality rate <20%) for each unit, using the icnarch-2015 model to predict the risk of death. we used this data to calculate the proportion of high-risk patients(predicted mortality >20%) in each unit, the mortality rate for high-risk patients, the riskadjusted mortality rate and we compared the overall risk-adjusted mortality between low and high volume units. the median number of annual new-patient admissions among 18 participating units was 390; units below this were defined as lowvolume and those above as high-volume units. the proportion of all admissions to each unit who were high-risk ranged from 8% to 54%(mean 34%). unit mortality rates for high-risk patients ranged from 33% to 69%. the ratio of observed to expected mortality(standardized mortality ratio -smr) for high risk admissions in each unit ranged from 0.87 to 1.34(mean 1.07). in fig. 1 introduction: adl weakening is often seen after intensive care and called postintensive-care syndrome (pics). this is also seen in even outside icu and proposed to be called post-acute-care syndrome (pacs), especially in elderly patients. in patients with infection, sofa score is famous for predicting in-hospital mortality, but there are no tools for predicting adl weakening during admission. to search for risk factors for adl weakening during admission other than the age, we conducted a retrospective observational study. the subjects were surviving patients with infection, aged from 16 to 89 who were admitted to our department from april 1, 2018 to may 31, 2019. information of basic characteristics, laboratory data on admission and adjunctive therapies were extracted from our database. we use barthel index (bi) as adl evaluation, and the bi at discharge were evaluated by nurses. we stratified patients by bi at discharge of over 60 or not, and investigated factors that predicted it. we compared each factor between 2 groups, and perform a logistic regression analysis with those that had a significant effect clinically or statistically. despite improved outcomes of intensive care unit (icu) patients, sleep deprivation remains a major concern after icu discharge. multifaceted causes make it difficult to treat and understand [1] . not many studies have explored sleep deprivation beyond icu. this is evidenced by findings from a recent systematic review [2] which included 8 studies with only one study [3] reporting sleep deprivation beyond icu. the aim of this paper is to present findings of sleep deprivation beyond icu from a larger study that examined the experience of critical illness in icu and beyond in the context of daily sedation interruption. hermeneutic phenomenology was used to conduct the study. 12 participants aged 18 years and above who fulfilled the enrolment criteria were enrolled into the study. the cohort comprised 7 male and 5 female participants. in-depth face to face interviews at two weeks after discharge were conducted and repeated at six to eleven months. interviews were audio taped, transcribed and thematically analysed. significant statements were highlighted and categorized for emergent themes. six participants continued to experience sleep deprivation up to eleven months after icu. two cited dreams about icu, three could not explain why they continued to fail to sleep and one stated that he continued hearing icu alarms in the silence of the night. sleep deprivation continues beyond icu due to nightmares, delusional memories and unexplained reasons. further research is needed to establish causes of sleep deprivation and explore ways to promote sleep in critical illness survivors after icu discharge. frailty is being increasingly seen as an independent syndrome. frail patients now account for an increasing proportion of hospital and critical care admissions [1] . we aimed to compare frailty and mortality in our intensive care unit. clinical frailty score (cfs) was incorporated within the electronic health record (ehr) 2019. we performed this retrospective analysis on the data collected between jan'19 and oct'19. the predictor and outcome for this study were frailty and hospital mortality respectively. all demographic data, acute physiology score, critical care and hospital outcome data were automatically collected in the ehr and recorded. we used a cut off of cfs>3 and above to define non-frail and frail respectively. chi-squared test, simple and multiple logistic regression were used. adjustment was done for icnarc score and age. total number of patients was 848, of which 140 (16.5%) died in hospital. within the patients<65 years (n=392), 79 (20%) were recorded as frail or vulnerable. the number of elective and emergency admission were 292(34%) and 556(66%) respectively. in the frail and nonfrail, mortality rates were 30% and 9.5% (p<0.001) respectively, with odds ratio of 4.14 (95% ci 2.8, 6; p<0.001) ( age is a well-known risk factor for critical care (cc) outcome and is incorporated into many prognostic tools; however, this has been criticized for assumption of normal physiology for young at baseline. in recent years, frailty in cc prognostication has been of interest, with meta-analysis correlating worsening outcomes with increasing frailty [1] . in this study, we compared the effect of frailty versus age for determining hospital survival for critically ill patients. we conducted a prospective cohort in 16 brazilian hospitals including 1616 survivors of an icu stay > 72h. we compared chronic critically ill patients (icu stay> 10 days) and the other patients. we performed psychological and functional presential assessment in patients within 48 hours of icu discharge and by telephone at 3 and 6 months. the prevalence of chronic critically ill patients was 26%. regarding outcomes, chronic critically ill patients had a higher incidence of depressive symptoms than other patients in the immediate post-icu discharge (p = 0.004), as well as a higher incidence of muscle weakness (p <0.001). however, in subsequent evaluations, we found no difference between groups regarding psychological symptoms -depression, anxiety and post-traumatic stress. higher functional dependence was observed in critically ill patients, but without difference in the quality of life score, both in the physical (p = 0.87) and mental (p = 0.84) domains. chronic critically ill patients, when compared to patients with stay> 72h, have a higher incidence of depressive symptoms at icu discharge. this difference disappears in the follow up. chronic critically ill patients present higher levels of functional dependence but without repercussions on quality of life scores. introduction: activation of the inflammatory response after cardiac arrest (ca) is a welldocumented phenomenon that may lead to multi-organ failure and death. we hypothesized that white blood cell count (wbc), one marker of inflammation, is associated with one-year mortality in icu treated ca patients. we used a nationwide registry with data from five academic icus to identify adult ca patients treated between january 1 st 2003 and december 31 st 2013. we evaluated the association between the most abnormal wbc within 24 hours of hospital admission and one-year mortality. we accounted for baseline risk of death using multivariable logistic regression (adjusted for age, gender and 24h sequential organ failure assessment [sofa] score). a total of 5,543 patients were included in the analysis. of those patients 2,387 (43%) were alive one year after ca. we plotted wbc against baseline risk of death and through graphic examination of a locally weighted scatterplot smoothing (lowess) curve found the lowest risk of death to be associated with a wbc of 12 (e 9 /l) ( figure 1 mrps were identified by a specialist icu pharmacist during this programme and classified by their significance on a scale of one to four. logistic regression was used to determine if demographic factors were associated with the occurrence of a clinically significant mrp -a significance score of two or above (figure 1) . the adjusted model included age, icu los, hospital los, apache ii, number of days of renal replacement therapy, number of days of ventilation, the number of medications prescribed at icu discharge, and the who analgesia classification at ins:pire. there were increased odds of having a clinically significant mrp for hospital los (or results: 62·8% (n=115) of patients required at least one pharmacy intervention. the median number of interventions required per patient was one (iqr 0-2); the maximum number was six. 198 mrps were recorded in this cohort. the most common intervention was clarifying duration of treatment (n=44), followed by education (n=33), and correcting drug omissions (n=27). the bnf drug class most frequently associated with mrps was neurological (n=65), which comprises analgesics (n=45) and psychiatric medications (n=20) ( figure 1 ). this was followed by cardiovascular medications (n=40), gastrointestinal medications (n=34), nutritional medications (n=25), and others (n=34). many icu survivors experience mrps. the most common class of mrp was neurological, reflecting the high incidence of chronic pain and psychiatric illness in this population following discussion with icu staff, ward staff and fy1 doctors, a formal standardized handover system was introduced. this involved a verbal handover to the appropriate fy1 by an icu doctor and the patient drug chart to be rewritten in icu at the time of handover. the next change was to display posters on the wards to alert staff that the medical team are to be contacted when a patient comes to the ward from icu and to ensure the drug chart is completed. the baseline data showed a median time delay of 4 hours, with one patient waiting 14 hours for a drug chart. following the interventions the median time delay has decreased to 0 hours within 4 months as demonstrated in figure 1 . the changes have received positive feedback from icu staff, ward staff and fy1 doctors. the aim of reducing the time delay by 50% has been achieved with the median time delay now 0 hours. this has improved patient safety by significantly reduced delays in medications and through the introduction of a standardized handover. this has also provided an opportunity for junior doctors on the wards to seek clarification regarding medications and the clinical management plan for the patient. this has established a communication channel between icu and the wards making patient care safer and more effective. telemonitoring outside the icu is scarce. but with innovative wearables measuring respiratory and heart rate wirelessly, culture on intrahospital telemonitoring should definitely change. however, culture has been known to be one of the most crucial success factors in innovation, especially in health care. human design thinking is a promising tool in health care innovation but rarely used in a multidisciplinary team to initiate an innovation culture and stimulate sustainable collaboration. the aim of this study was to initiate a pilot project with a multidisciplinary team to start using wearables for early warning score (ews) on a clinical ward. human design thinking was used to write a value proposition on wearables in clinically admitted neutropenic hematologic patients in an academic center. a multidisciplinary team was performed to cover all disciplines involved in the technical, clinical and administrative parts of the project. a vendor was chosen based on its product specifications in relation to the present hospital monitoring infrastructure. in design thinking sessions, critical appraisal of multiple telemonitoring factors was performed by sub teams and a canvas projectplan was constructed. the project team was formed of registered nurses, physicians, itspecialists, electronic health record consultants; a critical care physician was appointed as project leader. the main critical factors were: unseamlessly transmitting of both heart and respiratory rates including appropriate movements filtering to the nurse's smartphones direct uploading into electronic health record with automated ews calculation nurse driven protocol on ews follow up. philips healthcare with their intellivue guardian wearable biosensor was the chosen vendor ( figure 1 ). design thinking in a multidisciplinary health care team could positively influence the innovation culture. scientific evaluation of this wearable will focus on both nurse's acceptance and data storage and is expected in the summer of 2020. severity, readmission and lengh of stay were lower in patients receiving discharges directly to home. it seems like a safe way to discharge low-risk short stay patients. it seems to save resources and reduce costs, as well as the need for hospital beds. however, futher estudies are needed to actualy evaluate this safety. forty-four cultures were analyzed with eplex ( figure 1 ). complete agreement with conventional diagnostics was observed in 38/44 cases. no false-positive results were observed, yielding a sensitivity and specificity of 90% and 100% respectively for target pathogens. time to result was, on average, 10.4 h faster with eplex compared to conventional diagnostics. antimicrobial therapy could have been optimized in 5 patients based on the eplex result, but treatment was only changed in one case (e.coli ctx-m+) receiving meropenem 8.5 h before the antibiogram was available. the eplex blood culture panels provide high accuracy and significantly faster results. the current implementation offers substantial potential value at a minimal cost, and is a feasible approach to 24-h/ 7 days blood culture diagnostics in many hospital settings. however, efforts to increase adherence are needed. the rapid increase of extended spectrum β-lactamases (esbl)-producing pathogens worldwide makes it difficult to choose appropriate antibiotics in patients with gram-negative bacterial infection. cica-beta reagent (kanto chemical, tokyo, japan) is a chromogenic test to detect beta-lactamases such as esbl from bacterial colonies. the purpose of the study was to reveal whether cica-beta reagent could detect esbl-producing pathogens directly from urine rather than bacterial colonies to make a rapid bedside diagnosis of the antibiotic susceptibility of gramnegative pathogens. we conducted a prospective observational study from july 2019 to october 2019. patients were eligible if they were performed urinary culture tests and gram negative pathogens were detected at least 1+ from their urine samples. the urine sample was centrifugated at 200 x g for 5min. the supernatant of sample was re-centrifugated at 1500 x g for 5min and the pellet was mixed with cica-beta reagent. the test was considered positive when the enzymatic reaction turned from yellow to red or orange. (fig.1) . the bundle approach could be an effective strategy to prevent hospital-acquisition of drug-resistant pathogens in icus. fig. 1 in the aspect-np trial, c/t was noninferior to mem for the treatment of habp/vabp. we evaluated outcomes from that study in the subgroup of pts failing current antibacterial therapy for habp/vabp at enrollment. methods: aspect-np was a randomized, controlled, double-blind, phase 3 trial in which mechanically ventilated pts with habp/vabp received 3 g c/t or 1 g mem every 8 h for 8-14 days. pts with >24 h of active gram-negative antibacterial therapy within 72 h prior to first dose of study therapy were excluded, except those pts failing current treatment (i.e. signs/symptoms of the current habp/vabp were persisting/worsening despite ≥48h of antibiotic treatment). primary and key secondary endpoints, respectively, were 28-day all-cause mortality (acm) and clinical response at test of cure (toc; 7-14 days after end of therapy) in the intent to treat (itt) population. pts failing current antibacterial therapy for habp/vabp were prospectively categorized as a clinically relevant subgroup. at baseline, failing current therapy for habp/vabp was reported in 53/362 (15%) c/t and 40/364 (11%) mem itt pts, mostly piperacillin/ tazobactam (34%), 3rd/4th-generation cephalosporins (31%), fluoroquinolones (29%), and aminoglycosides (12%). baseline demographic and clinical characteristics in this subgroup, including prior therapy regimen, were generally similar between treatment arms. there were greater proportions of patients with esbl+ enterobacterales (30%) and pseudomonas aeruginosa (25%) in the c/t arm than the mem arm (20% and 13%, respectively). lower 28-day acm was seen with c/t than mem, as evidenced by 95% confidence intervals for treatment differences that excluded zero ( figure 1 ); statistical significance cannot be assumed because subgroup analyses in this study were not corrected for multiplicity. conclusions: c/t was an effective treatment for habp/vabp pts who had failed initial therapy. catheter-related blood stream infection (crbsi) is common serious infections and associated with increased mortality in intensive care units (icu). one of the most important strategy to prevent crbsi is to minimize the duration of central venous catheterization. we built a medical team consisting of doctors, nurses and pharmacists in icu to discuss whether patients needed central venous catheter (cvc) in terms of monitoring hemodynamics and administering drugs, and recommend catheter removal to attending physicians every day in april 2019. the purpose of this study is to evaluate whether our team-based approach could shorten the total duration of catheterization and reduce crbsi. this was a retrospective historical control study conducted from april 2018 to october 2019 in the icu of a tertiary care hospital in japan. every patient admitted to the icu during the study period was eligible if they were inserted cvc. patients were divided into 2 groups: conventional (from april 2018 to march 2019) or intervention (from april 2019 to october 2019). we set the primary endpoint as onset of crbsi. the secondary endpoints included the duration of central venous catheterization, the length of icu stay and hospital mortality. crbsi was defined as bloodstream infection in patients with cvc, not related to another site. we included 428 patients: 259 in the conventional group and 169 in the intervention group. the reduced, though nonsignificant, tendency of crbsi was observed in the intervention group [hazard ratio, 0.341(95% confidence interval, 0.074-1.557; p = 0.213)]. the intervention group was significantly associated with reduced duration of central venous catheterization (5 days vs 7 days; p < 0.01). no difference was observed in the length of icu stay and in-hospital mortality between groups. the team-based approach to assess cvc necessity could shorten the duration of central venous catheterization and might reduce crbsi. introduction: empiric antibiotic therapy decisions are based upon a combined prediction of infecting pathogen and local antibiotic susceptibility, adapted to patients' characteristics. the objective of this study was to describe the pathogen predominance and to evaluate the probability of covering the most common gram-negative pathogens in icu patients with respiratory infections. methods: data were collected from multiple us and european hospitals as part of the smart surveillance program (2018). mic (mg/l) testing was performed by broth microdilution, with susceptibility defined as follows for p. aeruginosa & enterobacterales: ceftolozane/tazobactam results: 78 hospitals from 24 countries provided 3384 gram-negative respiratory isolates from patients located in an icu in the us (22%), eastern europe (40%) and western europe (38%) in 2018. the 4 most common pathogens isolated were p. aeruginosa (26%), k. pneumoniae (15%), e. coli (13%), and a. baumannii (10%). among enterobacterales, 30% (588/1955) were esbl positive. figure 1 provides the probability of covering the most common respiratory gram-negative pathogens from icu patients. co-resistance between commonly prescribed first line β-lactam antibiotics is common: when nonsusceptibility (ns) of one agent was present, susceptibility to other βlactams was generally <35%. ceftolozane/tazobactam provided the most reliable in vitro activity in both empiric and adjustment prescribing scenarios compared to other β-lactam antibiotics. ceftolozane/tazobactam ensured a wide coverage of the most common gram-negative respiratory pathogens demonstrating high susceptibility levels and provided the most reliable in vitro activity in both empiric and adjustment antibiotic prescribing scenarios. further studies are needed to define the clinical benefits that may translate from these findings. evaluation of compliance of icu staff for vap prevention strategies on the outcome of patients a kaur fortis hospital, critical care, mohali, india critical care 2020, 24(suppl 1):p426 ventilator-associated pneumonia is the most common nosocomial infection diagnosed in adult critical care units. it is associated with prolonged duration of mechanical ventilation, increased icu stay and increased mortality. it continues to be a major challenge to the critical care physicians despite advances in diagnostic and treatment modalities. the primary objective of the study was to determine the compliance of icu staff towards vap prevention bundle and secondary objective was to determine the incidence, risk factors and outcome of vap patients. single center, prospective, observational study carried out from february 2017 to july 2018. patients mechanically ventilated for more than 48 hours and satisfying the inclusion and exclusion criteria were enrolled in the study. vap was diagnosed using the cdc criteria and clinical pulmonary infection score. vap preventive strategies were employed and compliance of icu staff was assessed. a total of 1617 patients were admitted to icu over the set time period and out of them 483 patients were ventilated for more than 48 hours. among them only 166 patients fulfilled the inclusion and exclusion criteria and were enrolled in the present study. excellent compliance was observed in head end elevation, sedation vacation, stress ulcer prophylaxis, and heat moist exchanger filter use, good compliance in oral care and hand hygiene and moderate to poor compliance in subglottic suctioning. the incidence of vap was 24.7% with a vap rate of 30.87/1000 ventilator days. there was a significant correlation between primary diagnosis, hemodialysis, massive blood transfusion and development of vap (p<0.05)). mean duration of ventilation (p<0.001) and mortality (p<0.05) were highly significant in vap patients. conclusions: improvement in compliance towards vap bundle and reduction of risk factors can help decrease incidence of vap and related morbidity and mortality. preventive strategies are effective in reducing ventilation-associated pneumonia (vap) in adults [1, 2] . in paediatric population there are no data about vap prevention, so we introduced a new bundle (vap-p) based on the available evidence for adults. this was designed as a before-after study. we enrolled all patients admitted to 8-bed medical-surgical paediatric icu at gemelli hospital in rome, requiring mechanical ventilation for at least 48 hours. patients with pre-existing tracheostomy were excluded. vap-p has been introduced since 2018 in order to improve quality of assistance. our bundle consisted in twice a day oral hygiene with chlorhexidine swab, daily check of oral bacterial colonization and aspiration prevention. comparison was made with an historical group including patients admitted before vap-p introduction (since 2016 to 2017). all data about demographics, antimicrobial therapy, icu stay and treatments, were collected. results: 162 patients were included (82 after and 80 before vap-p introduction). 5(6%) events of vap were recorded in vap-p group compared to 16 (20%, p=0.01) vap-p group had less vap per days of mechanical ventilation (1/100 compared to 3.3/100 p=0.01). multivariate analysis yielded an or of 0.23 (95%ci 0.07-0.81) for vap incidence after bundle introduction. mortality rate was slightly reduced in vap-p group (2.4%vs 6.2% p=ns). patients who developed vap required more days on mechanical ventilation and had higher mortality rate (12 vs 5 days p<0.001 and 14%vs 3% p=0.047, respectively). our vap-p seems effective in reducing vap incidence in critically ill paediatric population. introduction: ceftolozane/tazobactam (c/t) is a new antibiotic against mdr gramnegative bacteria infections, whose target population are the critically ill patients. even though 2/1 g dose safety administered as a 3hour-infusion has been already assessed, these patients can be under renal replacement therapy (rrt) and suffer changes in their volume of distribution (vd) that may affect antibiotic concentrations. the objective was to determine concentration reached by 3g c/t (3hour infusion) in septic patients on rrt (cvvhdf) and interdose behavior. we have used rrt machine prismaflex with oxyris filter and m100. hplc-uv method was used for simultaneous quantification of c/t. study population consisted of three obese critically ill patients with sepsis, on cvvhdf while receiving 3g c/t every 8 hours. samples were taken of prefilter, post filter blood and effluent, 30 min before infusion and 1, 2 and 4 hours after the end of it. we found great interpatient variability with the lowest cconcentration values in the patient with more hemodynamic instability using oxyris filter. even though cmax was less than reported in healthy subjects, we found similar values of auc and t ½ in comparison with healthy population studies. cmax of t was also compromised in comparison with values reported in healthy subjects, but with higher auc and t ½. cvvhdf contributes to c/t clearance. m100 filter showed the least clearance and higher values of auc and t ½. extraction rate was similar in all patients and filters (figure 1) . cmax achieved may be impaired because of the varying vd caused by obesity and rrt, but not affecting the antibiotic characteristics and behaviour. we conclude that because of the variety of clinical conditions, c-concentration is compromised particularly in hemodynamically unstable patients. however, the small sample doesn´t let us extrapolate these results. the extended infusion seems to be adequate to achieve the interdose antibiotic concentration. the use of biomarkers in sepsis is useful for early diagnosis and prognosis. the desired marker should be sensitive, specific, fast and accurate. procalcitonin (pct) measurement is approved by the fda even its efficacy is still under question. the determination of alfatorquetenovirus (ttv) could be a useful marker [1] . we analyzed 55 samples from 23 patients admitted to icu with clinical suspicion of sepsis. analytical data of c-reactive protein (crp), neutrophils and procalcitonin were collected. the sofa and apache ii scales were calculated and patients stratified according to these values in good and poor prognosis. ttv quantitative determination was carried by using a quantitative crp 2 . we calculated area under the curve (auc) of ttv plasma levels as a function of time. the statistical analysis involved u-mann-whitney and spearman test, using chi 2 for qualitative variables. results showed a not significant (ns) inverse relationship between the ttv auc and the patient proinflammatory level. a tendency (ns) was found between poor prognosis and the pct median values and crp being higher in the poor prognosis.group. a trend showed lower ttv dna count related to worse prognosis. an inverse relationship was found between pct and crp values and the ttv copies /ml plasma, ns correlation in the case of pct. there was a clear trend between the neutrophils´expansion and the regression line slope, obtained between ttv loads in the first two study steps. fig. 1 (abstract p432) . patient pk/pd measurements value>0.05), suggesting that the adsorptive mechanism wasn't primarily mediated by plasma protein. ha330 was saturated after adsorption of a total of 280.28±12.33 mg of van. the adsorptive kinetics showed an exponential reduction of van mass that reached a plateau after 30 minutes of circulation. in our study, simulating in vivo conditions of hp using ha330 during sepsis, a rapid and clinically relevant removal of van has been shown. after 2 hours of hp, we suggest to assess van plasma concentration and a loading dose of van should be considered. however, not knowing the potential interactions with other drugs, further in vivo studies are warranted to confirm these findings. assessing the volume of blood taken for blood culture and culture positivitydo we need to take less blood? it is commonly accepted that larger blood culture (bc) volumes (bcv) increase the yield of true positive cultures, and optimally 20 cc of blood should be obtained per set (2 bottles). only scarce data exists on the matter of optimal bcv. it is unknown what is the minimal volume that is acceptable for bc. the objective of this study was to determine the association between bcv and the rate of positive bc. blood taken for cultures in bd bactec plus aerobic/f negative bottles was collected from icus and acute care floors at 8 hospitals at the dmc over 6 months. blood volume was estimated automatically from blood background signal data in the bd bactec fx instrument. cultures were analyzed for each bottle. data was summarized for every month as the average volume and number of cultures taken and rate of positive bc for every unit. units were classified according to unit type (icu, medicine, surgery, mixed, emergency department (ed), organ/bmt or "other" which did not fit the previous categories) and analyzed as a group. a total of 23795 cultures were taken in 84 units. there is a positive association between bv and positive bc rate for ed and "other" units (irr=1.27, p=0.006 for the ed, irr=5.00, p<0.001 for "other" unit). all other units had no association between bv and positive bc rate (figure 1 ). secondary analysis, excluding pediatric units, gave very similar results. when comparing bv between unit types, the ed and "other" unit had significantly lower bv (2.4 ml in the ed and 3.5 ml in "other" unit compared to 4.9 ml in the icu, 4.7 ml in surgery, 4.2 ml in mixed and 7.7 ml in bmt). the correlation between bv and positive bc rate is probably limited to units taking very low bv for cultures. units taking volumes above 4 ml show no improvement in positive bc rate when higher volumes are taken. better prospective studies should be done to further establish the minimal bcv needed and spare unnecessary blood loss to hospitalized patients without compromising bc yield. de-escalating antibiotics in sepsis with the use of t2mr in a 35bed greek university icu c vrettou, e douka, i papachatzakis, k sarri, e gavrielatou, e mizi, s zakynthinos 1st icu department, university of athens, evangelismos general hospital, icu, athens, greece critical care 2020, 24(suppl 1):p440 in septic patients, the early use of appropriate empiric antibiotic therapy reduces morbidity and mortality. de-escalation refers to narrowing the broad-spectrum antibiotics once the pathogen and sensitivities are known. t2 magnetic resonance (t2mr) is a novel method of detecting eskape pathogens. we aim at investigating if using t2mr technology can expedite de-escalation of broad spectrum antibiotics. this is a prospective observational study conducted in our 35-bed university icu. inclusion criteria were critically ill patients age>18 y.o., with newly diagnosed sepsis and clinical suspicion of eskape bloodstream infection. a sample for t2mr and a blood culture (bc) sample were collected simultaneously from the patients enrolled. the t2mr bacteria panel test was run according to the manufacturer's guidelines and the bcs were processed according to the hospital standard procedures. we recorded clinical data and administered antibiotics. results: 26 patients were included in the study. mean time to culture positivity was 84 hours while mean time to t2mr result was 3.5 hours. in 20 patients the results of t2mr were in concordance with the bcs. in the remaining 6 cases, the bcs were negative while the t2 mr detected one or more eskape pathogens. there were no false negative results. de-escalation in at least one drug was applied to 8 patients (30.8%). no escalation was applied to 15 patients (57.7%) and antibiotic escalation in 3 (11.5%). conclusions: t2mr provides a quicker detection time that could shorten the time to targeted therapy. in our population this corresponded to early (within 6-12h) antibiotic de-escalation in approximately 1/3 of the included patients. antibiotic stewardship in icu. a single experience l forcelledo 1 , e garcía-prieto 1 , l lópez-amor 1 , e salgado 1 , j fernández dominguez 2 , m alaguero 3 , e garcía-carús 4 the increasing antibiotic resistance in microorganisms urged interventions such as the antibiotic stewardship programs in icu focused on reducing the inappropriate use of antibiotics by improving the antibiotic selection, the dosage, administration route and length as well as improving clinical outcomes and reducing antibiotic resistance. retrospective study where antibiotic consumption was analysed and measured in days of therapy (dots) between 2015 and 2018 in a medical-surgical icu of a university hospital where a multimodal educational program was established. specific training in infectious diseases in critically ill patients, periodic clinical and formative sessions fig. 1 (abstract p439) . correlation of blood culture positivity rate with blood culture volume by unit type were performed for icu staff and specific leaders within the icu staff designated. results: 4128 patients were admitted to icu. there was a reduction of 20,5% in dots (figure 1 ), reduction in antimicrobial resistance rates (14,36 in 2015, 7,4 in 2018 [days of resistant microorganism/1000 patientdays]) without an impact in icu global mortality (19,7% in 2015, 19,4% in 2018). the resistant bacteria registered were acinetobacter baumannii, s. aureus mr, blee and carbapenemase-producing enterobacteriaceae, pseudomonas aeruginosa mr and clostridium difficile. the safe in antimicrobial consumption was 391500€ (70% reduction). the icu stay decreased from 8,2 days (2015) to 6,9 (2018) , with no variation in mean apache ii (17,8) . the bigger decrease in antibiotic consumption was in colistin related to the reduction in resistance bacteria, in special acinetobacter baumannii, in linezolid and in piperacilin/tazobactam, even more remarkable in 2018 due to shortage of supplies which meant an increase in meropenem. the application of an antibiotic stewardship program in icu succeeded in reducing antibiotic consumption, antibiotic resistance and costs without an impact in clinical outcomes like mortality or icu stay. clinical outcomes of isavuconazole versus voriconazole for the primary treatment of invasive aspergillosis: subset analysis of indian data from secure trial p kundu, s kamat, a mane pfizer limited, medical affairs, mumbai, india critical care 2020, 24(suppl 1):p442 the secure trial was designed to compare the safety and efficacy of isavuconazole (a) versus voriconazole (v) for primary treatment of invasive mould disease caused by aspergillus and other filamentous fungi. the present analysis is aimed at comparing the indian subset of patients with that of the overall trial population and to ascertain any similarity or difference in the primary efficacy endpoint and safety/tolerability in these two groups. in secure trial, 258 patients in one group received (i) & another 258 patients received (v). the indian subset had 29 patients. we have done a qualitative analysis as the sample size of the indian subset was small. non-inferiority of (i) to (v) in terms of all cause mortality from first dose to day 42 was assessed in overall patients. the treatment difference between (i) and (v) group in the indian subset of patients was analyzed. proportion of patients who had to discontinue treatment due to teaes was analyzed. the all-cause mortality in the overall trial population met noninferiority margin (table 1 ). in the indian subset, it was higher for (i) than (v). there was a lower incidence of ocular, hepatobiliary, skin & subcutaneous tissue disorders in the (i) treated patients (see table 1 ). in indian subset, the above adverse events were less in the (i) group, but statistical inference could not be done due to small sample size. however, similar trend of less number of patients discontinuing therapy due to teaes in the (i) treated patients was seen in the overall patients & the indian subset. the all-cause mortality in the indian subset was higher in the (i) patients. a trend similar to the overall population regarding safety parameters favoring (i) was seen in the indian patients. considering the significantly higher prevalence of ia in india, suitably powered study design is necessary to draw definitive conclusions on the non-inferior efficacy & better safety & tolerability of (i) over (v) in patients of ia. introduction: ventilator-associated pneumonia (vap) is one of the most frequent healthcare-associated infections, correlated with increased mortality,extended hospital stay and prolonged mechanical ventilation. considering the latest outbreak of multiresistant a. baumannii infections in the critically ill patients with vap, there is a growing concern regarding challenges of the antibiotherapy in these patients. although ceftazidim-avibactam is considered to have limited effects on a. baumannii, it is reported to have a synergic activity in combination with other antibiotics. we performed a retrospective, observational study which included 24 icu patients diagnosed with vap(cpis > 6). oxa 23 a. baumannii was isolated from the tracheal secretions using a rapid molecular diagnostic platform(unyvero a50 system). patients were divided in two groups according to the antibiotherapy:group a meropenem + colistin and group b meropenem + colistin + ceftazidim-avibactam.statistical analysis was performed using graphpad6 applying t-test and kaplan-meier curves, having the in-hospital mortality as primary outcome and days of mechanical ventilation and hospital stay as secondary outcomes. mean age(y.o) in group a was 46 and 52 in group b and in both groups mean charlson comorbidity index was 3 points. survival percent was higher in the group treated with ceftazidim-avibactam (67 % vs 57 %, p = 0.08)(fig. 1) . length of stay was significantly decreased in group b (26.5 days vs 43 days in group a, p = 0.046). number of days under mechanical ventilation was also decreased in the ceftazidim-avibactam group (19 vs 22) but the data was not statistically significant. in light of the important thread of multiresistant a. baumannii and the lack of therapeutic measures, the synergistic activity of ceftazidim-avibactam use in combination with other antibiotics may be a promising approach to lower the mortality and hospitalization in critically ill patients diagnosed with vap. impact of patient colonization on admission to intensive care on 28 and 90 days mortality g dabar 1 , c harmouch 2 , e nasser ayoub 3 , y habli 4 , g sleilaty 5 , j infections caused by multi resistant bacteria are a major health problem, especially in icus, and it may be associated with high mortality rates. colonization precedes infection in most instances; therefore it may be a marker of a poor outcome. we tried to determine the impact of colonization on mortality at 28 and 90 days in a population of patients admitted to one medical and one surgical icu in the same institution. medical records review over three years 2016-2018 of all patients admitted to one surgical et one medical icu at hotel dieu de france hospital staying more than 24h. colonization to resistant bacteria was defined as mrsa, esbl, mdr, and vre. all patient received a nasal and rectal screen on icu admission, in intubated patients tracheal aspirate was considered as colonization in the absence of clinical respiratory tract infection. demographics, apache, sofa, immunosupression, charleston comorbidity index, length of stay, mechanical ventilation, hospitalization and antibiotic use in the previous 3 month were collected. mortality at 28 and 90 days was assessed through medical records or phone call. pearson chi-square was calculated for the association of colonization and mortality at 28 and 90 days, and subsequently odd ratio was estimated. introduction: critically unwell patients have been observed to respond unpredictably to traditional intermittent dosing (id) schedules of vancomycin, likely due to the complex physiological derangements caused by critical illness. continuous infusion (ci) of vancomycin has been suggested to overcome such problems by allowing more regular therapeutic drug monitoring and subsequent effective dose titration [1] . this study conducted at a tertiary intensive care unit, reports our experience following implementation of a continuous vancomycin infusion protocol. prospective data was collected over two consecuative periods of three months, initially capturing plasma levels for id (target level of 15-20mg/l) followed by reviewing plasma concentration levels in a ci protocol (target level of 20-25 mg/l). patients recieving renal replacement therapy were excluded. a total of 22 intermittent vancomycin prescriptions were administered and dosing levels observed. in the three month ci period, 26 patients received ci vancomycin and levels subsequently checked. the ci protocol resulted in increased blood sampling (107 samples in ci group vs. 73 samples in id cohort). two non serious incidents were reported in the ci cohort relating to preparation of vancomycin. both groups had a comparable median time to therapeutic range (48 hours). however, ci vancomycin group had a greater proportion of first samples outside the desired therapeutic range (70%vs 36%) (figure 1 ). as the therapy continued, ci vancomycin demonstrated a greater propensity towards consistent therapeutic levels than that observed with id. 83% of patients on a ci regime achieve the desired target levels compared to 77% in the id cohort (fig. 1) . it was positive for single or multiple microbes in 9(26.5%) and 22(64.7%) samples respectively. single or multiple resistance genes were detected in 5(25%) and 20(80%) samples respectively. bfpcr was positive only for bacteria in 13(38.2%), virus in 2(5.9%) and for both in 16(47.1%) cases. influenza a was found in 10(29.4%) cases. the most common organisms in community and hospital acquired pneumonia were streptococcus pneumoniae (4/12) and a. baumannii (10/22) respectively. bacterial cultures were concordant with bfpcr in 11/11 (100%) of positive cases. decisions to change antibiotics could be taken earlier based on bfpcr (p< 0.001) than if were based solely on culturesboth in culture positive (9.7± 14.3 vs 50.03±6.0 hrs) and negative cases (14.7±14.9 vs 48.0+4.3 hrs) where antibiotics would have remained unchanged. based on bfpcr antibiotics were escalated in 17(50%) patients and teicoplanin (11/ 19) was most often stopped. bal bfpcr were obtained significantly earlier, identified more organisms and bacterial resistance than culture reports and lead to more frequent and earlier antibiotic changes. severe community-acquired pneumonia (scap) is a frequent cause of hospitalization and mortality. ceftaroline is efficacious for treatment of cap (port risk class iii or iv). most severe patients were excluded from the clinical trials, so the efficacy of ceftaroline in these kind of patients is unknown methods: this is a health record-based retrospective before-after study in a tertiary care hospital. all scap patients admitted in icu between november 2017 and february 2019 receiving ceftaroline were included. control group included patients with same inclusion criteria but receiving ceftriaxone. propensity scores to adjust for potential baseline differences between groups were performed. levofloxacin or azythromicin were administered in both groups. primary outcome was the change in sofa score over the first 96h and secondary were days of mechanical ventilation, respiratory failure at 96h, need of rescue antibiotics, length of stay and mortality results: there were 28 patients in ceftaroline group and 43 in ceftriaxone group. baseline characteristics were similar except from more intubated patients in ceftaroline group (figure 1 ). there were less respiratory failure at 96h in patients with ceftaroline treatment (-73.3% vs. -51.6%; p 0,015), but no differences in other organ failures, mortality, days of mechanical ventilation or los. there were more need of rescue antibiotics in ceftriaxone group (7.1% vs .46.5%; p 0,001). we found more streptococcus pneumoniae isolation in ceftaroline group (18 (64.2%) vs 11 (25.5%); p = 0.001); more empiric use of oseltamir (16 (57.1%) vs 11 (25.5%); p = 0.012), but no more influenzae infections (11 (39.2%) vs 8 (18.6%); p = 0.101). s. aureus was detected in 1 patient in ceftaroline group and in 5 in ceftriaxone group. introduction: acute respiratory failure (arf) due to pulmonary infections is a usual cause of intensive care unit (icu) admission. immigration patterns and iatrogenic immune-suppression have made tuberculosis (tb) a common disease in western europe. severe tb requiring icu care is rare. nevertheless, mortality associated with active tb and arf is poor [1] . adult patients with tb admitted to icu from 2014-2018 were identified retrospectively. diagnosis was based on: positive cultures of sputum, bronchial aspirates or bronchioalveolar lavage fluid. demographic characteristics, reasons for admission, hiv status, anti-tb treatment and mortality were recorded. total of 25 patients with tb were admitted to icu. mean apache ii score was 20,2±6,9. sixteen were male. mean age 49,1±14,7 years. eight (32%) were hiv-positive, 3 (12%) diabetes mellitus type 2, 3 (12%) chronic liver disease. six (24%) had other causes of immunesuppression. main causes for icu admission were arf due to nonmycobacterium tuberculosis pathogens in 64%, acute liver failure in 12%, septic shock due to non-respiratory cause in 8%. overall, 52% were on anti-tb treatment at time of admission. tb involved the lung parenchyma in all patients. pleural involvement was present in 12% and lymph node in 20%. extrapulmonary sites were present in 28%: urogenital, gastrointestinal, bone marrow. pathogens identified in over-infections: 16% gram positive coccus, 20% gram negative bacilli, 16% fungal, 4% mdr-pathogen. one patient hiv-positive suffered arf due to pneumocystis jiroveci. overall, 64% died during icu stay. besides its latent evolution, mortality of tb patients admitted to icu is extremely high. arf due to over-infection seems to be the main cause for icu admission and mortality. better preventive approach of these patients may improve their outcome. introduction: human african trypanosomiasis (hat) is rarely encountered by critical care clinicians, but is an important differential for fever in the returning tropical traveler. late disease is characterized by seizures, fever and multi-organ failure [1, 2] . we present an anonymized case presenting from an endemic area in zambia referred for tertiary critical care management. the patient was too obtunded to give informed consent and his relatives could not be contacted despite extensive efforts. a middle-aged man with no past medical history from rural zambia presented to a local clinical officer post with fever and arthralgia. he was treated twice with anti-malarial medication without resolution of symptoms. two months later he was admitted febrile and obtunded to a local hospital with worsening confusion. he was transferred 8 hours by ambulance to our facility in lusaka, which is the only public tertiary critical care unit in zambia results: gcs on arrival was e3m4v2 without localizing neurology. microbiology investigations were negative, including for toxoplasma, cryptococcus, hiv or malaria. the patient suffered a generalized seizure followed by a sustained gcs of 3 and was admitted to the icu for invasive ventilation and seizure control. peripheral blood smears demonstrated trypanosomes consistent with hat secondary to trypanosoma brucei rhodesiense. he was commenced on melarsoprol but rapidly deteriorated, with signs of melarsoprol-induced arsenic encephalopathy and subsequent tonsillar herniation. his death was confirmed by neurological criteria. conclusions: icu management of fulminant hat involves supportive neurocritical care plus melarsoprol, a toxic arsenic compound with common side effects of hepatotoxicity and dysrhythmia. arsenic encephalopathy occurs in 10% of late hat, with a fatality rate of 70% [1] . early diagnosis is associated with a 95% survival rate in developed world travelers repatriated from endemic areas [2] . lithium chloride to prevent endothelial damage by serum from septic shock patients (in vitro study) a kuzovlev 1 the aim of the study was to investigate into effectiveness of lithium chloride (licl) as agent that prevents damage to the monolayer of endothelial cells under the action of serum from multiple trauma patients with septic shock. methods: serum from 5 pts with septic shock (sepsis-3) and 5 healthy donors was withdrawn. monolayer of ea.hy926 endothelial cells were incubated for 3 hrs at 37°c with healthy person's serum and with septic patient's serum without licl and with it at concentrations of 0.01 mmol, 0.1 mmol, 1 mmol, 10 mmol. licl was added 1 hour before the change of serum. after incubation cells were washed and fixed with 2% paraform solution and permeabilized with 1% triton x-100 solution. fixed cells were stained with primary antibodies to vecadherin and then incubated with secondary antibodies conjugated with oregon green 488 fluorescent dye as well as with phalloid red and hoechst dye 33342. images were processed by fluorescence microscope and imagej 1.44p and metavue 4.6 programs. western blotting was used to detect antibodies to ve-cadherin, claudin and gsk-3beta. statistics included mann-whitney test and chi-square test. incubation of a monolayer of endothelial cells with 5% serum of septic shock patients led to loss of ve-cadherin contacts and decrease of claudine. preincubation with licl 0.01 mmol did not prevent dismantling of claudine, actin, ve-cadherins; 0.1 mmol licl prevented it (p>0.05), but at higher concentrations (1 mmol, 10 mmol) almost completely protected endothelial monolayer from destruction of intercellular contacts (p<0.05). serum had almost no effect on the phospho-gsk-3β level after 5 min, 15 min, 30 min and 1 hr, but caused a significant (60%) decrease in its level after 2 and 4 hrs. licl (1 mmol) caused a significant increase in phospho-gsk-3β already 15 mins and up to 4 hrs after exposure. licl prevents septic damage to the monolayer of endothelial cells in vitro in a gsk-3beta mediated way. introduction: the autonomic nervous system (ans) controls both heart rate and vascular tone, which are known to be impaired during septic shock (ss) . acute inflammation is presumed to increase arterial stiffness of large arteries in experimental studies [1] . the objectives of this work are to verify if standard ss resuscitation modulate mechanical vascular properties and to verify if alterations in these vascular properties and ans activity are correlated. a protocol of fecal peritonitis septic shock and standard resuscitation (fluids and noradrenaline) was applied on 6 pigs. the arterial blood pressure waveform was recorded in the central aorta and in the femoral and radial arteries. the characteristic arterial time constant tau was computed at the three arterial sites, based on the twoelement windkessel model [2] . the total arterial compliance (ac) and the total peripheral resistance (tpr) were also estimated. baroreflex sensitivity (brs), low frequency (lf, 0.04-0.15 hz) spectral power of diastolic blood pressure, and indices of heart rate variability (hrv) were computed to assess ans functionality. results: septic shock induced a severe vascular disarray, decoupling the usual pressure wave propagation from central to peripheral sites, as shown by the inversion of pulse pressure (pp) amplification, with a higher pp in the central aorta than in the peripheral arteries during shock. the time constant tau together with ac and tpr were independently decreased. a decrease in brs, lf power, and hrv describe an ans dysfunction. after the administration of fluids and noradrenaline, both vascular and autonomic dysfunction persisted and these were found to be significantly correlated. measures of mechanical vascular function and ans activity could represent an useful end-point to guide further clinical investigations and refine our understanding of ss mechanisms, especially under medical treatment. introduction: lipopolysaccharide (lps), is a component of gram-negative bacteria known for its activation of the host immune system. the phospholipid transfer protein (pltp) has previously been shown to promote the binding of lps to lipoproteins, to limit inflammation and to lower mortality following injections of lps or bacterial infection. the aim of the present study was to investigate the role of pltp and lipoproteins in the detoxification of lps from the peritoneal cavity. injection of lps intra-peritoneally (ip) (1mg/kg) to wild type (wt) and pltp knocked-out mice (pltp-ko) (n = 9 per group). mass concentration and activity of lps were quantitated by lcmsms analysis of 3-hydroxymyristate and lal bioassay, respectively. lipoprotein fractions in plasma were separated by ultracentrifugation (n=10 vs n =12). following intra-peritoneal injection, clearance of intra-abdominal lps was faster and plasma neutralization was more efficient in wt than in pltp-ko mice ( figure 1) . indeed, lps found in plasma of wt mice was proportionally less active, sustaining a higher capacity for wt mice to neutralize lps (figure 1b) . quantitative dosage of lps in portal blood, 15 minutes after ip injection, revealed that plasma lps associates rapidly with the lipoprotein fraction (hdl plus ldl), and in higher proportions as compared to pltp-ko mice (66 [62-72] % vs 50 [41-54] %, respectively; p < 0.01). in line with previous studies, these observations now indicate that, lps readily associates with lipoproteins in a neutralizing process pltp mediated. finally, even with a heavy lps load (25 mg/kg), the bulk of lps was still found in the lipoprotein fraction (80 [80-90] %), suggesting that lipoproteins plus pltp in wt mice have a high capacity to detoxify intraperitoneal lps. in a model of peritonitis, lipoproteins and pltp were found to constitute key playors for peritoneal clearance and neutralization of lps. it emerges as a key pathway for the resolution of the inflammatory response in peritonitis. introduction: autotaxin (atx, enpp2) is a secreted enzyme present in biological fluids that catalyses the production of lysophosphatidic acid (lpa). lpa is a bioactive phospholipid evoking various cellular responses in most cell types. upregulated atx levels have been reported in various chronic inflammatory diseases. given the established role of lpa in the inflammatory response, we investigated a possible role for the atx/lpa axis in lps-induced endotoxemia. methods: lps was injected intraperitoneally (20 mg/kg) in mice producing 50% atx levels (atx df/+ , heterozygous null mutant mice), in mice producing 20-30% reduced atx levels upon inducible inactivation (r26creer t2 /enpp2 n/n mice) and in mice expressing 150-200% increased atx levels (enpp2-tg mice). kaplan-meier survival analysis was performed. atx activity was measured using the toos activity assay. results: atx df/+ mice that produce almost 50% reduced serum atx levels show increased survival compared to their littermate controls. for the inducible inactivation of atx, enpp2 n/n targeted mice were crossed with the r26cre-er t2 mice and tamoxifen induction enabled temporal control of floxed gene expression. r26creer t2 /enpp2 n/n mice were more protected against lps-induced endotoxemia compared to control mice. enpp2-tg mice overexpressing autotaxin and showing a 2-fold increase in plasma levels do not display improved survival rates compared to control group. conclusions: atx participates in systemic inflammation, as reduced atx levels in circulation decrease lethality of mice from caused by lps. the excess amount of circulating atx does not exacerbate the systemic inflammatory response to lps. introduction: pneumonia (pn) is a prevalent and severe infectious lung disease. host genetics plays an essential role in the pathogenesis of infectious diseases including pn [1] . the aim of the study was to analyze the variability of genes associated with neutrophil activation in pneumonia. to identify differential expressed genes (degs) in communityacquired (cap) and hospital-acquired pneumonia (hap) dataset «genome-wide blood transcriptional profiling in critically ill patients -mars consortium» (gse65682) from gene expression omnibus was analyzed (logfc≥2.0, fdr-corrected p-value<0.05). degs associated with neutrophil activation were selected according to gene ontology go:0042119 («neutrophil activation»). with the use of gtex portal and blood eqtl browser, we searched for esnps (expression single nucleotide polymorphisms) in whole blood for neutrophil activation genes differentially expressed in cap/hap. these esnps were further analyzed for their association with pn via the global biobank engine (gbe). a total of 46 degs from gse65682 correspond to go:0042119 genes (43 up-and 3 down-regulated) of which 39 genes were common to cap and hap. functional enrichment of 46 degs based on disgenet detected top-5 diseases associated with these genes (fdr-corrected p-value<0.05): myeloid leukemia, chronic; sepsis; asthma; lung diseases; allergic asthma. for these 46 genes 1366 esnps common to gtex portal and blood eqtl browser were identified. more than half of all variants were located on the second chromosome and influenced the expression of tnfaip6 and il18rap genes. among all esnps we identified variants associated with pn in the gbe (table 1) . we identified genes related to neutrophil activation, genetic variability of which was associated with pneumonia. sepsis was induced in wild-type c57bl6 mice (n=41) and cse knockout mice (n=41) by i.p. injection of 10 8 cfu/mice mdr p. aeruginosa. similar experiments were repeated after cyclophosphamide induced neutropenia. survival was recorded for 7 days. mice were sacrificed for determination of bacterial load and myeloperoxidase (mpo) activity as a surrogate marker of myeloid cell recruitment. cytokines were measured in serum by legendplex inflammatory panel. total leukocytes from mice spleens, with or without pretreatment with the h 2 s donor gyy3147, were incubated with 1 x 10 4 cfu/ml mdr p. aeruginosa. bacterial clearance was recorded. we observed a significant decrease in survival of cse -/mice as compared to cse +/+ mice (12% vs. 47%; p: 0.025). this survival advantage was eliminated in neutropenic mice (17% for both groups, p: 0.873). cse -/mice had increased pathogen load in the liver (6.57 ± 0.13 vs 5.26 ± 0.50, p: 0.029) and lung (6.70 ± 0.17 vs 5.29 ± 0.55, p: 0.035). mpo activity was lower in cse -/mice in the liver (634 ± 71 vs 1029± 179, p: 0.048) and lung (7627 ± 585 vs 11121 ± 1468, p: 0.34). cse +/+ mice had increased serum levels of il-23 (121.13 ± 33.68 vs 31.41 ± 7.02 of cse -/-, p: 0.001); mcp-1 (4769.91 ± 908.83 vs 1940.37 ± 1062.65, p: 0.026) and gm-csf (22.91 ± 4.66 vs 8.11 ± 1.92, p: 0.004). phagocytic activity of leukocytes from cse -/mice was reduced compared to cse +/+ mice. this deficit was eliminated after gyy4137 pretreatment (fig. 1) . deficiency of host-derived h 2 s leads to increased susceptibility to mdr p. aeruginosa infection due to an inefficient neutrophil chemotaxis and neutrophil mediated phagocytosis. acknowledgement funded by the itn horizon 2020 marie-curie european sepsis academy introduction: neuroinflammation often develops in sepsis along with increasing permeability of the blood-brain barrier (bbb), which leads to septic encephalopathy [1] . the barrier is formed by tight junction structures between the cerebral endothelial cells [2] . we investigated the expression of tight junction proteins related to endothelial permeability in brain autopsy specimens in critically ill patients deceased with sepsis, and analyzed the relationship of bbb damage and measures systemic inflammation and systemic organ dysfunction. case series included all adult patients deceased with sepsis in the years 2007-2015 with brain specimens taken at autopsy available. specimens were categorized according to anatomical location (cerebrum, hippocampus, cerebellum). the immunohistochemical stainings were performed for occludin, zo-1 and claudin. patients were categorized as having bbb damage if there was no expression of occludin in the endothelium of cerebral microvessels. results: 38% (18/47) developed multiple organ failure before death. 74.5% (35/47) had septic shock. the deceased with bbb damage had higher sofa maximum scores (16 vs.14, p=0.04), and had more often procalcitonin levels above 10 (56 % vs.28 %, p= 0.045). bbb damage in cerebellum was more common in cases with c reactive protein above 100 mg/l as compared with crp less than 100 (69% vs. 31 %, p=0.025). absence of zo-1 expression in cerebral meningeal samples associated with bbb damage (17 % vs. 0 %, p=0.046). positive blood cultures (n = 22) were associated to absence of zo-1 expression in cerebellar glial cells (92 % vs. 44 %, p=0.018). in fatal sepsis, damaged bbb defined as loss of cerebral endothelial expression of occludin ( figure 1 ) is related with severe organ dysfunction and systemic inflammation. loss of zo-1 in endothelial cells associates with bbb damage, and sepsis contributes to zo-1 loss in cerebellar glial cells. oxylipins are oxidative breakdown products of cell membrane fatty acids. animal models have demonstrated that various vasoactive oxylipin pathways may be implicated in septic shock pathophysiology but these have been poorly studied in humans. oxylipin profiling was performed on serum samples collected on enrolment to the vanish (vasopressin vs. norepinephrine as initial therapy in septic shock) trial. samples were analysed with liquid chromatography-mass spectrometry. patients were followed up until 28 days. results: samples were collected from 154 of 409 (37.7%) patients on inclusion to the trial and 39 (25.3%) had died by 28 days. non-survivors were found to have higher levels of a number of oxylipins including: 14,15-dihydroxyeicosatrienoic acid (dhet) (p<0.01), 11,12-dhet (p=0.03), 15(s)-hydroxyeicosatetraenoic acid (p=0.02), 14-hydroxyoctadeca-pentaenoic acid (p=0.04) but lower levels of the precursor eicosapentaenoic acid (p=0.012). when corrected for multiple comparisons with the benjamini-hochberg test, only 14,15-dhet remained significant (p=0.025). although there was a difference in median 14,15-dhet levels between survivors and non-survivors, many values were below the level of detection (n=84/154 (54.5%)). as such, we also analysed 14-15-dhet as a binary variable (figure 1 ). patients with detectable 14,15-dhet were more likely to die (hr 2.4 [95% ci 1.2-4.6], p< 0.01) and have a higher median lactate (p =0.01) and total sofa score (p< 0.01) than those patients where baseline 14,15-dhet was undetectable. our study suggests the oxylipin 14,15-dhet may be associated with septic shock severity and 28-day mortality. these results are consistent with the known vasodilatory actions of this class of oxylipin. more work is needed to confirm its exact role in septic shock and whether this pathway is amenable to therapeutic intervention. introduction: activation of neutrophils is a mandatory stage and a sensitive marker of systemic inflammatory conditions that can lead to the development of multiorgan failure. the aim of the study was to investigate into the antiinflammatory effects of lithium chloride on human neutrophils in vitro. study was carried out on neutrophils isolated from the blood of 5 healthy donors. 50% of neutrophils were activated by 100 mkm fmlp, 50% -by 100 ng/ml lipopolysaccharide (lps); then their activity was evaluated by fluorescent antibodies to cd11b and cd66b degranulation markers. intact and activated neutrophils were treated with a solution of lithium chloride (9 mmol). immunoblotting was used to assess gsk3b activity in neutrophils. mann-whitney criterion and p<0.05 were used for statistics. results: lithium chloride 9 mmol decreased the level of expression of cd11b on intact neutrophils by 16% (p=0.07), cd66b by 15% (p=0.07). fmlp increased cd11b expression on neutrophils by 2.6 times (p=0.0007), cd66b by 2.5 times (p=0, 0022). addition of lithium chloride solution to fmlp activated neutrophils reduced the expression of cd11b (p= 0.0317) and cd66b (p=0.0079). lps increased cd11b and cd 66b expression by 2.1 times (p=0.0007, p=0.0022, respectively); addition of lithium chloride reduced the expression of cd11b (p=0,0317) and cd66b (p=0.0079) on neutrophils. fmlp led to a dephosphorylation of gsk-3b by 47% (p<0.05), lithium chloride increased its phosphorylation by 387% (p <0.05). adding lithium chloride to activated fmlp neutrophils restored the level of gsk-3b phosphorylation by 277% compared to controls (p<0.05). lithium chloride modulates the inflammatory activation of neutrophils by bacterial components through the phosphorylation of gsk3b in neutrophils. human host immune responses to lipopolysaccharide: a comparison study between in vivo endotoxemia model and ex vivo lipopolysaccharide stimulations using an immune profiling panel dm tawfik introduction: sepsis, a leading cause of mortality among critically-ill patients in the icu, recently recognized by the who as a global health burden. patients that suffer from sepsis exhibit an early hyper-inflammatory immune response which can lead to organ failure and death. in our study, we assessed the immune modulations in the human in vivo endotoxemia model and compared it to ex vivo lipopolysaccharides (lps) stimulation using 38 transcriptomic markers. methods: eight healthy volunteers were challenged with intravenous lps in vivo. in parallel, blood from another 8 volunteers was challenged with lps ex vivo. blood was collected before and after 4 hours of lps challenge and tested with the immune profiling panel (ipp) prototype using the filmarray® system. the use of ipp showed that markers from the innate immunity dominated the response to lps in vivo, mainly markers related to monocytes and neutrophils. comparing the two models, in vivo and ex vivo, revealed that most of the markers were modulated in a similar pattern (68%). some cytokine markers such as tnf, ifn-γ and il-1β were under-expressed ex vivo compared to in vivo. t-cell markers were either unchanged or up-modulated ex vivo, compared to a down-modulation in vivo. interestingly, markers related to neutrophils were expressed in opposite directions, which might be due to the presence of cell recruitment and feedback loops in vivo. the majority of ipp markers showed similar patterns of expression post-lps challenge in both models, except for several markers related to neutrophils and t-cells. the ipp tool was able to capture the early immune response in the human in vivo endotoxemia model, which is a translational model mimicking immune host response in septic patients. introduction: serum levels of tyrosine kinase receptor mer and its ligand gas6 predict mortality in septic patients in the intensive care unit. however, whether their early measurement at emergency department (ed) presentation also predicts mortality and organ failure still needs to be clarified. in this multicentre observational study, septic patients admitted to 5 italian eds were included [1] . at ed presentation blood samples were taken for routine biochemical analyses and serum mer and gas6 measurement. urinalyses, blood gas analyses and chest x-ray were routinely performed. mortality at 7 and 30 days, as well as the presence of organ damage such as acute kidney injury (aki), thrombocytopenia, pt-inr derangement and sepsis-induced coagulopathy (sic) were evaluated according to baseline levels of mer and gas6. in conclusion, neither mer nor gas6 are early predictors of mortality in septic patients at ed presentation. however, mer independently predicted the development of sic, thrombocytopenia and pt-inr derangement in this population. glycocalyx shedding correlates with positive fluid balance and respiratory failure in patients with septic shock n takeyama, y kajita, t terajima, h mori, t irahara, m tsuda, h kano aichi medical university, department of emergency and critical care medicine, aichi, japan critical care 2020, 24(suppl 1):p463 endothelial hyperpermeability would play a major role in septic shock related organ failure. the aim of this study is to clarify the relationship between glycocalyx shedding and respiratory failure, sofa score, plasma angiopoietin (ang)-2 level and patient survival. methods: plasma samples were collected from 30 septic shock patients from admission to icu discharge and 10 healthy volunteers. plasma syndecan (syn)-1 and ang-2 were measured and clinical data was also collected. septic shock patients were classified into 3 groups according to the time-course change of syn-1 levels. excess syn-1 (>400 ng/ml) during 0 to 3 days and remaining high following 4 to 7 days were assigned to group i. excess ang-2 during 0 to 3 days and decreased following 4 to 7 days were assigned to group ii. moderate increase (<400 ng/ml) during 0 to 7 days were assigned to group iii. results: plasma syn-1 levels are positively associated with increased ang-2 levels (r2=0.41, p= 0.005), suggesting that ang-2 is involved in endothelial hyperpermeability. fluid balance and ventilator-free days (vfd) are significantly increased in group i as compared with group iii. sofa score, apache ii and patient outcome does not show any differences between groups i, ii, and iii. the positive correlation between glycocalyx shedding and fluid balance indicates plasma syn-1 may be a valuable marker for endothelial hyperpermeability. the negative correlation between glycocalyx shedding and vfd indicates plasma syn-1 may be a valuable marker for respiratory failure. the plasma level of syn-1 for prognosis and organ failure excluding ards in patients with septic shock requires further investigation. serial procalcitonin measurements in the intensive care unit at hiroshima university hospital k hosokawa, s yamaga, m fujino, k ota, n shime hiroshima university hospital, department of emergency and critical care medicine, hiroshima, japan critical care 2020, 24(suppl 1):p464 introduction: serum procalcitonin (pct) is a promising biomarker for differentiating bacterial infections from other inflammatory states. moreover, including serial pct measurements in the management of acute respiratory infection reduces the duration of antibiotic therapy without increasing the mortality. however, limited real-world information is available regarding the use of pct in intensive care units (icus). we extracted and analysed data from january 1 to december 31, 2018 from all the orders and results of pct measurements in the icu (26 beds) at hiroshima university hospital. a total of 1,252 pct measurements from 409 icu patients were included. in 170 patients, pct was tested ≥3 times during a single icu stay. serial pct measurements showed a fade-out pattern (76 [45%] patients), a second day-peaked decrease pattern (35 [21%] patients), and a series of negative patterns (30 [18%] patients). compared to patients who demonstrated the fade-out pattern, those who demonstrated the second day-peaked decrease pattern had higher mortality rates (3% vs. 20%, p < 0.01). approximately one-third patients in the icu who had decreasing serial pct values demonstrated the second day-peaked decrease pattern. since this group of patients had poorer survival, further studies are needed to clarify the association between a late rise in pct levels and delayed therapeutic intervention. the research was performed on 200 full-term newborns; no clinical signs of bacterial infection were diagnosed. on the 1, 5, 20 days the plasmà concentration of il-1ß, il-6, il-8, tnf-α, g-csf, sfas, fgf, no was determined by capture elisa; cd3cd19, cd3cd4, cd3cd8, cd69, cd71, cd95, hla-dr, cd34, cd14, cd3cd56, lymphocytes in apoptosis -immunophenotype analysis. by applying the statistical cluster population analysis of the immunological criteria under study we have evaluated the feasibility of sepsis diagnostics at the admission to the intensive therapy unit. the diagnostic rule for sepsis has been formulated by applying the "decision tree" approach to the "r" statistic medium. the cluster analysis confirms the presence of two clusters (presence of absence of sepsis: these two components explain the 60.81% of the point variability). the diagnostic rule for the early diagnostics of sepsis is as follows: disease develops providing during the first 48 hours cd95≥16.8%, no≤9.6 mkmol/l or cd95≤16.8%, cd34≤0.2%, cd69≥4.12% or cd95≤16.8%, cd34≤0.2%, cd69≤4.12% and lymphocytes annexinv-fitc+pi-≥12.3%. 45 newborns featured the confirmed sepsis development. the accuracy of this diagnostics amounts to 95.41%; sensitivity to 97.06%; specificity to 94.67%; diagnostic false positive share to 5.33%; diagnostic false positive share to 2.94%; positive result accuracy to 89.19%; negative result accuracy to 98.61%. the aggregate determination of cd95, cd69, annexinv-fitc+ pi-, cd34 and the plasma concentration of no enables the pre-clinical diagnostics of sepsis development. efficacy of pancreatic stone protein in diagnosis of infection in adults: a systemic review and metaanalysis of raw patient data j prazak 1 , p egimann 2 , i irincheva 3 , mj llewelyn 4 , d stolz 5 , lg de guadiana-romualdo 6 , r graf 7 , t reding 7 , hj klein 8 , ya que 1 fig. 1 (abstract p469) . impact of 24h lactate and bio-adm values in patients with elevated lactate level at admission. the green curve in the left km-plot illustrates data from 75 patients with 5 events; the red curve 70 patients with 18 events. the green curve in the right km-plot illustrates data from 28 patients with 4 events; the red curve 96 patients with 48 events. of note, differences in numbers between admission (n=328) and 24h (n=269) is related to initial mortality introduction: adrenomedullin (am) is a peptide synthesized in vascular endothelial cells and cleared by the lungs. the use of am as an inflammatory biomarker and his predictive value has been studied in critically ill patients, but not yet in veno-venous extracorporeal membrane oxygenation (ecmo). the purpose of this study was to describe the plasmatic levels of am in patients supported with ecmo for acute respiratory failure methods: am (normal values <0.55 nmol/l) was measured at 5 time points: immediately before (t0), 24-h (t1) and 72-h after (t3) ecmo initiation and immediately before (t4) and 72-h (t5) after ecmo removal, in consecutive patients with severe respiratory failure supported with ecmo enrolled in the gatra study (nct03208270) at fondazione irccs ca' granda -policlinico of milan. data are reported as median (25 th -75 th percentile). statistical analysis was performed using logistic and random effects regression models (to account for repeated measurements within individuals) results: a total of 131 measurements were taken in 32 consecutive patients. am (nmol/l) decreased along the course of ecmo: t0=2.0 (1.5-6.4), t2=2.0 (1.5-6.4), t3=1.6 (1.1-3.1), t4=1.3 (0.8-2.0), t5=0.9 (0.6-2.1) (mean diff.= -0.65, 95%: ci -0.96, -0.35). am was lower in patients with viral compared to bacterial ards (mean diff.= -2.7, 95%ci -5.2, -0.2) (figure 1 ). am was higher in more severe patients (sofa>= 10, n=14) compared to less severe patients (sofa< 10, n=18): 5.7±4.8 vs 1.4±0.8 nmol/l, respectively p<0.001. basal values of am could not predict mortality at 28 days (or=0.8, 95%ci: 0.5-1.2) after conditioning for sofa score and respiratory failure etiology conclusions: am plasmatic values seem to be higher in more severe patients and in patients with bacterial ards. am decreased along the ecmo course but could not predict mortality in our group of patients fig. 1 (abstract p471) . plasmatic adrenomedullin during ecmo heparin binding protein (hbp) is released from activated neutrophils upon stimulation of b2 integrins. this pro-inflammatory effect generates the hypothesis that it can be a sepsis biomarker for patients admitted at the emergency department (ed) methods: the prompt study (clinicaltrials.gov nct03295825) took place at the ed of six greek hospitals. participants were admitted with suspected acute infection and at least one vital sign change. hbp was measured by an enzyme immunosorbent assay in plasma. sepsis was diagnosed by the sepsis-3 criteria. the primary study endpoint was the sensitivity for the diagnosis of sepsis. outcome prediction was the secondary endpoint. a total of 371 patients were enrolled; 166 had sepsis. the most common infections among patients without and with sepsis were upper respiratory tract infections in 30.2% and 1.2%; community-acquired pneumonia in 6.8% and 28.3%; and acute pyelonephritis in 9.3% and 28.3%. median hbp was 24.0 and 32.7 ng/ml respectively (p: 0.027). following analysis of the area under the curve (auc) it was found that the best discriminatory cut-off for sepsis was 19.8ng/ml. the comparative diagnostic performance of hbp versus qsofa score is shown in figure 1 . the odds ratio for sepsis with hbp above 19.80 ng/ml was 2.07 (p: 0.001). at the same cut-off point the sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) for the prediction of early death after 72 hours was 100%, 35.7%, 4.1% and 100% respectively. hbp is more sensitive but less specific than qsofa for the diagnosis of sepsis in the ed. the rule-out prediction of early death seems the great merit. chronobiological and recurrence quantification analysis of temperature rhythmicity in critically ill patients introduction: rhythmicity and complexity of several circadian biomarkers, such as melatonin, cortisol and temperature have been found to be modified by critical illness. we examined the potential alterations of core body temperature (cbt) fluctuations and complexity in three groups (n=21): patients with septic shock upon icu admission (group a, n=10), patients who developed septic shock at icu hospitalization (group b, n= 6) and controls (group c, n=5). the hourly, average cbt was computed for 24 h upon icu admission and discharge in groups a and c, as well as during septic shock onset in group b. cosinor analysis of cbt curves was performed leading to the estimation of mesor (mean value), amplitude (the difference between peak and mean values) and acrophase (phase shift of maximum values in hours). complexity of cbt signals was evaluated with recurrence quantification analysis (rqa). no significant alterations in any circadian feature within groups were found, except for amplitude. controls exhibited increased entry cbt amplitude (0.45 ± 0.19) compared to groups a (0.28 ± 0.18, p < 0.05) and b (0.32 ± 0.13, p < 0.05). higher entry cbt amplitude in groups b and c was related with lower saps ii (r = -0.72 and -0.84, p < 0.003) and apache ii scores (r = -0.70 and -0.6, p < 0.003) respectively, reduced icu and hospital stay in group b (r = -0.62 and -0.64, p < 0.003) and entry sofa score in group c (r = -0.82, p < 0.003). recovery cbt time series appeared more periodic in relation with icu entry, for all groups. a more random cbt signals pattern upon results: among 23.011.601 individuals, 159.691 received inpatient treatment for sepsis. 41% had severe sepsis. 21% of sepsis and 28% of severe sepsis patients had an explicitly coded hai. the proportion of hai was higher in patients that received icu-treatment than in patients without icu-treatment (35% in icu/14% in non-icu sepsis, 37% in icu/17% in non-icu severe sepsis patients). tab. 1 shows the foci of explicitly coded hai. nosocomial pneumonia was the most common hai in all patient groups. clabsi occurred more frequently in icutreated patients; 21% were affected. cauti and c. diff infections were more common among non-icu-treated sepsis patients. more than one quarter of non-icu-treated sepsis patients had a c. diff infection. hai are common causes of sepsis and pose a significant healthcare burden. the proportion of patients affected and the distribution of foci differ between non-icu-and icu-treated sepsis patients with important implications for sepsis management within hospitals. impact of sepsis protocol triggered by ramathibodi early warning score (rews) in ipd sepsis on clinical outcomes s matupumanon 1 , y sutherasan 2 , d junhasawasdikul 2 , p theerawit 3 sepsis is now early identified and managed during triage in the emergency department. however, there is less focus on the effect of patients' management at the ward level. we aim to evaluate the impact of the implementation of the sepsis protocol on clinical outcomes in in-patients with new-onset sepsis. we conducted a prospective observational cohort study among adult medical patients admitted to the general wards in a university hospital. a 25-month pre-protocol period (august 2016 to august 2018) was assigned to a control group, and a 14-month protocol period (september 2018 to october 2019) was allocated to a protocol group. an in-patient sepsis protocol comprised nurse-initiated sepsis protocol by ramathibodi early warning score (rews)≥ 2 plus suspected infection, prompt antibiotic, lactate measurement, and fluid resuscitation was implemented. (table 1) . the implementation of in-hospital sepsis protocol was associated with significant improvement in patients' outcomes, namely lactate measurement, starting antibiotic within 1 hr, fluid management, and the shorter length of icu stay. icu routine nursing procedures interfere with cerebral hemodynamics in a prolonged porcine fecal peritonitis model sl liu 1 , dc casoni 2 , w z'graggen 3 , d bervini 3 , d berger 1 , sj jakob 1 routine nursing procedures (np) can interfere with blood pressure and cardiac output and may therefore alter cerebral hemodynamics in critical illness. this may be risk factor of sepsis-associated encephalopathy. methods: 20 sedated and mechanically ventilated pigs were randomized to fecal peritonitis or controls (n=10, each). after 8 hours of untreated peritonitis, the animals were resuscitated for 76 hours (resuscitation period). np [assessment of sedation (as), tracheal suctioning (ts), change in body position (cp), lung recruitment maneuver (rm)] were performed at baseline and 8h, 32h, 56h and 72h after start of rp. systemic and cerebral hemodynamics and o 2 saturations were recorded continuously. shock is the most common cause of death in the postsurgical icu, including septic shock and hypovolemic shock, reaching the 50-60% mortality in septic shock. the inadequate response of the immune system to the infection triggers a potent inflammatory cascade, where the c-reactive protein (crp) is an essential key in the amplification and maintenance of this cascade. the gene encoding to crp is located on the proximal long arm of human chromosome 1 (1q32). the gt polymorphism in the promoter sequence of crp gene (rs2794521) has been associated with invasive pneumococcal disease. thus, we analyze the relationship between rs2794521 polymorphism and the risk of developing septic shock in postsurgical patients. an observational, retrospective and single-center study was conducted on a sample of caucasian patients undergoing major abdominal surgery, of which one part developed septic shock and another part developed systemic inflammatory response syndrome, who were used as control. the rs2794521 polymorphism was analyzed by vasoactive medications are commonly used in sepsis treatment but may correlate with peripheral ischemia and the well-publicized complication of limb and digit loss. yet, the association between limb and digit threat and the intensity, duration, and pattern of vasopressor exposure are unknown. we studied adults (2010-2014) at 12 hospitals in an integrated health system who met criteria for sepsis-3. we identified the time to clinically apparent limb or digit threat using clinical adjudication among those with vasopressor-dependent sepsis (i.e. >1 hour of vasopressors at sepsis onset) who had a surgical evaluation within 28-days of sepsis onset. we defined daily vasopressor intensity as 0 to 4 vasopressors administered. then, we created a time-dependent model for threat with mortality as a competing risk with a weight function to estimates the varying contribution of vasopressors over time. we determined the subdistribution hazard (sh) ratio of threat for various patterns of vasopressor exposure and intensity, adjusted for age, baseline risk factors, and sequential organ failure assessment (sofa) score at sepsis onset. of 110,621 adults with sepsis, 13,147 (12%) were vasopressordependent (age, 66 [iqr, 56-77]; 7,040 [54%] males; max sofa score, 8 [sd 5] ). of these, 3,664 (28%) died and 117 (0.9%) had evaluations for limb or digit threat 4 [iqr, 1-8] days after sepsis onset. the model-based weight function showed the contribution of vasopressors to threat was stable over time ( fig 1a) . overall, a 1 unit increase in cumulative vasopressor exposure was associated with risk of threat (sh ratio, 2.60 [95%ci, 1.60-4.23], p<.001). for various patterns of vasopressor exposure, greater intensity associated with increased risk of threat ( fig 1b) . compared to constant exposure, an increasing and peak pattern associated with the greatest sh (fig 1c) . cumulative vasopressor exposure was associated with an increased risk-adjusted hazard of limb or digit threat following sepsis. fig. 1 (abstract p509) . relationship between vasopressor exposure and limb or digit threat following vasopressor-dependent sepsis. panel a demonstrates the estimated contribution of daily vasopressor intensity prior to surgical evaluation for limb or digit threat, with mortality as a competing risk. panel b and c explore the relationship between threat and both cumulative vasopressor exposure and the pattern of exposure following sepsis onset. (b) the maximum cumulative vasopressor exposure was associated with the highest risk of limb or digit threat (shr 17.5) when compared to reference exposure pattern (shr 1.0, reference). (c) increasing (shr 1.2) and peak (shr 1.2) patterns of cumulative exposure were associate with an increased sh of limb threat, while a decreasing pattern was associated with a lower risk (shr 0.8) when compared to constant intensity (shr 1.0, reference). abbreviations: shr: subdistribution hazard ratio proportion of encounters transitioning from phenotype at presentation within 24hrs, by arrival phenotype assignment and probability of membership. (c) tsne plots for α-type, ß-type, y-type, and ∂-type, with core (dark), marginal (light), and non-members (grey) in plots on the left and core, marginal, non members, and transitioning members (black) on the right fig. 1 (abstract p005). isolated microorganisms critical care references: 1. wertz et al. critical care explorations 1: e0058 the process investigators choosing wisely guidelines for the provision of intensive care services, version 2. ics structured patient handovers references: 1. care of the critically ill woman in childbirth the proqol manual: the professional quality of life scale:compassion satisfaction, burnout & compassion fatigue/secondary trauma scales references: 1. shimabukuro-vornhagen a et al. ca the code: professional standards of practice and behaviour for nurses, midwives and nursing associates p415 introduction: the aim of this study was to compare factors associated with the icu mortality for vap due to multidrug-resistant (mdr) klebsiella spp. in case of monobacterial (mo) vs polibacterial (po) origin. methods: retrospective data analysis of patients treated in icu with mdr klebsiella spp. strains as pathogens of vap during three year period was carried out. results: data of 71 patients were evaluated. mo vs po of mdr klebsiella spp. vap cases was found to be 35 (49.3 %) vs 36 (50.7%), p = 0.906. the icu mortality was 9/35 (25.7%) in mo, and 17/36 (47.2%) in po one, p = 0.060. statistical significant differences of survivors vs non-survivors in mo and po vap due to mdr klebsiella spp. were found in medians of neutrophilosis 78 p430 introduction: we study the population structure and resistome of mdr enterobacterales and pseudomonas aeruginosa isolates, c/t-susceptible or -resistant, recovered from low respiratory, intraabdominal and urinary tract infections of icu patients of 11 portuguese hospitals (step study results: in e. coli, two vim-2 producers were found (st131-b2-h30-o25:h4-ctx-m-15 and st88-c-h39-o22:h4) (c/t-mic=0.5/4-1/4 mg/l). a kpc-3-st5463-cladev-h160-o164:h56 (16/4 mg/l) was also detected. the most frequent esbl-e. coli clone was st131 cpr klebsiella pneumoniae (32 patients), candida spp. (21 patients). the comparison subgroup consisted of 217 patients with bacteremia caused by non-escape pathogens. we evaluated the days of mechanical ventilation, duration of antibiotic therapy (amt), icu length of stay (los), hospital los and mortality (table 1). results: mortality in patients with bacteremia caused by non-eskape pathogens was 23.5%, candida spp vancomycin mass removal over 120 minutes of hemoperfusion using ha330. bars refer to vancomycin mass (mg): blue (experiment 1) and red (experiment2) bars using blood while green (experiment 3) bar using balanced solution. yellow dashes are mean mass values of the three experiments (with standard deviations) and yellow line represents the reduction curve over time table 1 (abstract p438). results. * p-value versus non-eskape subgroup mechanical ventilation p453 translational value of the microbial profile in experimental sepsis studies sp tallósy 1 , a rutai 1 , l juhász 1 , mz poles 1 , k burián 2 , d érces 1 , a szabó 1 , m boros 1 invasive hemodynamic monitoring and blood gas analyses were performed on anesthetized animals between 18-24h of sepsis. the respiratory, cardiovascular, renal, hepatic and metabolic dysfunctions were evaluated with the species-specific sequential organ failure assessment (sssofa) score, the microbial profile was determined with selective media and maldi-tof ms in the initial inoculum and in the abdominal fluid taken 20h after sepsis induction. results: strong correlation was found between the initial dose of the inoculum (cfu) and the sssofa scores for organ dysfunction (rats: r = 0.656, p=0.0186; pigs: r=0.570, p = 0.0391) p466 introduction: pancreatic stone protein (psp) has shown promise as a biomarker of infection however, its diagnostic potential has not been systematically evaluated. we performed a systematic review and meta-analysis of available data on psp to evaluate its value for detecting infection in adults and determining a plasma or serum threshold value. methods: the pubmed and cochrane library database were searched for studies on psp in adult patients and their raw data were analyzed to estimate the best psp cut-off value that could detect infected patients using the youden's index. the cut-off sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) were computed and compared to those for procalcitonin (pct) and c-reactive protein (crp). finally, we explored the potential value of a model combining all three biomarkers to detect infection. results: from a total of 44 potentially eligible published studies, 5 containing 631 patients were included in quantitative analysis. among them, 370 patients suffered from a clinically confirmed infection. the median appropriate statistical tests were used using spss 23. cd 64 was expressed as % age of neutrophils expressing positivity. results: sixty patients were analyzed. all parameters were compared between survivors and non survivors. demographics were comparable. most common source of sepsis was lungs and majority were admitted due to medical reason. non-survivors had significantly increased number of days with septic shock. at day 8 median values of all the biomarkers and the sofa score were significantly higher in the nonsurvivor group (p<0.05). there was a decreasing trend of all 3 biomarkers and sofa score amongst survivors. on multivariate logistic regression analysis, increased cd64 and crp levels between baseline and day 8, increased days with septic shock and increased sofa references: 1 introduction: we characterized the association of c-reactive protein (crp) with extracellular vesicles (evs) in plasma from sepsis patients and assessed a commercial crp adsorbent (pentrasorb, pentracor, hennigsdorf, germany) to deplete free and ev-associated crp. in addition, we characterized the potential pro-inflammatory effects of ev-bound crp on monocytes and endothelial cells monocytes and human umbilical vein endothelial cells (huvecs) were stimulated with isolated evs (20,000 g, 30 min) monocyte il-8 secretion was quantified by elisa; the activation of huvecs was assessed by their expression of icam-1 and e-selectin using confocal microscopy. results: septic plasma (n=30) contained 227.0±88.6 mg/l crp vs. 0.7±0.4 mg/ l for healthy controls (n=5). both, total evs and crp + evs were significantly elevated in septic plasma as incubation of septic plasma with pentrasorb resulted in depletion of free crp (247.2±72.6 mg/l before vs. 1.8±0.7 mg/l after adsorption) as well as in a significant reduction in crp evs from crp-depleted septic plasma induced significantly lower il-8 levels. huvec icam-1 or e-selectin expression, however, did not increase upon stimulation with septic evs. conclusions: treatment of septic plasma with pentrasorb efficiently removes free crp and detaches crp from the ev surface, resulting in reduced proinflammatory effects flow cytometry confirmed the association of monocytes with platelets and platelet-derived evs as well as the uptake of evs by monocytes. conclusions: storage of isolated monocytes induces a shift towards cd16 expressing proinflammatory monocytes, which seems to be mediated by residual platelets and platelet-derived evs. it remains to be clarified whether evs released from activated platelets can also trigger a shift towards proinflammatory, intermediate monocytes in vivo ethical approval was provided by ucl research ethics committee (5060/001). paired parametric analyses were performed and data displayed as mean +/-95% ci. results: plasma calprotectin concentration began to increase 1.5hours after endotoxin administration, was significantly higher than baseline by 2 hours (356.7ng/ml vs. 737ng/ml, p <0.01), peaked at 4 hours (mean 1373ng/ml, figure 1) and normalized by 24 hrs. calprotectin peaked earlier than comparator soluble mediators (procalcitonin 8hrs, crp, 24hrs) and exhibited 100% sensitivity; all participants demonstrating a minimum 2-fold increase from baseline (mean 3.84x). calprotectin displayed greater baseline variability (sd 147.9ng/ml) than either crp or procalcitonin. conclusions: our results indicate the potential of plasma calprotectin as a biomarker for bacterial infection. it increases earlier and peaks more rapidly than standard biomarkers. whilst higher baseline variability was observed p501 a multicenter randomized controlled study on landiolol for the treatment of sepsis-related tachyarrhythmia: subanalysis of the j-land 3s study o nishida kagoshima university graduate school of medical and dental sciences, department of emergency and intensive care medicine methods: we analyzed a retrospective cohort of electronic health records from adult sepsis patients at 12 upmc hospitals from 2010 to 2014. we defined sepsis-3 by i.) suspected infection (e.g., administration of antibiotics or body fluid culture) & ii.) organ dysfunction (e.g., 2 or more sofa points) in the first 6 hours of care. data were organized by hour and included vital signs, lab values, and treatments (e.g., total hourly iv fluids (ml) and norepinephrine equivalent dose). for each hour we describe, i.) available data elements, ii.) presence of sepsis-3, and iii by hour 6, most patients had vital signs (99%; n=70,559), basic labs (88%; n=62,719), fluid cultures (94%, n= 66,995), while serum lactate was completed in 24% (n=17,818) conclusions: early sepsis care patterns are variable. iv fluids were given during early hours, when uncertainty about sepsis was greatest, while vasopressors were administered after sepsis-3 elements were present. p504 effects of abdominal negative pressure treatment on splanchnic hemodynamics and liver and kidney function in a porcine fecal peritonitis model sl liu 1 department of intensive care medicine splanchnic hemodynamics and laboratory parameters were measured at baseline (bl, start of rp), and 24h, 48h and 72h after start of rp. two/three-way rm-anova or mixed-effects analysis, and student t tests were performed. results: npt in controls had no effect. after sepsis induction, mean arterial pressure (map) decreased by 15 (7-22) mmhg, cardiac output (co) by 1.3 (0.7-2.2) l/min, and arterial lactate increased by 0.2 (0.1-0.5) mmol/l. sepsis and resuscitation was associated with increasing hepatic and renal arterial flows (p≤0.002, both), and increasing prothrombin time npt in sepsis resulted in numerically less noradrenaline administration (0.3±0.3 ug/ min/kg in sepsis with npt vs. 0.8±0.7 ug/min/kg without npt, p= 0.310) and positive fluid balance (2.8±0.4 ml/h/kg with npt vs. 3.1± 0.4 ml/h/kg without, p=0.241). conclusions: in our experimental fecal peritonitis model, npt did neither impair splanchnic hemodynamics nor abdominal organ function. whether npt helps to reduce noradrenaline and volume administration in abdominal sepsis should be evaluated in further studies. p505 association between a c-reactive protein gene polymorphism (rs2794521) with the risk of develop septic shock in postsurgical patients of major abdominal surgery p martínez-paz 1 valladolid, spain; 2 hospital of medina del campo notably, the three groups received a comparable pro kg dose of acetaminophen. no difference was found between groups in term of toxic effects. patients carrying the cyp3a5p showed a more pronounced effect on body temperature in respect of wt and ugt1a1p °c respectively, but it does not reach statistical significance (fig.1b). only 50% of the patients reach a temperature <38°c at t2 and only 20% <37.5°c. conclusions: polymorphisms in enzymes involved in the metabolism of acetaminophen are relatively common. cyp3a5p seems to lead to higher peak plasmatic concentration and a slightly increased efficacy in fever control panel a: variations of acetaminophen plasmatic levels after 30 minutes (t1) and 2 hours (t2) after administration of an iv dose of 1g of paracetamol in wt patients and patients carrying mutation; panel b: body temperature variations in wt patients and patients carrying mutations clinical research, investigation, and systems modeling of acute illness (crisma) center, department of biostatistics we determined phenotype cohesiveness using probability of assignment at presentation, defining core members as ≥90% and marginal as <90% probability. we determined how members transitioned to other phenotypes over 24hrs using t-distributed stochastic neighbor embedding (tsne) plots and determined the odds (95%ci) of transition. results: we studied 37,198 adult sepsis encounters (median age 69 1c) the odds of ever transitioning from presenting phenotype increased significantly for marginal members vs publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank the department of education of the basque government (piba 2019-57) and the university of the basque country upv/ehu (ppg17/65, giu 17/32) for their financial support. a great disaster affects the family-and friend-performance of bcpr by diminishing the willingness of family and friend bystanders to follow the instruction provided by dispatchers. the experimental method ifitem could be an alternative of fibtem in cases when internal coagulation pathways assessment is prioritized (i.e. heparinized patients on extracorporeal supports). patients undergoing limitation of life-sustaining therapy had lower karnofsky scale scores. therefore, this scale may be useful to guide end-of-life decisions in the future, but further studies with larger number of patients are needed. readmission after discharge home from critical care: a qualitative study c robinson 1 , f nicolson 1 , p mactavish 1 , t quasim 2 , jm mcpeake 1 1 nhs greater glasgow and clyde, nhs greater glasgow and clyde, glasgow, united kingdom; 2 university of glasgow, nhs greater glasgow and clyde, glasgow, united kingdom critical care 2020, 24(suppl 1):p392 readmissions to acute care occur in a high number of critically ill patients within 90 days of hospital discharge [1] . biomedical drivers such as frailty and pre-existing co-morbidities have been identified as drivers for readmission. however at present there is limited data on the influence of social problems on readmission. this study, using a grounded theory approach, sought to understand from a patient/caregiver perspective what the drivers for readmission to acute care were. ethical approval was granted from the west of scotland research ethics service (19/ws/0091). a grounded theory approach was used to explore from a patient and caregiver perspective what the drivers for readmission are [2] . using a clinical database, we identified those patients who had an icu admission ≥ 3 days who were readmitted to acute care within 90 days of hospital discharge. the researcher attended the ward and after discussion with the direct care team conducted a semi-structured interview with patient and/or caregiver. the interview was recorded and transcribed verbatim. the transcripts were analysed to generate initial codes, followed by the development categories and sub-categories. theoretical sampling was undertaken. results: 15 participants were interviewed.10(66.6%) were patients and 5 (33.3%) were caregivers. the themes that have emerged from the data were: pain and polypharmacy; lack of social support and/or isolation; strained relationships with primary care providers and information provision across the patient journey. subsequent theory development is underway to understand how this learning could help reduce readmissions in future. in conclusion, both social and biomedical drivers are likely to contribute to acute care readmission in this group. future interventional work is required in order to identify modifiable factors to reduce this burden for patients and the healthcare service. frailty has shown to have prognostic relevance for patients with critical illness. since a wide range of tools has been described to screen for frailty, we aimed to describe the association of two frailty screening tools, the clinical frailty scale (cfs) score and the modified frailty index (mfi) in critically ill patients. we performed a post-hoc analysis of a multicenter cohort of patients admitted to six canadian intensive care units (icu) between february 2010 and july 2011. frailty was identified using the clinical frailty scale (cfs) and the modified frailty index (mfi). concordance of the frailty screening tools was evaluated with partial spearman rank correlation and intraclass correlation (icc). discrimination and predictive ability of the tools for hospital mortality, 1-year mortality, hospital readmission and adverse events were compared using concordance statistic (c-statistic) and calibration plot adjusting for age, sex, sequential organ failure assessment (sofa) score and icu admission source, respectively. the cohort included 421 patients. prevalence of frailty was 32.8% (95% confidence interval [ci] 28.3%-37.5%) with the cfs and 39.2% (95% ci 34.5%-44.0%) with the mfi. concordance between the two tools was low [(icc of 0.37; 95% ci 0.29-0.45) and partial correlation coefficient of 0.38 (95% ci 0.29-0.47)], even after adjustment. hospital and 1-year mortality were greater for frail compared to non-frail patients using of both tools. similarly, both tools found frail patients were less likely to be living independently after hospital discharge, and more likely to be rehospitalized when compared to non-frail patients. while the cfs and mfi show low concordance, both showed good discrimination and predictive validity for hospital mortality. both tools identify a subgroup of patients more likely to have worse clinical outcomes. the post-intensive care syndrome (pics) is a myriad of physical, psychiatric and cognitive disorders secondary to critical illness, leading to a decreased quality of life and an important socioeconomic burden. this study aimed to identify if the conformity to a pics prevention bundle was able to reduce the incidence of the syndrome at icu discharge. all patients admitted to the icu from january 1 st to december 31 st 2018 were included. the conformity to each of the ten components of the pics prevention bundle was assessed daily, and the patients were evaluated for anxiety, depression, cognitive dysfunction, muscular weakness, mobility impairment and nutritional risk at icu discharge and at a 3-to-6-months follow-up consultation. the patient cohort was divided in terciles according to bundle conformity for the analysis. results: from the 1145 enrolled patients, 352 (31%) were evaluated at icu discharge, and 103 (29%) attended to the follow-up consultation. there was no difference in baseline characteristics between the cohorts. there was no correlation between the prevalence of pics at discharge and bundle conformity during icu stay (90% vs. 87% vs 87%, p 0.834), though there was a decrease in nutritional risk and days in mechanical ventilation (table 1) . after 3 to 6 months there was a reduction on the prevalence of any kind of pics, mobility impairment, muscular weakness and nutritional risk. the patients that developed pics were older and had a higher simplified acute physiology score iii at icu admission. a higher adhesion to a pics prevention bundle was not able to prevent the occurrence of the syndrome. post intensive care syndrome (pics) is well recognized following general icu care [1] . intensive care syndrome:promoting independence and return to employment (ins:pire) is a multidisciplinary complex intervention designed to address pics [2] . with a paucity of evidence on pics after cardiothoracic intensive care, we aim to evaluate pics and the feasibility of the ins:pire intervention in this population. those attending the clinic received 5 weeks of intervention including individual appointments with icm nurse, physician, pharmacist, and physiotherapist. a café area facilitated peer support alongside psychology group sessions. primary outcome was quality of life measured by eq-5d-5l. further surveys included: pain, mental health, and selfefficacy. questionnaires were taken at baseline, 3 and 12 months. results: over 5 cohorts, 27 patients attended, 67% male, median age 66 years (iqr 61-75), median apache 2 score of 17 (iqr 14-18.5), and median icu length of stay was 13 days (iqr 9-21). a total of 14 (53%) patients completed surveys at one year. scheduled admissions represented 56% of those attending. mean euroqol eq-vas score was 70/ 100 (sd +/-18) at baseline increasing to 78/100 (sd +/-16) by 1 year (table 1) . those with problems in at least one domain of eq-5d-5l fell from 92% at baseline to 73% at 1-year with the breakdown shown in table 1. severe problems were seen in 22% falling to 18% at 1 year. hads demonstrated an anxiety or depression rate of 44%. brief pain inventory identified 14 patients (52%) with ongoing chronic pain. mean self-efficacy was 32/40 (sd +/-6) at baseline and 34/40 (sd +/-5) at 1 year. cardiothoracic intensive care patients have ongoing and persistent features of pics with significant effects on health-related quality of life. further, the ins:pire multi-professional complex intervention is feasible within this specialist group. screening approach might be implemented whenever screening of the total icu population is not deemed feasible. influenza is an acute viral illness with a significant financial burden. point of care testing for influenza is available and has demonstrated accuracy [1, 2] , the current gap in knowledge is the question around the opportunity cost of influenza testing. if poct is financially a less costly test this could free up scarce resource. the study adopts a cost minimisation approach. the point of care test is the roche cobas® liat® machine which can detect flu a/b and is compared with the west of scotland specialist virology centre's established in house multiplex real time pcr assay.the model was developed using microsoft excel and has 2 arms comparing analysis of the above mentioned tests. the model estimates that the total cost of poct per patient tested is £3926.33 compared with £4053.92 for lab testing ( figure 1 ). this is a saving of £127.60 per patient when poct is used. the result swings in favour of the lab test when poct specificity falls to 95.72%. if the lab could provide the result of influenza testing within 12 hours the result would swing in favour of lab testing. zanamivir which will potentially be used increasingly in the intensive care setting can more than double the difference between the 2 tests in favour of poct. this research suggests that poct offers potential cost savings in the icu setting. this is the case as long as poct specificity is higher than a threshold of 97.52% and the lab take longer that 12 hours to return the result. the sensitivity analysis should allow for external validity given the usual variations in icu practice. the aim of the present study is to describe the demographic, clinical, microbiological aspects and the outcome of patients with intensive care unit-related (icu-related) bacteremia. moreover, we aimed to study the patient outcome in association with colistin susceptibility. retrospective, single-center study in a 16-bed icu for 12 months, from 1/10/2018 to 30/9/2019. icu-related bacteremia was defined as bacteremia in patients with icu stay >48 hours or icu readmission (first admission ≥ 1 month before). only the first episode of bacteremia was considered. the primary outcome was 28-day mortality. data regarding clinical, demographic and outcome characteristics were retrieved from the patient files. the hospital's ethics committee approved the present protocol. moreover, the patients with bacteremia due to colistin-resistant pathogens were compared with the patients affected by colistin sensitive microbes. forty episodes of gram-negative icu bacteremia were collected during the aforementioned period in 40 patients (61.5% male) with a mean age and apache ii of 60.6±16.8 years and 18±8.1, respectively. the event had taken place at an average of 13.7 days. the responsible isolates were resistant to carbapenems in 82.5% of the episodes. the majority of the events were due to a single isolate (85%). acinetobacter baumannii and klebsiella pneumoniae presented the majority of the implicated microbes (35% and 37.5%, respectively). the crude 28-day mortality was 30%. finally, we could not detect any difference in mortality between the colistin sensitive and the colistin-resistant pathogens ( figure 1 ). the present study denotes that, in a setting of extremely drugresistant pathogens with limited treatment options, gram-negative bacteremia in the icu is associated with increased mortality. image 1 : characterization of resistance mechanisms affecting ceftolozane/ tazobactam in enterobacterales and pseudomonas aeruginosa icu isolates using whole genome sequencing (step study) m hernández-garcia 1 , cc chaves 2 , jm melo-cristino 3 , ds silva 4 , ar vieira 5 , mp f. pinto 6 , jd diogo 7 , eg gonçalves 8 , jr romano 9 , rc cantón 1 1 hospital ramón y cajal-irycis, microbiology department, madrid, spain; 2 introduction: clostridium difficile infection (cdi) is the main cause of hospital acquired diarrhoea [1] . the aim of this study was to compare characteristics of cdi during yr 2011 and 2015. a retrospective observational study was carried out in lithuanian university of health sciences hospital -the largest teaching facility of tertiary care in country. according to department of infection control records, patients (pt) with (w.) diarrhoea and the first positive stool test for c.difficile toxin a/b were included. age, charlson comorbidity index (cci) score, profile of hospital department (medical (md), surgical or icu) where cdi was diagnosed, type of cdi (healthcare-associated (ha), hospital or community-acquired) and rate of risk factors (rf) have been estimated in both 2011 and 2015. ibm spss 23.0; pearson's chi-square, fisher's exact tests were used for statistics. p < 0.05 was statistically significant. results: in total 7 pt from 2011, 72 from 2015 were enrolled. in 2011 n=4 (57%) pt were ≥65 yr old, in 2015 -n=45 (63%), (p=0.045). in 2011 cci>5 was estimated in n=6 (86%) pt in comparison of n=46 (64%) in 2015, (p=0.025). in 2011 n=0 (0%) of cdi cases were ha, in 2015 -n=12 (17%), (p=0.01). in 2011 n=5 (71%) of cdi were diagnosed in md in comparison of n=60 (83%) in 2015, (p=0.01). in 2011 12 weeks prior to cdi n=5 (71%) pt have been admitted to hospitals, n=7 (100%) have been treated w. antibiotics, n=4 (50%) -w. ppis, n=5 (36%) -w. h2 antagonists, n=3 (43%) -w. immunosupressants in comparison of n=51 (71%), n=69 (96%), n=36 (57%), n=26 (71%) and n=21 (29%) in 2015, respectively, (p>0.05). overall rate of cdi cases among in-hospital patients increased tenfold by yr 2011 and 2015. in 2015, more elderly patients had cdi and severe comorbidities were less frequent in comparison with 2011. in 2015, more cases of cdi were hospital-acquired and have occured in medical departments. rate of risk factors of cdi remained unchanged.these results indicate a possible relationship between ttv dna count and immunological alteration. the ttv quantitative determination could be useful as a proinflammatory marker in sepsis, with some benefits: low cost, easy determination and good correlation with immune system functionalit. it will be necessary to perform a larger study to check our hypothesis and to establish a ttv level threshold that may allow to anticípate the disease prognosis. introduction: acute kidney injury (aki) is a serious complication in sepsis and associated with high morbidity and mortality. the combination antimicrobial regimens with vancomycin (vcm) and broad-spectrum betalactams (bsbl), such as piperacillin tazobactam and cefepime, have been identified as potentially nephrotoxic combinations, but existing studies have not provided sufficient evidence. the aim of this study was to evaluate detailed association between the combination antimicrobial therapy and the risk of aki in septic patients. this investigation was a post hoc analysis of 2 prospective nationwide cohorts enrolling consecutive adult patients with sepsis in intensive care units in japan. in this study, progression of aki was defined as one or more elevation of renal sub-score in sequential organ failure assessment score from day 1 to day 4. we regarded anti-pseudomonal penicillins, fourth generation cephalosporines, and carbapenems as bsbl. multivariable logistic regression analysis including a two-way interaction term (vcm x bsbl) was performed to assess the add-on effects of each antimicrobial agent on the progression of aki. the final study cohort comprised 1837 patients with sepsis. among them, 45 received vcm without bsbl, 1055 received bsbl without vcm, 249 received both vcm and bsbl, and 488 received other type of antimicrobials. the administration of vcm was associated with an increased risk of aki in patients with bsbl [odds ratio (or), 1.57 (0.96-2.57); p=0.072]. however, the tendency was not evident in patients without bsbl [or, 0.23 (0.03-1.56); p=0.133]. the interaction effect on the progression of aki between vcm and bsbl were statistically significant (p for interaction=0.038). the regression model including two-way interaction term suggested that the combination of vcm and bsbl might synergistically increase the risk of aki in patients with sepsis. increasing resistance to carbapenems due to carbapenemase productionone of main actual problems of antibacterial resistance in burn icu. production of several types of carbapenemases (kpc, ndm and oxa-48) is common in k. pneumoniae strains. carbapemenase production is a marker of extreme antibacterial resistance. the aim of our study was to investigate the epidemiology of nosocomial infections caused by producing kpc, ndm and oxa-48 k. pneumonia strains in burn icu. total of 26 patients with nosocomial infections caused by 26 carbapenem resistance strains of k. pneumoniae were included in the study, from whom 3 had lower respiratory tract infection, 23 had skin and skin structure infection. initial identification of isolates was performed in laboratory by automatic microbiological analyzer. for all of k. pneumoniae isolates presence of bla ndm , bla oxa-48 and bla kpcgenes were examined by pcr method. baseline characteristics of patients: me (iqr) of age -50 (39; 64) years, me (iqr) of tbsa -40 (29; 52) percent, me (iqr) of icu los -30 (21; 35) days. inhalation injury was diagnosed in 10 (38.4%) patients. total of 11 patients died, mortality rate was 42.3%. all patients were diagnosed with nosocomial infection caused by k. pneumoniae. from 26 k. pneumonia strains 1 (3.8%) were found to be producing kpc, 3 (11.5%)producing ndm and 20 (76.9%) -producing oxa48. only 5 (19.2%) carbapenem resistance k. pneumoniae isolates were not producing carbapenemases. from 20 patients infected by oxa48 producing k. pneumoniae 20 patients died, mortality rate was 40%. from 23 patients infected by oxa48 or ndm producing k. pneumoniae 10 patients died, mortality rate was 43.5%. from 5 patients infected by non-carbapenemase producing k. pneumonia no one died. carbapenemase producing strains are widely spread among carbapenem resistance strains of k. pneumoniae in burn icu. mortality of patients infected by producing oxa48 or ndm k. pneumoniae strains reaches 43.5%. the rationale for blood purification as adjunctive therapy during sepsis involved the capacity in removing endogenous and exogenous toxins, but currently no recommendations exists [1] . a critical point may be the potential interaction with antimicrobial therapy, which remains the mainstay of sepsis treatment. the aim of our study was to investigate the vancomycin (van) removal during blood purification using an in vitro model of hemoperfusion (hp) with ha330 cartridge (jafron, zhuhai city, china), most widely used in china and actually available in europe. this is an experimental study. three independent experiments were performed: we injected 250 mg of van in 500ml of whole blood from healthy donors (experiment 1 and 2) or in 500ml of balanced solution (experiment 3) in order to assess membrane saturation. a closed-circuit (blood flow of 250ml/min) simulating hp ran using ha330. samples were collected from arterial line at 0, 5, 10, 15, 30, 45, 60, 90, 120 minutes; van plasma concentrations were measured and removal was evaluated using mass balance analysis. differences in mass removal was assessed using kruskal-wallis test. results: figure 1 shows van mass at each timepoints. we observed no difference between in blood and in balanced solution experiments (p the aim of this study is to determine if routine bbv testing in the icu contributes to the discovery of undiagnosed bbv infections. icu patients may require renal replacement therapy (rrt). sharing rrt equipment carries a risk of bbv transmission, which mainly relates to hepatitis b (hbv), hepatitis c (hcv) and hiv. since 2012, all glasgow royal infirmary icu patients undergo routine bbv screening, with rrt machines allocated for patients with specific bbv statuses. routine bbv testing is beneficial to both the individual and society. hcv is a pertinent health issue in scotland. the scottish government aims to eliminate hcv by 2030 and is researching innovative and costeffective methods to identify undiagnosed infections. this single-centre retrospective observational study examined prospectively collected clinical data from 1069 icu admissions. proportions were compared using a two-proportion z-test and a logistic regression model was carried out to determine if deprivation quintile was independently associated with the seroprevalence of bbvs. the bbv seroprevalence in the cohort studied: 0.45% (hbv), 11.7% (hcv), 0.91% (hiv). the seroprevalence of hbv in the cohort studied was similar to that of scotland (p=0.11), but the seroprevalence of hcv (p<0.001) and hiv (p=0.01) were statistically significantly higher than that of scotland. due to the small number of reactive test results for hbv and hiv, the relationship between deprivation and bbv seroprevalence was explored for hcv only. the only independent variable associated with a reactive anti-hcv test result was "current or previous illicit drug use" (adjusted odds ratio of 40.2; 95% confidence interval of 21.1-76.4; p<0.001). this study shows that routine bbv testing in the icu is useful in discovering new bbv infections. this is the first observational study focusing on the value of routine bbv testing in an icu setting to our knowledge. continuous infusion vancomycin protocol is a safe, acceptable and effective alternative to intermittent dosing of vancomycin in critical care. ceftaroline is an efficacious treatment in patients with severe cap, admitted in icu. it relates to earlier resolution of respiratory failure and less rescue antibiotics. we need an adequately pragmatic trial to confirm our findings organ dysfunction in scrub typhus, incidence and risk factor a sarkar 1 , a guha 2 , r dey 3 [1, 2, 3, 4, 5] . its preads by bite of larval stageof thromboculid mites or chigger [1] . clinical features may include fever, headache, myalgia, lymphadenopathy, eschar, skinrash. it may also cause pneumonia, renal failure, shock, meningoencephalitis, multiple organ failure [1, 2] . our study aims to discuss the incidence of organ dysfunction in a comprehensive way taking the overall population of patients with identified scrub typhus infection. there is lack of data in eastern india regarding the incidence and risk factors of developing multiorgan dysfunction syndrome (mods) in scrub typhus. in this retrospective study we studied the incidence of various organ involvement and the risk factors associated with the development of mods in scrub typhus. we collected data from december 2016 to november 2019 in tertiary care hospital at kolkata. we have included all patients who are having fever, scrub typhus igm antibody positive, age more than 14 years. sofa score was used in evaluating patients with mods. exclusion criteria involves patient who are having coinfectional ong with scrub typhus. in a cohort (n=114), patients with multiorgan dysfunction syndrome was seen in 27 patients (23.68%), the mean age in group of patients with mods was 50.0+/-14.96 years (mean+/-sd). in group of patients with mods, fever duration in days was of 11+/-3.58 days (mean+/-sd), interval from treatment to defervescenc in days was 5.11+/-2.39 days (mean +/-sd). among patients with mods, hematologic involvement was seen in 7 patients (25.92%), hepatic involvement was seen in 19 patients (70.37%), renal involvement was seen in 17 patients (62.96%), neurologic involvement was seen in 24 patients (88%), respiratory involvement was seen in 14 patients (51.85%), cardiovascular was seen in 8 patients (29.63%), icu shifting was necessary in 20 patients (74.07%), mechanical intubation was needed in 14 patients (51.85%) in multiorgan dysfunction syndrome patients. hospital mortality in patients with mods was 3 patients (11.11%). no mortality was seen in patients without mods. other parameters were evaluated among patients with mods. they include eschar in 1 patient (3.7%), seizure in 7 patients (25.93%), hepatoslenomegaly in 26 patients (96.3%), leucopenia in 3 patients (11.11%), leucocytosis in 13 patients (48.14%), thromnbocytopenia in 7 patients (25.92%),decreased hemoglobin in 22 patients (81.48%), transaminitis in 19 patients (70.37%). the risk factors associated with the development of mods are platelet counts, bilirubin, transaminitis, glasgow coma scale, time interval from treatment to defervescence, hemoglobin, total leucocyte count and fever duration. scrub typhus is an important cause of acute febrile illness in this part of the country and is frequently associated with organ dysfunction. however, the overall mortality is low which is similar to other studies done before [2] . score at baseline were significant (p<0.05) predictors of mortality.highest area under the roc curve was obtained for number of days with septic shock (0.857) followed by increased cd64 between baseline and day 8 (0.798). though serial pct levels significantly increased amongst non-survivors, it did not predict mortality. serial level of biomarkers in icu patients may predict mortality. larger trials are needed to confirm the results. plasma strem-1 levels were retrospectively measured at day 1-2, 3-4 and 6-8 in 116 septic shock patients from the immunosepsis cohort (nct02803346), included between 01/2016 and 12/2018, using a validated elisa method. the associations between strem-1, mhla-dr, 28-day survival status, and occurrence of icu-acquired nosocomial infection (ni) were assessed. neither strem-1 nor mhla-dr levels at d1/2 were associated with the occurrence of icu-acquired ni. however, 28-day mortality was significantly higher in patients with d1-2 strem-1 value superior to the median (39.6% vs 11.3%, p=0.0103; median=539 pg/ml). a significant inverse correlation was found between mhla-dr at d6-8 and strem-1 at d1-2 (sp -0.378, p<0.0001) and at d6-8 (sp -0.382, p<0.0001). at d6-8, when stratifying patients based on strem-1 (400pg/ml) and mhla-dr (5000 ab/c), patients combining elevated strem-1 and low mhla-dr presented with significantly higher 28day mortality (47.6% vs 8.7%, p = 0.0003, chi-squared test) and ni incidence (31.8 vs 12%, p=0.044) compared with patients with low strem-1 / high mhla-dr. this study shows for the first time that trem-1 pathway activation is associated with septic shock-induced immunosuppression, as shown by an inverse correlation between strem-1 at baseline and mhla-dr expression at d6-8. persisting high strem-1 values and low mhla-dr expression in septic shock patients are significantly associated with higher rate of icu-acquired infection and mortality. introduction: sepsis mortality remains high [1] . the surviving sepsis campaign (ssc) recommends to guide resuscitation on normalization of lactate levels [2] , however this is debated [3] . we have shown that plasma levels of bio-adrenomedullin (bio-adm) were associated with patient outcome during sepsis [4] . we therefore aimed to evaluate the added value of bio-adm to lactate measurement in the adrenoss cohort. this is a post-hoc analysis of the adrenomedullin and outcome in severe sepsis and septic shock (adrenoss) cohort study. the adre-noss study is a prospective observational study conducted in twenty-four centers and included 583 septic patients [4] . we studied the relationship between the association of initial evolution of lactate plasma levels and bio-adm level at 24h and outcome in patients for whom both markers were available at admission and one day later ("24h"). bio-adm levels below 70 pg/ml were considered as low, and high if greater than 70 pg/ml [4] . in patients with high lactate levels (>2 mmol/l) at admission (n=328), lactate normalization (<2 mmol/l) at 24h was associated with better outcome than in patients with persistently high lactate at 24h (28day mortality 15.9% vs 41.9% respectively, hr 3.3 [2.0-5.3], p<0.001) ( figure 1 ). among patients with decreasing lactate, high and low bio-adm levels at 24h identified patients with different outcomes (28day mortality 7% vs 26% for low vs high bio-adm respectively, hr 4.4 [1.6-11.7], p<0.005). high and low bio-adm levels at 24h also differentiated outcome of patients with persistently elevated lactate (hr 4.5 [1.6-12.3], p<0.005). in patients with low initial lactate, neither lactate or bio-adm had no added prognostic. our data suggest that measurement of bio-adm in addition to lactate may help physicians to refine risk stratification and therefore to guide resuscitation during sepsis. the effect of fluid replacement in sepsis, severe sepsis and septic shock in first 24 hrs in clot quality and microstructure s pillai 1 , g davies 2 the inflammatory response in sepsis can lead to a spectrum of coagulation system defects [1] . sepsis and severe sepsis is associated with a hypercoagulable state where the clot microstructure is known to be a tight and highly elastic clot, which is potentially resistant to fibrinolysis ( figure 1 ). conversely, septic shock is associated with a hypocoagulable state where the clot microstructure is loose and structurally weak. the study aim to investigate the effect of fluid resuscitation and replacement in clot microstructure over 24 hours. methods: 100 patients (50 sepsis, 20 severe sepsis and 30 septic shock) were included in the study. all these patients received standard fluid replacement therapy with crystalloids. blood samples were collected at 0 hours, 4 hours and 24 hours. clot microstructure, standard markers of coagulation and inflammatory markers were measured. in sepsis group following fluid administration, the d f reduced initially and then remained stable (1.78-0 hours, 1.74-4 hours, 1.73-24 hours, normal d f range 1.73 ± 0.04). in severe sepsis group, the d f reduced initially, then increased (1.80-0 hours, 1.71-4 hours, 1.76-24 hours) and in septic shock, the df was very low to start with and there were only slight increase with fluid administration (1.66-0 hours, 1.68-4 hours, 1.67-24 hours). the hypercoagulable state and clot quality in both sepsis and severe sepsis group improved with fluid resuscitation, however despite an early improvement in clot quality, ongoing fluid resuscitation resulted in markedly reduced functional clot with very low clot strength and functionality. this study demonstrates that d f as a marker of clot quality and function may have potential in fluid and component replacement in critical illness and injury. this study analyses the prognostic ability of white blood cell count (wbc), neutrophil:lymphocyte ratio (nlr) and c-reactive protein (crp). hypo-and hyperimmune responses have been associated with increased mortality from septic shock [1] . patients with septic shock (sepsis 3.0) admitted to queen elizabeth hospital birmingham, between december 2017 and july 2019 were included. the primary outcome was 90-day mortality. data was tested for normality and presented as median (iqr) and analysed using a mann whitney u test. categorical data was presented as % and analysed using a chi-squared test. a p value of < 0.05 was used to determine significance. a multivariate binary logistic regression analysis was conducted using age, apache ii, charlson comorbidity index, performance status, and initial lactate as covariates. a hosmer lemeshow test of >0.05 indicated good fit. results: 474 patients were admitted with septic shock. the majority (61%) were male, with a median age of 64 (55-75) and a 90-day mortality of 37%. on day 1, wbc was lower in patients who died compared to patients who survived (9 [7] [8] [9] [10] [11] [12] [13] [14] [15] patients who died of septic shock had a lower wbc, nlr and crp response early on compared to survivors. this may represent early immunoparesis that allows infection to propagate unchecked. however, this was not independently associated with mortality when confounding factors were accounted for. a specific metabolite of mitochondriaitaconic acid is formed upon proinflammatory activation. the attempts of various researches to find the itaconic acid in peripherical blood of patients with sepsis were unsuccessful [1] . some phenylcarboxylic acids (phcas) are known to be microbial metabolites and sepsis biomarkers; they also affect the mitochondrial functions [2] . concentrations of phcas (phenyllactic, p-hydroxyphenylacetic, phydroxyphenyllactic acids) and mitochondrial metabolites (succinic, itaconic acids) in 48 serum samples from 8 patients on the 1 st day of diagnosis of sepsis and 35 serum samples from 22 patients with late stages of sepsis (sepsis-3) were measured by gas chromatographymass spectrometry; control group -20 donors. results: itaconic acid was found in low concentrations (0.5-2.3 μm) only at early stage of sepsis. the multiple increase in levels of phcas and mitochondrial metabolites were detected in patients with late stage of sepsis in comparison with early stage and donors, p<0.001. increased succinic acid (up to 100-1000 μm) concentration is the result of succinate dehydrogenase inhibition by microbial metabolism intermediates (phcas), which was confirmed by in vitro experiments in isolated mitochondria (fig.1) . itaconic acid may be a promising marker in early stage of sepsis, which needs to be proved. prediction of severe events in clinical sepsis is challenging. for such prediction we aimed to compare the novel biomarker calprotectin in plasma, with routine biomarkers. in a prospective study, blood samples were collected from consecutive patients who triggered the sepsis alert in the emergency department in our hospital. c-reactive protein (crp), procalcitonin, neutrophils, and lymphocytes were analysed according to routine practice. p-calprotectin was analysed using a specific particle enhanced turbidimetric assay (gentian diagnostics as). the composite endpoint, which was termed severe event, was defined as death or admission to the intensive care unit (icu)/high dependency unit (hdu) within 48 hours from arrival. the study included 367 patients with written informed consent, of whom 335 were considered to have infection (defined as obtained blood culture and subsequent antibiotic therapy for at least 4 days or until discharge or death), and 32 had no infection. seventy-four patients (22%) with infection developed a severe event. mean pcalprotectin was 2.99 mg/l (standard deviation (sd) 2.10) among patients with infection and 2.35 mg/l (sd 2.64) among patients without infection (p=0.02). in patients with infection mean p-calprotectin was 3.81 mg/l (sd 3.18) among those with and 2.75 mg/l (sd 2.50) among those without a severe event (p=0.006). analysis of area under the receiver-operating characteristic (roc) curve for prediction of severe events showed superiority for p-calprotectin compared with procalcitonin and neutrophil-lymphocyte-ratio, both regarding all sepsis alert cases and regarding the patients with infection (p< 0.05 for all comparisons), fig 1. in addition, there was a trend toward superior performance compared to crp (p=0.10 and 0.15). in sepsis alert patients, p-calprotectin was elevated in those who subsequently developed severe events. p-calprotectin was superior to traditional biomarkers for prediction of severe events. introduction: rapid diagnosis of acute infections and sepsis is critical in emergency departments (eds). current tests have slow turnaround times, low sensitivities, and/or signals from contaminant or commensal organisms. empirical antimicrobial treatment may result in severe adverse events and contributes to antimicrobial resistance. diagnostics to distinguish bacterial from viral infections and noninfectious etiologies support clinicians in efforts toward antimicrobial stewardship. in a prospective, non-interventional study in the eds of 6 sites in greece (prompt study nct03295825), we evaluated hostdx sepsis, a host response test for suspected acute infections and suspected sepsis. hostdx sepsis measures 29 human mrna targets and employs advanced machine learning to differentiate patients with bacterial and viral infections, and noninfectious etiologies. adult patients presenting with suspected acute infection and at least one vital sign change were enrolled. whole blood rna was quantified using nano-string ncounter. predicted probabilities of bacterial and viral infection were calculated (bvn-1 algorithm). patients were adjudicated in a retrospective chart review by 3 independent infectious disease specialists blinded to hostdx sepsis results. among 396 patients adjudicated as bacterial (56), viral (45), noninfected (1), or indeterminate (294) the area under the receiver operating characteristics (auroc) of hostdx sepsis for predicting bacterial vs. viral/non-infected patients was 0.92, and auroc for viral vs. bacterial/non-infected patients was 0.87 (fig.1) . our results indicate that hostdx sepsis distinguishes bacterial from viral infections and other etiologies with high accuracy. hostdx sepsis is currently developed as a rapid point-of-care device with a turnaround-time of less than 30 minutes. hostdx sepsis may therefore assist ed doctors in making appropriate treatment decisions earlier, towards the ultimate goal of antimicrobial stewardship. we studied the diagnostic value of a leukocyte deformability assay that rapidly quantifies the immune activation signatures of sepsis in an undifferentiated population of adults presenting to the ed. ed clinicians must balance the benefits of early intervention against the risks of indiscriminate use of resource-intensive interventions. there are no currently available rapid diagnostics with acceptable performance to achieve this balance. we prospectively enrolled adult patients within 5 hours of presentation with signs of suspicion of infection in two eds in the usa. edta-anticoagulated blood was drawn and analyzed using deformability cytometry [1] . procalcitonin (pct) levels were also measured. patients were retrospectively adjudicated for sepsis-3 by physician committee using the entire medical record. diagnostic performance characteristics and receiver operating curves were used to examine the diagnostic performance of the assay as well as pct. of the 190 patients enrolled, 17.4% were adjudicated as septic. the leukocyte deformability assay demonstrated 91% sensitivity, 68% specificity, and 97% negative predictive value for a single cutoff. the auc was 0.86 ( figure 1 ). pct with a cutoff of 0.5 ng/ml had 55% sensitivity, 87% specificity, and 90% negative predictive value. the auc for pct (as continuous variable) was 0.8. the leukocyte deformability assay of immune activation signatures demonstrated superior diagnostic performance for sepsis when compared to pct. the assay's diagnostic performance and rapid turnaround time of 5 minutes may positively impact patient outcomes while minimizing indiscriminate use of valuable resources in the ed. it is already known in literature that high levels of midregional proadrenomedullin (mrproadm) are related with organ disfunction in infections despite of source and pathogens [1] . similarly, microcirculatory impairment has been reported in sepsis. we examine the correlation between microcirculatory disfunction and mrproadm as a sign of early organ failure. we included 20 consecutive adult patients with suspected infection, sepsis or septic shock admitted to our intensive care unit (icu) as first hospital admission with an expected icu stay of > 24hours. mrproadm was measured daily during the first five consecutive days and sublingual microcirculation was assessed with incident dark field (idf) technology at t1, t2, and t5. we collected information on saps ii, apache scores, and sofa score for each timepoint. results: ten patients had septic shock, 5 sepsis and 5 infection. three patients died during icu stay. a mrproadm clearance of 20% or more between t1 and t2 was found associated with the improvement of mfi (mann-whitney u test, median increase 12.35% versus 2.23%, p= 0.005) (figure 1) . a mrproadm >1.42 nmol/l at the icu admission was associated with a worse sofa score at all the timepoint. moreover, mrproadm levels at admission was found significantly related with icu mortality (auc 0.941 [0.819-1]; p=0.017). mrproadm shown no relation with absolute value of mfi. the study shows a good correlation between the clearance of the biomarker and the improvement in mfi. moreover, our results support previous findings on the prognostic value of mrproadm in terms of sofa and icu-mortality. clinical performance of a rapid sepsis test on a near-patient molecular testing platform r brandon 1 , j kirk 2 , t yager 2 , s cermelli 2 , r davis 2 , d sampson 2 , p sillekens 3 , i keuleers 3 , t vanhoey 3 1 immunexpress, seattle, united states; 2 immunexpress, immunexpress, seattle, united states; 3 biocartis nv, biocartis, mechelen, belgium critical care 2020, 24(suppl 1):p481 the purpose of this study was to clinically validate a new, rapid version of the septicyte™ assay on a near-patient testing platform (biocartis idylla™). septicyte™ lab is the first-in-class sepsis diagnostic to gain fda-clearance but has a complex workflow and a turnaround time (tat) of~6 hours. the assay in idylla™ cartridge format is called septicyte™ rapid. septicyte™ lab was translated to the biocartis idylla™ near-patient testing platform and analytically validated. for this study, 0.9ml of peripheral blood paxgene tm solution from previously collected patient samples was pipetted directly into the cartridge and inserted into the idylla™ reader. patients were part of an independent cohort (n=200) from intensive care units located in the usa and europe. septicyte™ rapid results were reported as a septiscore™ between 0 and 10 with higher scores representing higher probability of sepsis. assay performance determined included technician hands-on-time (hot), assay tat, failure rates, and area under roc curve based on comparison to retrospective physician diagnosis. average hot was 2 minutes, and average tat was 65 minutes. clinical samples could be processed immediately with septicyte™ rapid and did not require 2 hour pre-incubation of paxgene blood, greatly improving tat. correlation of septiscore™ values between lab and rapid, based upon a subset of samples run on both platforms, was very high (r 2 >0.97). estimated roc auc performance for discriminating sepsis from non-infectious systemic inflammation (nisi/sirs) was similar to that previously reported for septicyte™ lab. this is the first demonstration of a validated, fully-integrated, rapid, reproducible, near-patient, immune-response sepsis diagnostic, providing actionable results~1 hr, to differentiate sepsis from non-infectious systemic inflammation / sirs. accuracy of septicyte™ for diagnosis of sepsis across a broad range of patients r brandon 1 , k navalkar 2 , d sampson 2 , r davis 2 , t yager 2 1 immunexpress, seattle, united states; 2 immunexpress, immunexpress, seattle, united states critical care 2020, 24(suppl 1):p482 the purpose of the study was to demonstrate sepsis diagnostic performance of the biomarkers of septicyte™ in subjects other than critically ill adults, and in hospital locations other than icu. septicyte™ lab was the first immune-response sepsis diagnostic assay to gain fda-clearance (k163260) and, as part of gaining this clearance, clinical validation was performed on adult patients admitted to intensive care (icu) only [1] . we therefore performed an in silico analysis across a broad range of patients using the septicyte™ host immune response biomarkers and algorithm. peripheral blood gene expression data, including public and private datasets, were chosen based on quality, annotation, and clinical context for the intended use of septicyte™. multiple comparisons were performed within datasets to better understand the diagnostic performance in certain cohorts including healthy subjects. diagnostic performance was determined using area under curve (auc). results: table 1 shows some characteristics of the selected datasets and patients, including number of datasets (n=22) and comparisons (n=55), number of cases (n=2234) and controls (n=2089) used in comparisons, patient category and hospital location. septicyte™ aucs for the three groups of adults, adult / pediatric and pediatric / neonates were 0.88, 0.85, and 0.87 respectively, which is similar to that previously reported (0.82 -0.89) [1] . these results suggest that the septicyte™ signature has diagnostic utility beyond adults suspected of sepsis and admitted to icu. this signature has now been translated to the near-patient testing platform biocartis idylla™ (as septicyte™ rapid) which promises rapid (~1 hour) diagnosis of sepsis in a broad patient population following further validation. introduction: especially extracorporeal cardio pulmonary bypass (cpb) is known to induce severe inflammation. postoperative inflammation is associated with a sepsis like syndrome including endothelial barrier disruption, volume depletion and hypotension. sphingosine-1-phosphate (s1p) is a signaling lipid regulating permeability and vascular tone. in septic humans decreased serum-s1p levels could be identified as marker for sepsis severity. we addressed three main issues: (1) are serum-s1p levels affected by cardiac surgery? (2) are potential alterations of serum-s1p levels related to changes of acute-phase proteins, s1p sources or carrier? (3) is the invasiveness of the surgery a factor that may influence serum-s1p levels? methods: 46 elective major cardiac surgery patients were prospectively enrolled in this study. serum samples were drawn pre-, post-procedure and on day 1 and day 4 after surgery. we analyzed s1pand its potential sources: red blood cells (rbc) and platelets. we further quantified levels of other inflammatory markers and documented other clinical parameters. median serum-s1p levels in all patients before the procedure were 0.77 (iqr 0.61-0.99) nmol/ml. serum-s1p levels decrease after surgery, whereas all other inflammatory markers increase. serum-s1p levels dropped by 58% in the on-pump and 31% in the off-pump group. changes of serum-s1p levels are associated with s1p sources and carriers: albumin, hdl and vwf:ag activity. patients with a full recovery of their serum-s1p levels after surgery compared to their individual baseline presented with a lower sofa score (p>0.05) and shorter icu stay (p<0.05). serum-s1p levels are disrupted by open heart surgery and levels might be negatively affected by endothelial injury or loss of s1p sources. low serum-s1p levels may contribute to prolonged icu stay and worse clinical status. future studies may investigate the beneficial effects of s1p administration during cardiac surgery. the aim of study is to measure and correlate the expression of ncd64, mhla-dr, pct (procalcitonin) and qcrp (quantitative creactive protein) to predict development of sepsis and its outcome. in this tertiary centre based longitudinal cohort study, a total 110 patients were enrolled in whom sepsis was suspected on the basis of clinical diagnosis and supported by lab investigations. they were divided into two groups sepsis/case and non-sepsis/control. disease severity in icu was assessed by sequential organ failure score (sofa). blood samples for routine lab investigations and biomarkers were taken at the time of admission in icu before administration of first dose of antibiotics at time d 0 /d 1. assessment of biomarkers was done simultaneously with tlc at d 0 /d 1 , d 3 and during follow up of patients till their final outcome. there was no significant (p>0.05) mean change in pct, qcrp, sofa, ncd64, mhla-dr from day 1 to day 3, however, mean change was higher among cases than controls.on comparison of mhla-dr between the groups across time periods, mhla-dr was significantly (p=0.0001) lower among septic patients than controls at both day 1 and day 3. all biomarker correctly predicted cases among different percentage of patients with different sensitivity and specificity. there was no significant (p>0.05) association of mortality with the study biomarkers except for pct. in our study, diagnostic value of pct in differentiating sepsis from non-sepsis was similar to ncd64 among all biomarkers studied. no advantage of ncd64 or mhla-dr was found over pct in diagnosis and correlation with disease progression and mortality. introduction: aqp4 is a water channel protein contributing to astrocyte and immune cells migration, blood-brain barrier maintenance and cell survival [1] [2] . aqp4 genetic variants represent biomarkers associating with outcome after traumatic brain injury and intracerebral hemorrhage [3] [4] . linking aqp4 genetic polymorphism to the course of sepsis has not been studied. methods: study cohort included 124 icu patients diagnosed according to sepsis-3 consensus. aqp4 rs11661256 polymorphism was studied by analyzing pcr products in a 2% agarose gel using an aqp4 specific polynucleotide tetraprimer set. data were analyzed by log rank test (medcalc 18.11.3), and odds ratios/hazard ratios were computed. statistical significance was determined by fisher test (ft) or mann-whitney test. results: 23 of 124 sepsis patients had the minor mutation a for snp rs11661256 located within the regulatory 3' region of the aqp4 gene. septic shock occurred more frequently in homozygotic carriers of aqp4 c allele vs. patients with aa or ca genotype: or=3.75 (95%ci: 1.47-9.56), p=0.006 (ft). lethality in septic shock patients, n= 85, significantly increased compared to sepsis patients with no shock, n=39 (82% vs. 20%, p=0.001, ft). maximum sofa values were significantly lower in patients with minor allele a compared to cc carriers of (9.6 vs. 12.0, respectively, p=0.008). in post-surgery group of patients, carriers of ac or aa genotypes had significantly increased survival compared to patients with cc genotypes: chi-square=5.804; hr=0.455 (95%ci: 0.24 -0.863) for lethality; p=0.016 (figure 1) . association of minor allele a of aqp4 snp rs11661256 with survival in sepsis patients seems secondary to linking the snp to decreased development of multiorgan failure and septic shock that contribute to mortality. validation of presepsin as a biomarker of sepsis in comparison to procalcitonin, il-6 and il-8 v chantziara 1 , f kaminari 1 , c sklavou 1 , s fortis 2 , p kogionou 2 , s perez 2 , a efthymiou 1 1 saint savvas hospital, icu, athens, greece; 2 saint savvas hospital, cancer immunology and immunotherapy center, athens, greece critical care 2020, 24(suppl 1):p486 sepsis is an everyday challenge for the intensivist and biomarkers are useful tools for identification and treatment of this syndrome. we sought to validate presepsin as a biomarker of sepsis in comparison to pct(procalcitonin) and interleukins (il-6,il-8). we enrolled 25 patients,18 men and 7 women average age 58 (39.5-74) years old, apache ii 16 (13.5-20.5), saps ii 48(40.5-58.5), sofa 8 (6.5-9). 11 patients were septic on admission (according to surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016), 9 had a septic episode during their hospitalization in the icu while 5 patients never endured sepsis. we measured presepsin, procalcitonin, il-6, il-8 during sepsis and on remission. results: all septic patients had increased values of presepsin, pct, il-6 and il-8 during sepsis with a cutoff value for presepsin 800pg/ml, while the values of these biomarkers were significantly decreased during remission or in comparison to non-septic patients(presepsin p = 0.002, pct p≤ 0.001, il-6 p≤ 0.001, il-8 p= 0.004. all patients who were not septic survived while among septic patients 8 died (40% mortality). presepsin correlated significantly with pct, il-6 and il-8 (p<0.05). presepsin is a valid biomarker of sepsis and correlates significantly with all the other values of pct, il-6 and il-8. clinical sepsis phenotypes are proposed at hospital presentation. these phenotypes, biomarker profiles, and outcomes are not yet reproduced in prospective data. even less is known about the biologic mechanism the drives these distinct groups. thus, we sought to validate clinical phenotypes and to determine markers of innate immunity, coagulation, tolerance and tissue damage in a prospective cohort. we prospectively studied patients with sepsis-3 criteria within 6 hours of presentation at 12 hospitals in pennsylvania (2018-2019) using automated electronic alerts. using 29 clinical variables, we predicted phenotypes (α, β, γ, δ) for each patient using euclidean distance anchored to published seneca phenotype centroids. discarded blood was analyzed in a subset (n=160) for markers of innate immunity (e.g. il-6, il-10), coagulation (e.g antithrombin iii, eselectin), tolerance (e.g. ho-1, igfbp7), and tissue damage (e.g. serum lactate, bicarbonate) results: among 549 patients, α-type was present in 146 (27%), β-type in 140 (25%), γ-type in 168 (31%) and δ-type in 95 (17%, figure 1a ). on average, β-type was older and more comorbid (mean 73, sd 9 yrs; mean elixhauser 4.6, sd 2.2) with renal dysfunction (median creatinine 1.8 [iqr 1.1 -2.9] mg/dl, p<0.01 all). the δ-type had more acidosis (mean hco3 -20.1, sd 4.7 meq/l), higher serum lactate (median 1.8 [iqr 1.0-3.5] mmol/l, p <0.01 both) and inpatient mortality (13%, figure 1b) . the γand δ-type had greater markers of innate immunity and abnormal coagulation (e.g il-6, icam p<0.01 both), while markers of increased tissue damage (lactate) and poor tolerance (ho-1) were present in δ-type, compared to α-type (figure 1c) . the distribution and characteristics of clinical sepsis phenotypes were reproduced in a prospective validation cohort. similar to the seneca study, distinct biomarker profiles of tissue damage, innate immunity and poor tolerance were present for the δ-type. the effect that neoadjuvant chemotherapy and hyperthermic intraperitoneal chemotherapy (hipec) may have in the postoperative kinetics of biomarkers remains unknow. some studies demonstrate that neoadjuvant chemotherapy and hipec do not invalidate the use of inflammatory markers in postoperative patient monitoring, but none have compared biomarkers kinetics between patients who underwent hipec or only cytoreduction surgery. our main purpose was to identify a difference pattern in c-reactive protein (crp). we conducted a single-center observational study from january 2015 to november 2019, including all patients who underwent cytoreductive surgery with or without hipec. crp was measured daily until seven post-operative day. we compared patients with and without hipec. a total of 19 patients were included, 15 were female. mean age was 63 yrs (44-76). no clinical and demographical differences were observed between groups. no documented infection was found. after surgery crp increased markedly in both groups. crp time-course from the day of surgery onwards was significantly different in hipec patients (9.78 ± 3.95 mg/dl vs 14.80 ± 5.63 mg/dl; p=0.035). multiple comparisons between hipec and non hipec patients were performed and crp concentration was significantly different on the 5th and 7th pod (figure 1 ). no differences were found in other biomarkers (leucocytes and platelets) neither in body temperature. after a major elective surgical insult crp levels markedly increase independently of hipec. serum crp time-course showed a higher pattern in hipec patients despite no infection detected. decreased thrombin generation potential is associated with increased thrombin generation markers in sepsis associated coagulopathy d hoppensteadt 1 , f siddiqui 1 , e bontekoe 1 , r laddu 1 , r matthew 2 , e brailovsky 3 , j fareed. introduction: sepsis associated coagulopathy (sac) is commonly seen in patients which leads to dysfunctional hemostasis in which uncontrolled protease generation results in the consumption of clotting factors. the purpose of this study is to determine the thrombin generation potential of baseline blood samples obtained from sac patients and demonstrate their relevance to thrombin generation markers. baseline citrated blood samples were prospectively collected from 49 patients with sac at the university of utah clinic. citrated normal controls (n=50) were obtained from george king biomedical (overland park, ks). thrombin generation studies were carried out using a flourogenic substrate method. tat and f1.2 were measured using elisa methods (seimens, indianapolis, in) . functional antithrombin levels were measured using a chromogenic substrate method. the peak thrombin levels and auc levels were lower in the sac patients in comparison to higher levels observed in the normal plasma ( table 1 ). the sac group showed much longer lag time in comparison to the normal group. wide variations in the results were observed in these parameters in the sac group. the f1.2 and tat levels in the sac group were much higher in comparison to the normal. the functional antithrombin levels were decreased in the sac group. these results validate that thrombin generation markers such as f1.2 and tat are elevated in patients with sac. however, thrombin generation parameters are significantly decreased in this group in comparison to normal. this may be due to the consumption of prothrombin due to the activation of the coagulation system. thus, persistent thrombin generation with simultaneous consumption of clotting factors such as prothrombin contributes to the consumption coagulopathy observed in sepsis patients. introduction: procalcitonin (pct) is used in the icu as an inflammatory marker to monitor bacterial infections and guide antibiotic therapy. whether pct can predict bacteremia and therefore could prevent expenses attached to bloodcultures is unknown . we investigated whether pct can predict the outcome of blood cultures in the icu and reduce expences. a single centre observational cohort study was performed in a dutch community teaching hospital . adult patients who were staying in the icu and were suspected of bacteremia were included. simultaneously with drawing of blood cultures, samples for pct measurement were obtained. expenses for pct measurement and bloodcultures were calculated. in the study period of one year, a total of 120 patients were included. three patients were excluded because of incomplete data. out of the 117 included patients, ten patients had positive blood cultures. there was a significant difference in pct levels between patients who had positive bloodcultures versus patients with negative bloodcultures (8.01 ng/ml vs 0.71 ng/ml) ( figure 1 ). the negative predictive value for negative blood cultures is 97% when pct is below 2ng/ml, there was no difference in crp levels between the two groups (148 mg/l vs 179 mg/l, p= 0.83).a set of negative blood cultures in our centre costs 35 euros. positive blood cultures however costs significantly more depending on the micro-organisms found. pct only costs 8.50 euros per measurement. so when blood cultures are omitted when the pct level is below 2ng/ml, a cost reduction of 38% can be achieved. a pct value below 2 ng/ml is a good predictor of a negative blood cultures in icu patients suspected of bacteremia. pct guided bloodculture management in these patients could lead to a significant cost reduction introduction: level of cfdna in plasma is a promising prognostic candidate biomarker in critical illness [1] . oxidized cfdna (ocfdna) have not been studied as a biomarker although its functional role in cellular stress have attracted attention of researches [2] . the goal of our study was to assess the early prognostic value of plasma cfdna/ocfdna for sepsis in a nicu setting. the cohort included 115 nicu patients diagnosed with stroke, intracerebral hemorrhage (ich), anoxia, encephalopathy. cfdna was isolated from day 1 plasma and stained with picogreen. oxidized dna was determined using dna immunoblotting with anti-8-oxo-desoxiguanosine antibodies. genotyping of allelic variants of the tlr9 rs352162 gene was performed using a pcr and designed allele-specific tetraprimers followed by electrophoretic separation of the products statistics was performed by the fisher test and mann-whitney test. results: sepsis was diagnosed by sepsis-3 criteria in 35 patients (30.4%). average nisu staying was 8,8±11,1 days. circulating dna plasma levels on day 1 predicted the future sepsis development (figure 1 ): or for cfdna was 7.54 (95%ci: 3.03-18.76), p<0.001; or for ocfdna was 5.57 (95%ci: 1.64-18.97), p=0.008. power of both performed tests with alpha=0.05: 1.0. log rank test demonstrated better predictive value of cfdna vs. ocfdna (figure) . concentrations of cfdna, but not ocfdna, on day 1 significantly positively correlated with maximum sofa values during hospitalization, day 3 and pre-outcome leukocyte count and neutrophil-to-lymphocyte ratios in a limited cohort of nisu patients with tlr9 rs352162 cc genotype and not in other patients with genotype tlr9 ct+tt. increased level of plasma cfdna better then ocfdna predicts sepsis development in nisu. further studies are warranted to clarify the fig. 1 (abstract p490) . pct values in patients with positive blood cultures and patients with negative blood cultures possible utility of tlr9 rs352162 polymorphism determining for sepsis risk stratification early on nisu admittance. admission was related with higher severity of illness and extension of icu stay for all groups. reduced cbt fluctuations upon icu admission was found to more severely ill patients with worse clinical outcomes, while the more periodic cbt patterns were correlated with high cbt rhythmicity and better outcome. the impact of sex on sepsis incidence and mortality have been elucidated in previous studies, and sex is increasingly recognized as one key factor in sepsis [1] . some studies indicate that women have better immunologic responses to infections [2] . later investigations assume this advantage is linked to immune modulating genes located on the x-chromosome [3] . the purpose of this study is to reveal sex differences in incidence of and mortality of sepsis in a large population-based cohort. methods: 64049 adult participants in the hunt2 study (1995-97) were followed from inclusion through end of 2011. incident bloodstream infections (bsi) from all local and regional hospitals in nord-trøndelag county were identified through linkage with the mid-norway sepsis register, which includes prospectively registered information on bsi used as a specific indicator of sepsis. we estimated age-adjusted cumulative incidence of first-time bsi and compared the risk of a first-time bsi and bsi mortality in men and women using age-adjusted cox proportional hazard regression. during a median follow-up of 14.8 years 1840 individuals experienced at least one episode of bsi, and 396 died within 30 days after a bsi. cumulative incidence and cumulative mortality curves are shown in fig. 1a introduction:the proportion of hospital-acquired infections (hai) among sepsis patients is unknown in germany. systematic differences in hai foci between sepsis patients with and without icu treatment are insufficiently described. retrospective cohort study based on nationwide health claims data of the german statutory health insurance aok. incident inpatient sepsis cases were identified in 2013/2014 among insured persons >15y without preceding sepsis in 24 months prior to index hospitalization. sepsis was defined according to explicit sepsis icd-10-codes (incl. severe sepsis/septic shock). hai were defined based on specific icd-10-codes for surgical site infection, catheterintroduction: elevated renin is associated with an increased risk of death in patients with vasodilatory shock (vs). recent data show that patients with vs and elevated renin levels have improved survival when treated with angiotensin ii (ang ii) + standard care (sc) vs placebo + sc. patients with acute respiratory distress syndrome (ards) can develop angiotensin-converting enzyme (ace) defects that can lead to elevated renin levels and insufficient endogenous ang ii production. we hypothesized that patients with severe ards and elevated renin shock would have improved survival when treated with ang ii + sc vs placebo + sc. in the randomized, placebo-controlled, double-blind athos-3 study, 321 patients with severe vs receiving >0.2 μg/kg/min of norepinephrine or the equivalent were randomized to intravenous ang ii (n= 163) or placebo (n=158). in a post hoc analysis, we assessed the subset of patients with elevated renin (defined as a renin level greater than the median value of the overall athos-3 population) and ards (defined by a pao2/fio2 ratio <300) at the time of randomization. survival to 28 days was compared between the ang ii group (n=41) and the placebo group (n=61). in patients with elevated renin and ards, baseline age, acute physiology and chronic health evaluation ii score, and blood pressure were similar in the ang ii and placebo groups. the median serum renin level was 459.5 pg/ml (iqr: 285.8-1036.0) compared to the normal range for serum renin: 5-58 pg/ml. a significantly higher proportion of patients receiving ang ii survived to day 28 compared to those in the placebo group (51% vs 31%; p=0.01). elevated renin identified patients with vs and ards who were most likely to gain a survival benefit from ang ii. elevated renin is likely caused by an ace defect and may describe an important subset of patients with a biotype that responds well to ang ii therapy. introduction: elevated renin levels have been shown to be associated with an increased risk of death and more severe acute kidney injury (aki) in patients with vasodilatory shock (vs). recent data show that patients with vs and elevated renin levels have improved survival when treated with angiotensin ii (ang ii) + standard care (sc) vs placebo (pbo) + sc. we hypothesized that vs patients with severe aki and elevated renin levels would have improved survival and enhanced renal recovery with ang ii treatment. in the randomized, pbo-controlled, double-blind athos-3 study, 321 patients with severe vs received >0.2 μg/kg/min of norepinephrine or the equivalent and were randomized to intravenous ang ii + sc (n=163) or pbo + sc (n=158). in a post hoc analysis, we assessed the subset of patients with elevated renin (defined as a renin level greater than the median value of the overall athos-3 population) and severe aki (defined as those with aki requiring renal replacement therapy [rrt] at baseline). survival and renal recovery were assessed in patients treated with ang ii + sc (n=45) and pbo + sc (n=60). in patients with elevated renin and severe aki, baseline age, acute physiology and chronic health evaluation ii score, and blood pressure were similar between ang ii + sc vs pbo + sc. the median baseline serum renin level in the whole group was 352.5 pg/ml (iqr: 115.9-785.4; normal range for serum renin: 5-58 pg/ml). a significantly higher proportion of patients receiving ang ii + sc vs pbo + sc survived to day 28 (43% vs 22%, respectively; p=0.03). ang ii recipients also had a higher rate of discontinuation from rrt by day 7 (43% vs 12%; p=0.04). in this study, elevated-renin shock patients with aki treated with ang ii + sc gained a survival benefit and earlier discontinuation from rrt compared to those receiving pbo + sc. elevated renin is likely caused by an angiotensin-converting enzyme defect and may identify those patients with a biotype that responds well to ang ii therapy. most clinical trials conclude the ineffective use of anticoagulation for sepsis-induced coagulopathy [1] . however, post hoc analyses of randomized control trials report positive results [2] , suggesting anticoagulation is effective in specific populations exhibiting coagulopathy. further, anticoagulants should be administered in the early phase [3] ; however, methods for precisely predicting the progression of sepsis-induced coagulopathy are not established. this study aimed to create and evaluate a prediction model of coagulopathy progression using machine-learning techniques. we performed a subgroup analysis of data from a retrospective cohort study involving adult septic patients in 40 japanese institutions from january 2011 to december 2013 and used the japanese association for acute medicine disseminated intravascular coagulation (dic) score as a dic severity index test. the predictive ability of δdic ([dic score on day 3] -[dic score on day 1]) was evaluated using various statistical methods. using variables available at the outset, we compared the predictive ability of random forest (rf) and support vector machine (svm) with that of multiple linear regression analysis. a total of 1110 adults with sepsis were included in the analysis. the root mean square error in δdic score for the multiple linear regression analysis model was 2.1168 compared with values of 1.6508 and 1.9394 for rf and svm, respectively. thus, the rf method predicted the progression of sepsis-induced coagulopathy more accurately than multiple linear regression analysis. conclusions: rf, a machine-learning technique, was superior to multiple linear regression analysis in predicting the progression of sepsis-induced coagulopathy. this prediction model might enable us to use anticoagulation in an early phase. this study examined the efficacy and safety of landiolol, an ultrashort-acting β1-blocker, for treating sepsis-related tachyarrhythmia, according to patient background characteristics. the j-land 3s study (japiccti-173767) was conducted in patients with sepsis, diagnosed according to the sepsis-3 criteria, and tachyarrhythmia (atrial fibrillation, atrial flutter, or sinus tachyarrhythmia). the patients had a mean heart rate of ≥100 beats/min and required catecholamine administration to maintain a mean blood pressure of ≥65 mmhg. the efficacy endpoint was the percentage of patients whose heart rate could be controlled within 60-94 beats/min at 24 h of registration. the safety endpoint was the incidence of adverse events within 168 h of registration. subgroup analyses of efficacy and safety were performed after stratifying the patients according to various patient background characteristics. a total of 151 patients were randomized, 76 to landiolol and 75 to the control group. the efficacy endpoint, percentage of patients with a heart rate of 60-94 beats/min at 24 h of registration, was significantly higher in the landiolol group (54.7% vs 33.3%; mantel-haenszel test: p = 0.0031). the incidence of adverse events was 63.6% and 59.5% in the landiolol and control groups, respectively, and there was no difference between the two groups. most adverse events were related to sepsis or septic shock. the subgroup analyses showed that no patient background characteristic clearly affected the efficacy and safety of landiolol. landiolol is a well tolerated and effective therapeutic agent for controlling heart rate in patients with sepsis-related tachyarrhythmias; its safety and efficacy were not affected by the patient background characteristics investigated. tissue oxygenation monitoring in sepsis r marinova, at temelkov umhat alexandrovska, anesthesiology and intensive care, sofia, bulgaria critical care 2020, 24(suppl 1):p502 near-infrared spectroscopy (nirs) was proposed as a concept in the end of 20th century. this method offers noninvasive monitoring of oxy-and deoxyhemoglobin in tissues.nirs could be measured on the thenar or forehead within few santimeters of the skin. it was first applied as a monitoring in cardiovascular surgery. patients with sepsis have changes in the microcirculation which are important target for therapy. invasive monitoring of oxygen delivery and consumption has been used in patients with sepsis but as every invasive technique such a monitoring hides risks. nirs offers a noninvasive method for tissue oxygenation monitoring (sto2) and could be useful in patients with sepsis and septic shock. the aim of the study is to compare noninvasive tissue oxygenation monitoring with hemodinamic monitoring and lactate values in patients with sepsis methods:the study includes 19 critically ill patients in icu of umhat alexandrovska, sofia. 10 of the patients fullfil the criteria for septic state. the other 9 patients do not have sepsis. in both group of patients are measured tissue oxygenation with invios monitor, mean arterial pressure, oxygen saturation in mixed venous blood and lactate values during 72 h after icu admission. patients with sepsis are reported with significantly lower values of tissue oxygenation, compared to patients without sepsis. the values of tissue oxygenation correlate well with the mixed venous blood oxygenation, mean arterial pressure and lactate values but not significantly with apache scores. conclusions: nirs when used for tissue oxygenation monitoring correlates well with the hemodinamic monitoring and lacate values in patients with sepsis and could be used as an noninvasive monitoring for guiding teurapeutic strategies. tissue oxygenation monitoring has no linear correlation with the severity of illness in patients with sepsis and could not be reccomended as a guidance in the early ressuscitating stage of sepsis. further investiganions in these field are needed.the sequenom´s massarray platform and a recessive inheritance model was selected (cc vs tt/ct). the possible association between the cc recessive form of the rs279451 polymorphism and the septic shock risk was analyzed, demonstrating a statistically significant relationship (p=0.02) between both conditions. among patients who developed septic shock, 79.2% presented a recessive inheritance pattern while 54.5% showed the ct/tt genotype. on the other hand, those patients with the recessive form of the rs279451 polymorphism were selected and a statistical analysis was performed comparing those patients who developed septic shock from those who did not develop it, obtaining a statistically significant relationship (p=0.036) between the presence of the recessive form of polymorphism and the likelihood of developing septic shock. the recessive form of rs279451 polymorphism is a risk factor for septic shock in post-operative patients of major abdominal surgery. introduction: sepsis remains one of the major causes of morbidity with mortality rates as high as 50 % worldwide, representing significant clinical challenge to confront highly intangible therapeutic needs. rnabased structures are emerging as versatile tools encompassing a variety of functions capable to bypass the current protein-and cellbased therapies. rna aptamers act as disease-associated protein antagonists. here, the effects of an aptamer, apta-1, were evaluated in animal models that mimic systemic inflammation in humans. high dose of lps endotoxin was used to induce systemic inflammation in mice and in non-human primate animal models. apta-1 was administered intravenously in two doses post lps infection. animals were monitored and blood samples collected up to 72 hours after apta-1 administration. healthy-and lps-only treated animals served as control groups. complex analyses of clinical parameters, hematology, serum biochemistry, inflammation and tissue damage markers were performed. results: apta-1 increased survival of endotoxin challenged animals up to 80% in a dose-dependent manner and exerted profound effects on wellbeing and recovery of healthy eating habits. administration of apta-1 led to delayed coagulation and enhanced fibrinolysis; maintained the complement cascade activated while preventing it from further amplification. expression of pro-inflammatory cytokines was reduced while anti-inflammatory increased. endogenous pro-inflammatory molecules (damps), secreted from injured cells, were preserved at healthy level in animals treated with apta-1. systemic inflammation and sepsis lead to severe dysregulation of several arms/axis of innate immune response. our studies showed that apta-1 affects various components of this system and restores the organism's control over its dysregulated immune response. thus, apta-1 might be a promising potential therapeutic candidate to treat life-threatening conditions such sepsis. several preclinical studies demonstrated beneficial effects for methane (ch 4 ) administration in various inflammatory conditions. our aim was to investigate the consequences of post-treatment with inhaled ch 4 in a clinically relevant intra-abdominal sepsis model. anesthetized minipigs were subjected to fecal peritonitis (0.6 g/kg, 5-9x10 6 cfu i.p.; n=22) or sham-operation (sterile saline i.p; n=5). invasive hemodynamic monitoring with blood gas analyses was started between 16-24 hours, organ dysfunction parameters (pao 2 /fio 2 ratio; mean arterial pressure; lactate, bilirubin, creatinine; urine output and platelet counts) were determined according to a modified porcinespecific sequential organ failure assessment (ps-sofa) score system, the perfusion rate (pr) of sublingual microcirculation was measured by incident dark field illumination imaging. the animals were divided into non-treated septic or septic shock groups (n=6-6) and ch 4treated septic or septic shock (n=5-5) subgroups, ch 4 inhalation started from the 18th hr (2.2% ch 4 in normoxic air; 500 ml/min). despite the standardized induction, heterogeneous severity of organ damage was evolved. in septic and septic shock groups the median values of ps-sofa score reached 5 (4.75-5.65) and 13 (11.75-14), respectively. septic shock was characterized by significant elevations of creatinine and bilirubin levels, while the platelet count decreased (from 332 to 76 *10 9 /l). inhalation of ch 4 increased the sublingual pr by 22% in the septic group, the creatinine and bilirubin levels were decreased by 28% and 80%, respectively. ch 4 post-treatment significantly decreased the ps-sofa score (to 1; 0.5-2.75) and resulted in lower values in septic shock group (to 10; 9.5-12.4). methane post-treatment effectively influences sepsis-related end organ dysfunction. up to a severity threshold it may be a promising additional organ protective tool. evaluation of sepsis awareness among various groups in turkey: a survey study s erel, o ermis, ö nadastepe, l karabıyık gazi university school of medicine, anesthesiology and intensive care, ankara, turkey critical care 2020, 24(suppl 1):p510 introduction: sepsis is a common life-threatening condition in critically ill patients [1] . public awareness is important for early recognition of sepsis and improvement of outcomes [2] . we aimed to evaluate sepsis awareness among different groups of people. methods: prospective paper-based surveys were issued between 1st july and 1st august 2019 to patients, the relatives of the patiens, hospital staff and general public who gave consent to participate in the study. the questionnaire included ten questions about demographic informations, occupational informations of hospital stuff and sepsis awareness. a total of 588 participated in the survey. of these participants, 87 (14.3%) were patients, 50 (8.5%) were relatives of patients, 134 (22.8%) were physicians, 125 (21.3%) were medical students, 49 (8.3%) were nurses, 51 (8.7%) were other hospital stuff and 92 (%15.6) were other people. of these participants, 425 (72.3%) had heard of the word "sepsis". 206 (35.0%) responded correctly regarding the definition of sepsis. 325 (55.3%) of the participants heard the word "sepsis" during their education, but only 53 (9%) heard it through the media. in the groups of high school graduates, university graduates and postgraduates, the rate of hearing the word sepsis and correctly identifying sepsis is significantly higher than the primary school graduates or illiterate groups. (p<0.05). physicians, nurses and medical students were heard of the word "sepsis" significantly more than other groups (p<0.005). physicians and medical students responded more accurately to the definition of sepsis than other groups (p<0.05). public awareness of sepsis is limited compared to healthcare workers. increasing public knowledge of sepsis through education and through media may contribute to raising public awareness and improving outcomes. the association between clinical phenotype cohesiveness and sepsis transitions after presentation jn kennedy 1 , eb brant 1 , km demerle 2 , ch chang 3 , s wang 4 , dc angus 1 , cw seymour 5 1 key: cord-341063-3rqnu5bu authors: nan title: 38th international symposium on intensive care and emergency medicine: brussels, belgium. 20-23 march 2018 date: 2018-03-29 journal: crit care doi: 10.1186/s13054-018-1973-5 sha: doc_id: 341063 cord_uid: 3rqnu5bu nan the relationship between systemic glycocalyx degradation markers and regional glycocalyx thickness in non-septic critically ill patients is unclear. conjunctival sidestream dark fieldimaging for the purpose of glycocalyx thickness estimation has never been performed. we aimed to investigate whether changes in glycocalyx thickness in conjunctival and sublingual mucosa are associated with global glycocalyx shedding markers. methods: in this single-centre prospective observational study, using techniques for direct in-vivo observation of the microcirculation, we performed a single measurement of glycocalyx thickness in both ocular conjunctiva and sublingual mucosa in mixed cardio surgical (n=18) and neurocritical patients (n=27) and compared these data with age-matched healthy controls (n=20). in addition we measured systemic syndecan-1 levels results: in the sublingual and conjunctival region we observed a significant increase of the perfused boundary region (pbr) in both neuro critical and cardiac surgical icu patients, compared to controls (2.20 7 ], p<0,05). we detected a weak correlation between syndecan-1 and sublingual pbr(r=0.40, p=0.002) but no correlations between global glycocalyx damage markers and conjuctival glycocalyx thickness. conclusions: conjunctival glycocalyx thickness evaluation using sdf videomicroscopy is suitable and is impaired in non-septic icu patients but only measurements in sublingual mucosa are correlating with systemic glycocalyx shedding markers. global glycocalyx damage is more severe in cardiac comparing to neuro critical patients. introduction: endothelial dysfunction plays a major role in the sepsis related organ dysfunction, and is featured by vascular leakage. amp-activated protein kinase (ampk) is known to regulate actin cytoskeleton organization and interendothelial junctions (iejs), contributing to endothelial barrier integrity. we have already demonstrated its role in defence against sepsis induced hyperpermeability [1] , but the underlying mechanisms remain unknown. this project aims to identify molecular targets involved in the beneficial action of ampk against endothelial barrier dysfunction. methods: experiments have been performed in human microvascular dermal endothelial cells. α1ampk activity has been modulated via the use of a specific sirna or treatment by two pharmacological ampk activators (aicar, 991). we have investigated the effect of this modulation on the expression/phosphorylation of connexin 43 (cx43) and heat shock protein 27 (hsp27), two proteins playing a key role in maintenance of iejs and actin dynamics respectively. results: we show that α1ampk is required to sustain the level of cx43 expression as it was drastically reduced in cells transfected with a sirna targeting specifically α1ampk. regarding hsp27, its expression level was not affected by α1ampk deletion. however, both ampk activators increased its phosphorylation on ser82, in a α1ampkdependent manner, while they had no effect on cx43. our results also reveal that hsp27 phosphorylation concurred with the appearance of actin stress fibers at the periphery of cells, suggesting a beneficial role for phsp27 as well as f-actin stress fibers in vascular barrier function through reinforcing the endothelial tethering. conclusions: our work identifies the regulation of cx43 expression and hsp27 phosphorylation as potential protective responses underlying the beneficial action of ampk against endothelial barrier dysfunction. ampk could consequently represent a new therapeutic target during sepsis. introduction: sepsis induced cardiomyopathy (sic) is a serious condition during sepsis with a mortality rate up to 70% (1) . sic is clinically manifested with left ventricle impaired contractility (2) . melusin is a muscle-specific protein involved in sustaining cardiomyocyte survival thorough the activation of akt signaling pathways (3) . pi3k-akt signaling pathway plays a pivotal role in regulating calcium channel activity (4) . we hypothesized that melusin overexpression could exert a protective effect on cardiac function during septic injury. methods: animals were treated with an intraperitoneal injection of lipopolysaccharide (lps) at 12 mg/kg. sv129 strain knockout mice (ko) for melusin gene and fvb strain with cardiac-specific overexpression (ov) of melusin were compared. each group was studied together with a control group (wt). hemocardiac parameters were studied at 0 hour and 6 hours through echocardiography. another cohort of animals was sacrificed 6 hours after 20 mg/kg lps treatment and cardiac tissues and blood sample were harvested for wb analysis to quantify the expression of akt, p-akt and cacna1c and elisa analysis for troponin levels. results: sv129 wt, ko melusin and fvb wt mice groups, fractional shortening (fs) was significantly impaired after lps challenge and was associated with compensatory tachycardia (fig. 1) . fvb ov mice group didn't show decrease in fs. consistent with the increased akt phosphorylation observed in ov mice, the expression of cacna1c was also significantly higher both at basal levels and after lps treatment in ov mice compared to wt mice (fig. 2) . troponin levels didn't differ between mice groups after lps treatment conclusion: melusin has protective role in lps induced cardiomyopathy, likely through akt phosphorylation controlling the cacna1c protein density. introduction: liver dysfunction is frequent in sepsis, but its pathophysiology remains incompletely understood. since altered liver function has also been described in icu patients without sepsis [1, 2] , the influence of sepsis may be overestimated. we hypothesized that sedation and prolonged mechanical ventilation after abdominal surgery is associated with impaired liver function independent of sepsis. methods: sedated and mechanically ventilated pigs underwent abdominal surgery for regional hemodynamic monitoring and were subsequently randomized to fecal peritonitis and controls, respectively (n=4, each), followed by 80 h observation. indocyanine green (icg) retention rate 15 minutes after injection of 0.25mg/kg icg (icg r15) was determined at baseline, and 11, 32 and 80 h after sepsis induction (si), and at the same time points in controls. concurrent with icg r15, plasma volume, total hepatic perfusion (ultrasound transit time), and bilirubin and liver enzymes were measured. anova for non-parametric repeated measurements was performed in both groups separately. results: icg r15 increased over time without significant differences between groups (table 1 ). there was a parallel increase in bilirubin in septic but not control animals. the other measured parameters were similar in both groups at the end of the experiment. conclusion: liver function was impaired under sedation and prolonged mechanical ventilation after abdominal surgery, even in animals without sepsis. the underlying reasons should be further explored. introduction: previous work has shown the cytoprotective properties of antithrombin-affinity depleted heparin (aadh), by neutralization of cytotoxic extracellular histones [1] , major mediators of death in sepsis [2, 3] . aadh was produced from clinical grade heparin, resulting in preparations that have lost >99,5% of their anticoagulant activity. to gain insight into the mechanisms and the basic pharmacological aspects of aadh protective properties, we performed a systematic analysis of how aadh is tolerated in mice and ascertained its effects in three different in vivo models of inflammation and infection. methods: dose ranging studies, short term and medium term, were performed in c57bl/6 mice. the effects of i.v. administration of extracellular histones in the presence or absence of aadh were assessed in mice. we further analysed the effect of aadh in models of concanavalin a-and mrsa-mediated lethality. in all studies we assessed clinical signs, lab parameters and histology. results: aadh was well tolerated in both short term and intermediate term (till 7 days) experiments in mice, in the absence of any signs of tissue bleeding. aadh was able to revert the cytotoxic properties of i.v. administered histones. in a concanavalin a mediated model of sterile inflammation, we confirmed that aadh has protective properties that counteract the cytotoxic effects of extracellular histones. in an in vivo lethal mrsa model, for the first time, aadh was shown to induce a survivalbenefit. conclusions: we conclude that aadh contributes to the overall increased survival by means of neutralization of extracellular histones and represents a promising product for further development into a drug for the treatment of inflammatory diseases and sepsis. introduction: urokinase (uk) and tissue plasminogen activator (tpa) mediate thrombolytic actions by activating endogenous plasminogen. thrombomodulin (tm) complexes with thrombin to activate protein c and thrombin activatable fibrinolysis inhibitor (tafi). activated protein c (apc) modulates coagulation by digesting factors v and viii and activates fibrinolysis by decreasing pai-1 functionality. methods: the purpose of this study is to compare the effects of rtm and apc on urokinase and tpa mediated thrombolysis utilizing thromboelastography. results: native whole blood was activated using a diluted intrinsic activator (aptt reagent, triniclot). the modulation of thrombolysis by tpa and uk (abbott, chicago, usa) was studied by supplementing these agents to whole blood and monitoring teg profiles. apc (haematologic technologies, vt, usa) and rtm (asahi kasai pharma, tokyo, japan) were supplemented to the activated blood at 0.02 -3.0 ug/ml. the modulation of tpa and uk induced thrombolysis by apc and rtm was studied in terms of thromboelastograph patterns. the effect of both apc and rtm on plasma based systems supplemented with tpa was also investigated. patients treated with antibiotic therapy were eligible for inclusion. the plausibility of infection (definite, probable, possible, none) was determined based on the centers for diseases control (cdc) criteria. patients with sepsis (definite/probable/possible infection and a sofa score increase of >=2) were screened for death within 60 days and secondary infections 48 h to 60 days after icu admission, using the cdc criteria. hla-dra and cd74 mrna expressions were determined by reverse transcription quantitative pcr. results: among 579 icu admissions, a blood sample for rna analysis was collected in 551 cases. two hundred fifty-seven patients met the inclusion criteria and provided written informed consent. sepsis was noted in 134 patients. the sepsis patients experienced death in 36 cases (27%), secondary infection in 32 cases (24%), and death and/or secondary infection in 60 cases (45%). table 1 shows the results of hla-dra and cd74 expression related to death and secondary infections. conclusions: the mrna expression of hla-dra on icu admission was significantly decreased in patients with sepsis who died or contracted secondary infections within 60 days. cd74 expression was not significantly decreased in patients with negative outcome. introduction: acid-base disturbances are common in patients with infection admitted to the intensive care unit (icu). more attention is given to hyperlactatemia in this patient population as a prognostic factor, although other acid-base disturbances may also have an impact on patient outcomes. our objective is to describe the acid-base profile of this patient population and determine the association between different acid-base abnormalities and icu mortality. methods: retrospective cohort of patients admitted with infection to an intensive care unit. patients were stratified according to ph (<7.35; 7.35 -7.45; > 7.45) and, then, according to the standard base excess (sbe) (< -2; -2 -+2; > +2). in each of these strata and the whole population, the proportions of acid-base disturbances were quantified during the first 24 hours of icu admission. to assess the association between acid-base disturbances and outcome, a logistic regression model was fit, adjusting for age, sex and saps 3 score. results: 605 patients were analysed. 304 (50%) patients were acidemic and 244 (40%) presented with a normal ph. metabolic acidosis (as assessed by sbe) was observed in all subgroups, regardless of ph levels (ph < 7 ). lactic acidosis was observed in 71% of the whole population; sig (strong ion gap) acidosis, in 75%; sid (hyperchloremic) acidosis, in 58%; metabolic alkalosis, in 7%; and respiratory acidosis, in 13% of the patients. introduction: sepsis-induced brain dysfunction has been neglected until recently due to the absence of specific clinical or biological markers. there is increasing evidence that sepsis may pose substantial risks for long term cognitive impairment. methods: to find out clinical and inflammatory factors associated with acute sepsis-induced brain dysfunction (sibd) serum levels of cytokines, complement breakdown products and neurodegeneration markers were measured by elisa in sera of 86 sibd patients and 33 healthy controls. association between these biological markers and cognitive test results was investigated. results: sibd patients showed significantly increased il-6, il-8, il-10 and c4d levels and decreased tnf-α, il-12, c5a and ic3b levels than healthy controls. no significant alteration was observed in neuronal loss and neurodegeneration marker (neuron specific enolase (nse), amyloid β, tau) levels. increased il-1β, il-6, il-8, il-10, tnf-α and decreased c4d, c5a and ic3b levels were associated with septic shock, coma and mortality. transient mild cognitive impairment was observed in 7 of 21 patients who underwent neuropsychological assessment. cognitive dysfunction and neuronal loss were associated with increased duration of septic shock and delirium but not baseline serum levels of inflammation and neurodegeneration markers. conclusions: increased cytokine levels, decreased complement activity and increased neuronal loss are indicators of poor prognosis and adverse events in sibd. cognitive dysfunction and neuronal destruction in sibd do not seem to be associated with systemic inflammation factors and alzheimer disease-type neurodegeneration but rather with increased duration of neuronal dysfunction and enhanced exposure of the brain to sepsisinducing pathogens. introduction: high levels of some aromatic microbial metabolites (amm) in serum are related to the severity and mortality of critically ill patients [1] . several studies have discussed the imbalance and loss of the diversity of gut microbiota but there are practically no data on the gut microbial metabolites in critical conditions, only a little -in healthy people [2, 3] . the aim of this work is to analyze the connection between serum and fecal levels of amm in icu patients. methods: 13 simultaneously serum and fecal samples (sfs) from icu patients with nosocomial pneumonia (group i), 21 sfs from icu neurorehabilitation patients (group ii) and 5 sfs from healthy people were taken for gc/ms analyses. the following amm were measured: phenylpropionic (phpa), phenyllactic (phla), p-hydroxybenzoic (p-hba), p-hydroxyphenyllactic (p-hphla), p-hydroxyphenylacetic (hphaa), p-hydroxyphenylpropionic (p-hphpa) and homovanillic (hva) acids. data were presented as medians with interquartile range (ir, 25-75%) using statistica 10. results: the sum of the level of 4 most relevant metabolites (4amm) -phla, p-hphla, p-hphaa, and hva -in serum samples from group i and group ii were equal to 0.9 (0.6-9.6) μ m and 0.7 (0.5-1.0) μ m, respectively, and were higher than in healthy people -0.4 (0.4-0.6) μ m (p<0.05). we suppose the presence of the correlation of amm profile in blood and intestine. particularly, sfs of healthy people are characterized by the prevalence of phpa; amm are not detected in feces of non-survivors but only hva dominates in their serum in the absence of other (fig. 1) . conclusions: the amm profiles in gut and serum are interrelated; amm in serum probably reflect the violation and loss of biodiversity of the gut microbiota in critically ill patients. introduction: since nitrogen oxide (no) is an essential component of the immune system, the dynamics of plasma no concentration was studied in order to predict the development of sepsis [1, 2] . methods: with the permission of the ethics committee included the 200 full-term newborns with respiratory diseases on a ventilator, retrospectively divided into two groups (i, n=46 -sepsis 4-5 days; ii, n=154 without sepsis), at 1, 3-5, 20 days was studied by elisa the plasma concentration of no, nos-2, nos-3, adma (multilabel coulter victor-21420, finland). to select points "cut-off" used the method of roc-lines. results: the statistical power of the study was 86.7% (î±<0.05). at admission in patients of groups i and ii decrease the concentration of no and increased adma in plasma (p<0.05) relative to healthy newborns. after 3-5 days, relatively in patients of groups introduction: sepsis-associated disseminated intravascular coagulation (sac) is associated with decreased platelet counts and formation. the widespread activation of platelets contribute to vascular occlusions, fibrin deposition, multi-organ dysfunction, contributing to a two-fold increase in mortality. the purpose was to measure markers of platelet function in the plasma of patients with clinically established sac and to determine association to disease severity and outcome. methods: plasma samples from 103 adult intensive care unit (icu) patients with sepsis and suspected sac were collected at baseline and on days 4 and 8. dic scores were calculated using platelet count, d-dimer, inr, and fibrinogen. patients were categorized as having no dic, non-overt dic, or overt dic. plasma levels of cd40l, von willebrand factor (vwf), platelet factor-4 (pf-4), and microparticles (mp) were quantified using commercially available elisa methods. results: markers of platelet activation were significantly elevated in patients with sepsis alone and with suspected dic compared to normal healthy individuals on icu day 0 (p<0.001). levels of platelet-associated biomarkers were compared between survivors and non-survivors. pf-4 was significantly decreased in non-survivors compared to survivors (p = 0.0156). patients were stratified based on platelet count and levels of markers were compared between groups. cd40l, vwf, pf4, and mp showed significant variation based on platelet count, with all markers exhibiting stepwise elevation with increasing platelet count. conclusions: markers of platelet activation were significantly elevated in patients with sac compared to healthy individuals. pf4 levels showed significant difference based on dic score or mortality, and differentiated the non-survivors compared to survivors. cd40l, vwf, pf4, and mp showed significant association with platelet count, increasing in a stepwise manner with increases in platelet count (table 1) . prognostic value of mean platelet volume in septic patients: a prospective study a chaari king hamad university hospital, bussaiteen, bahrain critical care 2018, 22(suppl 1):p024 introduction: mean platelet volume (mpv) has been reported as a valuable marker of inflammatory diseases. the aim of the current study is to assess the prognostic value of mpv in septic patients. methods: prospective study including all patients admitted to the intensive care unit (icu) with sepsis or septic shock. demographic, clinical and laboratory data were collected. the mpv was checked on admission and on day 3. two groups were compared: survivors and non-survivors. [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] days in survivors and 8.5 [3.5-12] days in non-survivors (p=0.623). conclusions: the decrease of the platelet count but not the increase of the mpv was associated with increased mortality in critically-ill septic patients. endotoxin activity assay levels measured within 24 hours after icu admission affected patients' severity assessments a kodaira 1 , t ikeda 2 , s ono 2 , s suda 2 , t nagura 2 1 tokyo medical university, tokyo, japan, 2 introduction: sepsis profoundly alters immune homeostasis by inducing first a systemic pro-inflammatory, then an anti-inflammatory state. we evaluate the prognostic value of ex vivo lipopolysaccharide (lps) stimulation of whole blood in septic patients, at day 1 and 7 after intensive care unit (icu) admission. methods: this prospective cohort study included patients with severe sepsis or septic shock admitted to a surgical icu of a university hospital. blood was drawn on day 1 and day 7, and stimulated ex vivo with lps for 24 hours. tumor necrosis factor alpha (tnf), interleukin (il) 1, il6 and il10 were measured. twenty-three healthy adults served as controls. outcomes were ventilator and icu-free days, sofa score at day 1 and 7, and need for dialysis during the course of sepsis. results: forty-nine patients were included (mean age 62 ± 15 years). the blood of septic patients was less responsive to ex vivo stimulation with lps than that of healthy controls, as demonstrated by lower tnf, il1, il6 and il10 release ( fig. 1 ). at day 1, patients above the 50th percentile of il10 release had significantly fewer ventilator and icu-free days than those in the lower 50th percentile (fig. 2) . in contrast, patients in whom il10 release increased between day 1 and day 7 had significantly lower sofa scores at day 1 and 7 and need for dialysis, and more icu-free days than patients in whom il10 release decreased (table 1) . conclusions: greater lps-stimulated il10 release in septic patients at day 1 was associated with poorer clinical outcomes and may reflect the severity of the forthcoming immunoparalysis. however, an increase in il10 release between day 1 and day 7 was associated with favorable outcomes, perhaps signaling immune restoration. introduction: hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (hipec-crs) is a curative treatment modality for peritoneal carcinomatosis. extensive debulking surgery, peritoneal stripping and multiple visceral resections followed by intraperitoneal installation of heated high-dose chemotherapeutic agents, a process leads to a 'high-inflammatory' syndrome. serum procalcitonin (pct), a biomarker for bacterial sepsis, in the heightened inflammatory state after hipec-crs might be of limited utility. our aim is to determine the trends of pct in the early postoperative phase of hipec-crs and to identify trends in patients with and without bacterial sepsis methods: in a case-control design, we reviewed all patients undergoing hipec-crs over a 24-month period (2015) (2016) (2017) . patients were divided into 2 groups based on whether they developed bacterial sepsis in the first 5 days after surgery (infected v/s non-infected). summary data are expressed as medians and ranges. two-tailed nonparametric tests were performed and considered significant at p values of less than 0.05 results: 82 patients' data was analyzed. infections developed in 16% (13 patients) with escherichia coli as the predominant pathogen isolated (36% isolates). pct levels (ngm/ml) were elevated postoperatively in both infected and non-infected patients; day 1 infected 0.97 (iqr 0. 5 introduction: early outcome in cardiac surgery has been an area of growing interest where the given risks raise several predictive models for assessment of postoperative outcome [1] . procacitonin (pct) emerges as a possible predictive tool in cardiothoracic intensive care unit (cticu).we aim at testing the predictive power of pct for early morbidity, prolonged ventilation, icu and hospital stay, in patients developing early fever after cardiac surgery methods: a retrospective descriptive study done in tertiary cardiac center, enrolling patients who stayed for more than 24 hours post-operatively in the cticu risk stratification included additive euro score and pct immunoluminometricaly prior to surgery and every 48 hours in response to onset of fever. results: we screened 501 consecutive patients who underwent open heart cardiac, of which 119 patients were enrolled in the study. patients were divided into two groups based on the level of pct, those with value > 2 ng/ml (group 1) and those with level < 2 ng/ml (group 2). patients in group 1 as compared to group 2, over the postoperative course was associated with prolonged icu stay (p=0.04), length of mechanical ventilation (p=0.05), length of hospitalization (p=0.05), acute kidney injury (p=0.04) and culture positivity (p=0.02). multivariate analysis showed that pct >2ng/ml was was significantly associated with positive cultures. (p=0.023) conclusions: a rise of serum pct carries the signals of early icu morbidity and lengths of ventilation, icu stay and hospital stay methods: 42 patients aged 153 (44-252) days (4-360 days) underwent cardiac surgery with cardiopulmonary bypass for severe congenital heart disease. in the dynamics levels of pct, mr-proadm, ct-proavp and mr-proanp were measured before surgery and on the 1, 2, 3 and 6 days after the operation with the kryptor compact plus analyzer. data are presented as medians with interquartile range. the mann-whitney u-test was used to compare the data. values of p <0.05 were statistically significant. results: 24 patients (57%) required alv for more than 72 hours. in this group statistically significant higher levels of pct, mr-proadm and mr-proanp were found throughout the period ( table 1 ). the level of ct-proavp had increased to statistical significance since the 3 day after the operation. 23 patients were in the icu for more than 168 hours. in this group statistically significant higher levels of pct, mr-proadm were found throughout the whole period ( table 2 ). the higher level of mr-proanp was statistically significant on the 1st and 6th days after surgery, mr-proanp had a tendency of increasing values on 2nd and 3rd days. ct-proavp increased to statistical significance since the 2nd day after the operation and persisted throughout the studied period. conclusions: pct, mr-proadm and mr-proanp can be used as predictors of prolonged alv for children of the first year of life after cardiac surgery with cardiopulmonary bypass. the level of ct-proavp can be considered since the 3 day after surgery. pct and mr-proadm may be used to predict the los in the icu. mr-proanp and ct-proavp can be considered since the 1 and 2 days after surgery respectively. introduction: early prediction of the risk of death among patients admitted at the emergency department (ed) remains an unmet need. the prognostic performance of hbp that is secreted by neutrophils was prospectively validated in a series of sequential ed admissions. methods: hbp and elements of qsofa were analyzed prospectively in 310 serial ed admissions (main reasons for admission: acute abdominal pain 28.4%; fever 24.5%; vomiting/diarrhea 23.9%; dyspnea 22.3%; neurologic signs 11.3%; non-specific complaints 38.1%; most patients admitted for more than one reasons). upon ed admission patients were scored as low-risk, intermediate-risk and high-risk at the discretion of the physician. hbp was measured in blood samples upon admission by an enzyme immunosorbent assay. results: hbp was significantly greater among patients who died very early (fig. 1 ). in five out of six of patients dying early hbp was greater than 15 ng/ml. we combined hbp more than 15 ng/ml and the presence of one sign of qsofa into a new score; this had 82.4% sensitivity to predict 30-day mortality. the respective sensitivity of two signs of qsofa was 23.5% (p: 0.002). the use of this new score allowed better stratification of patients originally considered at the triage as low-risk into high-risk (fig. 2) . conclusions: we propose hbp more than 15 ng/ml and one qsofa sign as an early score for 30-day mortality at the ed. introduction: despite of our growing knowledge in pathophysiology of septic shock still remain one of the most important factors of hospital mortality. it is thought that early diagnosis and treatment at early stage of septic shock would decrease its mortality. there have been on-going studies in recent years which research the usability of heparin binding protein (hbp) in early diagnosis of sepsis [1] . to seek the usability of c-reactive protein (c-rp), procalcitonin (pct) and hbp biomarker combination in early diagnosis of septic shock. methods: 30 patients, who have the diagnosis of septic shock, that are expected to stay in intensive care unit more than 24 hours, and aged between 22-75 are included in the study. data are collected from the patients' blood samples that are drawn on admission, on the 24th hour, and on the day of discharge or death. results: it has been found in our study that, best "cut-off" value 124 ng/ml, specificity 0.82 and sensitivity 0.77 for hbp. compared with other biomarkers, hbp was the best predictor of progression to organ dysfunction (area under the receiver operating characteristic curve (auc) = 0.801). conclusions: although there have been many biomarkers for early diagnose of septic shock, c-rp and pct are the most common used markers in nowadays' clinical practice. the usability of hbp in early diagnosis of sepsis is still being researched. we concluded that pct, c-rp and hbp biomarker combination is usable to diagnose septic shock at the end of our study. introduction: reduced adamts-13 and increased von willebrand factor (vwf)/adamts-13 ratio have been observed in sepsis and are associated with the severity of the disease [1, 2] . however, their change during the septic episode and in the event of a change in the clinical status of the septic patients has not been investigated. the aim of the study was to assess the variation of these hemostatic parameters in critically ill patients during the course of a septic episode. methods: we monitored 34 septic patients admitted in the intensive care unit (icu). 23 improved (group a) while 11 deteriorated (group b). we assessed vwf, adamts-13 and the vwf/adamts-13 ratio on admission in icu (time point 0) and at the time of a change in patients' clinical condition (remission or deterioration, time point 1). results: in group a, adamts-13 and the vwf/adamts-13 ratio did not significantly change (567.0±296.0 vs 670.7±534. 5 conclusions: hemostatic disorders, as assessed by vwf and adamts-13 levels were detected in septic patients, while their changes differed according to the evolution of the septic episode. adamts-13 changes may be associated with outcome. methods: 100 adult patients with at least one sign of qsofa and infection or acute pancreatitis or after operation were prospectively followed-up. blood was sampled the first 24 hours; those with hiv infection, neutropenia and multiple injuries were excluded. sepsis was diagnosed using the sepsis-3 criteria. soluble urokinase plasminogen activator receptor (supar) was measured by an enzyme immunoassay. results: sixty patients were classified with sepsis using the sepsis-3 definitions. presence of at least two signs of qsofa had 56.7% sensitivity, 95.0% specificity, 92.8% positive predictive value and 38.0% negative predictive value for the diagnosis of sepsis. the integration of qsofa signs and supar improved the diagnostic performance ( fig. 1) . conclusions: conclusions two signs of qsofa have significant positive prognostic value for sepsis but low sensitivity. this is improved after integration with supar. the intelligence-1 study is supported by the european commission through the seventh framework programme (fp7) hemospec. introduction: sepsis is a frequent reason for admission in the emergency department (ed) and its prognostic mainly relies on early diagnosis. in addition, no validated prognostic tool is currently available. therefore, identification of patients at high risk of worsening in the ed is key. the triage objective was to assess the prognostic value of a blood marker panel to predict early clinical worsening of patients admitted in the ed with suspected sepsis. methods: triage was a prospective, multicenter (11 sites in france and belgium) study on biological samples conducted in partnership with biomerieux s.a. patients admitted in the ed with suspected or confirmed community-acquired infection for less than 72h were included. exclusion criteria were: admission in the ed for more than 12 hours, septic shock at admission, immunodepression, sepsis syndrome 30 days prior to admission. the protocol included 5 clinical and biological time points (h0, h6, h24, h72, d28). patients were classified in 3 groups at admission (infection, sepsis, severe sepsis) and divided into 2 evolution/prognosis groups depending on worsening or not from their initial condition to severe sepsis or septic shock and sofa score's evolution. the evolution criteria were centrally evaluated by an independent adjudication committee of sepsis experts including emergency physicians and intensivists. patients were followed up to day 28 for mortality. results: the study duration was 3 years with 600 patients included (102 excluded). the centralized analysis is in progress to select the combination of biomarkers with the best prognostic performance comparing both evolution/prognosis groups. currently, 125 patients have been classified as worsening and some results will be available in 2018. conclusions: triage is the largest prospective multicenter study assessing the prognostic value of a panel of blood markers in eds which could help identification of septic patient at risk of worsening at time of admission in the ed and develop specific management. introduction: immune status characterization in intensive care unit (icu) patients presents a major challenge due to the heterogeneity of response. in this study, the filmarray® system was used with customized gene assays to assess the immune profile of critically-ill icu patients compared to healthy volunteers; from within the realism cohort. methods: a customized filmarray® pouch containing 24 assays was designed; 16 target and 8 reference genes. detection and semiquantification of assays from whole blood collected in paxgene tubes occurs in the device within 1 hour. a total of 20 subjects from the realism cohort were tested in duplicates: 1 trauma, 5 septic shock and 5 surgery patients, along with 9 healthy volunteers. the patients' selection was based on hla-dr expression on monocytes, and pha-(phytohaemagglutinin) stimulated t-cell proliferation assay, to have various immune profiles. results: quantification cycle values of the target genes were normalized by the geometrical mean of reference genes to account for the different cell counts among specimens. the number of the cd3+ cells and hla-dr, determined by flow cytometry, showed good correlation to cd3d and cd74 gene expression, respectively. seven genes showed significant differences in expression levels between the healthy volunteers and patient groups: cd3d, cd74, ctla4 & cx3cr1 were down-regulated, while il-10, il1rn and s100a9 were up-regulated in the patient populations. the use of relative quantitative difference of some markers was able to distinguish and introduction: early, rapid diagnosis is integral to the efficient effective treatment of sepsis; however, there is no gold standard for diagnosis, and biochemical surrogates are of limited and controversial utility. the cytovale system measures biophysical properties of cells by imaging thousands of single cells per second as they are hydrodynamically stretched in a microfluidic channel. this platform has been shown to measure dozens of mechanical, morphological, and cell surface biomarkers of wbc activation simultaneously [1, 2] . in this study, we show the performance of the cytovale system in measuring biophysical markers for sepsis detection in the emergency department (ed). methods: we conducted an irb-approved prospective cohort study of emergency department (ed) patients with 2+ sirs criteria and evidence of organ dysfunction. 307 patients were included for analysis. blood samples for the cytovale assay were collected in the ed, and the diagnosis of sepsis was adjudicated by blinded clinician review of the medical record. captured imaging data were analyzed using computer vision to quantify mechanical parameters per cell, and a logistic model was trained to discriminate patients who had sepsis from those who did not. results: we found substantial biophysical differences between cells from septic and non-septic patients as observed at both the single cell level (fig. 1) and when looking at the overall leukocyte populations (fig. 2) . a multiparameter classification algorithm to discriminate septic from non-septic patients based on biophysical markers currently yields a sensitivity of 88% with a negative predictive value of 95%. conclusions: in patients presenting to the ed with 2 of 4 sirs criteria and evidence of organ dysfunction, the cytovale system provides a potentially viable means for the early diagnosis of sepsis via the quantification of biophysical properties of leukocytes. oxidative stress and other biomarkers to predict the presence of sepsis in icu patients v tsolaki, m karapetsa, g ganeli, e zakynthinos icu, larissa, greece critical care 2018, 22(suppl 1):p040 introduction: early identification of sepsis adds a survival benefit in icu patients. several biomarkers have been evaluated, yet an optimal marker is still lacking [1] . methods: we prospectively determined oxidative status in patients admitted in a general intensive care unit of the university hospital of larisa. oxidative status was determined measuring the novel static (sorp) and capacity (corp) oxidation-reduction potential markers. other biomarkers (bnp, presepsin, crp) were measured, and the discriminative properties for the detection of sepsis were evaluated. results: oxidative status was evaluated in a hundred and fifty two consecutive patients. patients with severe sepsis and septic shock had significantly higher sorp values than patients without sepsis ( introduction: c-reactive protein (crp), is reported to be an effective marker for the assessment of vascular inflammation activity and acute coronary events prediction [1] .we hypothesized that preoperative crp elevation is related to the occurrence of postoperative adverse cardiovascular outcomes. methods: we prospectively included patients scheduled to undergo different vascular surgeries from december 2016 to september 2017. we assessed demographic data, comorbidities, revised cardiac risk index (rcri) and biomarkers (crp, cardiac troponin high sensitive ths, creatinine and urea) in the preoperative period. we also noted type and duration of surgery, intraoperative blood loss, icu stay and mortality. we evaluated crp as a predictive marker of major cardiovascular events defined as chest pain, ths elevation, electrocardiogram changes, arrhythmia, pulmonary embolism, stroke occuring within postoperative 3 months. results: during our study, 30 patients were scheduled to undergo vascular surgeries. from the 30 patients, 66% developed adverse cardiac events (table 1) . we showed the predictive value of crp in major cardiovascular event in a roc analysis (fig. 1) . the cuttoff value of cpr was 54 giving 85% of sensitivity and 82% of specificity. conclusions: our study pointed out that crp preoperative elevation could have a very strong predictive value of post-operative cardiovascular events in vascular surgery, this is in line with results showed by previous studies [1] . introduction: elderly are particularly susceptible to bacterial infections and sepsis, and they comprise an increasing proportion of intensive care unit (icu) admissions. our aim was to evaluate the impact of age on critically ill infected patients. methods: we performed a post-hoc analysis of all infected patients admitted to icu enrolled in a 1-year prospective, observational, multicenter study involving 14 icus. patients aged <65, 65-74 and >=75 years were compared (group a, b, and c). multidrug-resistance (mdr) was defined as acquired non-susceptibility to at least one agent within three or more antimicrobial categories. results: of the 3766 patients analyzed, 1652 (43.9%) were infected on icu admission. of these, 828 (50%) belonged to group a, 434 (23%) to group b and 440 (27%) to group c. group c were more dependent, had higher saps ii and charlson scores (p<0.05). icu and hospital length of stay did not differ between groups. microorganism isolation and bacteremia were higher in group b (53% and 24%, respectively) than groups a (45% and 19%, respectively) and c (47% and 17%, respectively; p<0.05). septic shock was present in 58% of patients and was more frequent in groups b (55%) and c (55%) than group a (48%). the most common sources of infections were respiratory and intra-abdominal. isolation of gram-negative bacteria was significantly increased in group b and c (p=0.034). the most common isolated bacteria were escherichia coli (17%), staphylococcus aureus (15%) and pseudomonas aeruginosa (8%) for all groups. in total, 151 isolates (22%) corresponded to mdr bacteria, of which 57% were staphylococcus aureus. age was not a risk factor for infection by mdr. all-cause mortality in icu and hospital was: 23% and 30%; 29% and 40%; 36% and 53% -respectively for groups a, b, and c (p < 0.001). conclusions: old patients (65-74 years) were more prone to present with bacteremia, which could account for the increased severity of sepsis and higher all-cause mortality. age was not a risk factor for mdr infection. introduction: the rapid identification of pathogens using patient samples is crucial. delays in this can potentially have serious implications for patients and infection prevention/control [1] . the aim of this project was to identify the number of microbiology samples sent, the number rejected and reasons for rejection, with the intention to reduce such instances. methods: data was collected retrospectively on icu admissions from january-june 2017 to a university hospital in the uk. patients were identified and data collected using the intensive care national audit and research centre (icnarc) database and from electronic patient records. data collected included: demographics, length of stay, microbiology samples sent and details on the rejected samples. results: 530 patients were identified with a total of 4725 (median: 4 samples/patient) samples sent to microbiology. 144 were rejected (3%). 100 (18%) patients had at least 1 sample rejected. the median number of samples rejected per patient was 1 (range: 1-10). the fig. 1 (abstract p041). the area under the curve for crp elevation is 0.891 most common samples rejected were urine (22%), blood (20%), faeces (19%) and sputum (8%). 69 (48%) of the samples were resent for testing (median 1 day; range 0-20). reasons for sample rejection are shown in table 1 . most rejections occurred within 48-hours of admission ( fig. 1) . conclusions: this study confirms a high number of samples are sent to microbiology. although a few are rejected, overall this represents a large number, with most occurring during the first days of admission. reasons for sample rejection are remedial through improved training and vigilance. a bespoke guide to sample collection for microbiology coupled with a training program for healthcare professionals has been introduced with the aim to reduce sample rejections from 3% to 0.5%. introduction: careful hand hygiene of health-care workers (hcws) is recommended to reduce transmission of pathogenic microorganisms to patients [1] . mobile phones are commonly used during work shifts and may act as vehicles of pathogens [2, 3] . the purpose of this study was to assess the colonization rate of icu hcws' mobile phones before and after work shifts. methods: prospective observational study conducted in an academic, tertiary-level icu. hcws (including medical and nursing staff) had their mobile phones sampled for microbiology before and after work shifts on 6 different days. samples were taken with eswab in a standardized modality and seeded on columbia agar plus 5% sheep blood. a semiquantitative growth evaluation was performed at 24 and 48 hours after incubation at 35°c. results: fifty hcws participated in the study (91% of department staff). one hundred swabs were taken from 50 mobile phones. fortythree hcws (86%) reported a habitual use of their phones during the work shift, and 38 of them (88.4%) usually kept their mobiles in the uniform pocket. all phones (100%) were positive for bacteria. the most frequently isolated bacteria were coagulase negative staphylococcus, bacillus sp. and mrsa (97%, 56%, 17%, respectively). no patient admitted to the icu during the study period was positive for bacteria found of hcws' mobile phones. no difference in bacteria types and burden was found between the beginning and the end of work shifts. conclusions: hcws' mobile phones are always colonized mainly by flora resident on hcw's hands, even before the work shift and irrespective of the microbiological patients' flora. further studies are warranted to investigate the role of mobile phones' bacterial colonization in the icu setting and to determine whether routine cleaning of hcws' mobile phones may reduce the rate of infection transmission in critical patients. methods: sixty samples were collected from aicu (n=25), picu (n=15) and or (n=20) during august to september 2017. samples were randomly selected and taken at the end of the hcws duty with a sterile swab covering all mp surfaces. the inoculation was made into blood sheep and eosyn methilene blue agar for culture. isolated bacteria were identified according to standard microbiological techniques. antibiotic sensitivity testing was performed using disc diffusion method. results: overall mp bacterial colonization rate was 95%. main results are detailed in table 1 . most common non pathogenic bacteria was staphylococcus epidermidis n=18 (90%). isolated pathogenic bacteria conclusions: we found high rates of mp colonization with pathogenic bacteria. an educational program is necessary to reduce the contamination and transmission of these high risk microorganisms. introduction: the objective of this study was to evaluate the variability in the dynamics and levels of airborne contamination within a hospital intensive care unit in order to establish an improved understanding of the extent to which airborne bioburden contributes to cross-infection of patients. microorganisms from the respiratory tract or skin can become airborne by coughing, sneezing and periods of increased activity such as bed changes and staff rounds. current knowledge of the clinical microflora is limited however it is estimated that 10-33% of nosocomial infections are transmitted via air. methods: environmental air monitoring was conducted in glasgow royal infirmary icu, in the open ward and in patient isolation rooms. a sieve impactor air sampler was used to collect 500 l air samples every 15 minutes over 10 hour (08:00-18:00 h) and 24 hour (08:00-08:00 h) periods. samples were collected, room activity logged and the bacterial contamination levels were recorded as cfu/m 3 of air. results: a high degree of variability in levels of airborne contamination was observed over the course of a 10 hour day and a 24 period in a hospital icu. counts ranged from 12-510 cfu/m 3 over 24 hours in an isolation room occupied for 10 days by a patient with c. difficile infection. contamination levels were found to be lowest during the night and in unoccupied rooms, with an average value of 20 cfu/m 3 . peaks in airborne contamination showed a direct relation to increased room activity. conclusions: this study demonstrates the degree of airborne contamination that can occur in an icu over a 24 hour period. numerous factors were found to contribute to microbial air contamination and consideration should be given to potential improved infection control strategies and decontamination technologies which could be deployed within the clinical environment to reduce the airborne contamination levels, with the ultimate aim of reducing healthcareassociated infections from environmental sources. new practice of fixing the venous catheter of the jugular on the thorax and its impact on the infection f goldstein, c carius, a coscia quintad'or, rio de janeiro, brazil critical care 2018, 22(suppl 1):p047 introduction: central line-associated bloodstream infection (clabsi) is an important concern in the icu, mainly in those with a high density of use of central venous catheter. any measures that may have an impact on the reduction of clabsi are important in reducing morbidity and mortality of hospitalized patients. therefore we present a retrospective study comparing the fixation site (neck vs. thorax) of the catheters implanted in the jugular vein, guided by ultrasonography and evaluating its impact on the incidence of clabsi. the purpose of our study was to identify if there is any positive impact on the reduction of clabsi when the catheter is fixated on the thorax. methods: a retrospective unicentric study comparing the infection rates between the year of 2012, when the traditional technique of catheter fixation on the neck was used, and 2015, when 100% of the catheters were fixated on the thoracic region. the criteria for clabsi were defined by the infection commission of quintad`or hospital and the data on clabsi were provided by the same commission. during this period there were no changes in the team of our unit and the patient's profile was the same. no deep vein catheter impregnated with antibiotics were used in the patients included in the study. the comparison used fisheŕs test as a tool. all the patients hospitalized in the intensive care unit with indication of the central venous catheter of short permanence in the internal jugular vein were included. patients with the central venous catheter of short permanence in other topographies, patients with hemodialysis catheter or with picc were excluded. results: during the year of 2012, 98 internal jugular vein catheters were installed in our unit using the traditional technique, fixing the catheter on the neck. in this period, 6 cases of clabsi were detected. on the other hand, in the year of 2015, 127 internal jugular vein catheters were installed in the same unit, all of them, using the thorax as the point of fixation. although the number of catheters installed this year was higher, there was no case of clabsi. it appears that this position, provides a better fixation of the catheter, avoiding that the bandage gets uncovered. conclusions: during the year of 2015, though there were more patients using deep vein catheters of short permanence, we had less clabsi events on our unity compared to the year of 2012. fisher's exact test identified a p-value of this association of 0.476. fixation of the internal jugular vein catheter in the thorax seems to contribute to the prevention of clabsi. further prospective and randomized studies are required to evaluate the contribution of fixation of the jugular vein catheter in the thorax in the clabsi prevention. introduction: the oral cavity of a patient who has been hospitalized presents a different flora from normal healthy people. after 48h hours of hospital stay, the flora presents a bigger number of microorganisms that can be responsible for secondary infections, like pneumonia, because of their growth and proliferation. the objective of our study was to assess the dental plaque index on patients on admission to an intensive care unit, and reassess 7 days later, to evaluate the efficacy of oral hygiene. methods: prospective, descriptive and observational study in an intensive care unit of the chp. demographic, admission motive, hospital length of stay, feeding protocol, respiratory support need and oral hygiene protocol data was collected. the greene & vermillion simplified oral hygiene index (iho-s) was used as the assessment tool on the first 24h and on 7th day. results: 74 patients were evaluated, 42 of which were excluded for not meeting the minimal dentition. 32 patients had a mean age of 60,53 ± 14,44 years, 53,1% were males and most of medical and surgical scope (37,5% each). mean hospital length of stay was 15,69 ±6,69 days. the majority of patients were sedated (75%), under ventilator support (81,3%) and with enteric nutritional support, under nasogastric tube feeding. initial iho-s score was 0,67±0,45, rising to 1,04±0,51 (p<0,05) 7 days later. conclusions: various studies have proven the importance of a good oral hygiene to avoid bacterial growth and reduce the risk for nosocomial infections. in this study, we've observed a significant worsening of oral hygiene one week after admission. although this could be unimportant for a one week staying patient, it could indicate an increased risk for nosocomial infections for longer staying patients, which could benefit from a more efficient oral hygiene protocol. positive pocket cultures and infection risk after cardiac electronic device implantation-a retrospective observational single-center cohort study p pekić 1 methods: we performed a retrospective observational single-center cohort study on 251 patients who received de novo implantation of pacemaker, cardioverter-defibrillator or cardiac resynchronization therapy device in a two-year period. each patient was implanted using standard aseptic procedure according to local protocol and antibiotic (cefazolin) prophylaxis before the procedure. pocket aspirate was taken after irrigating the wound with normal saline just before device placement. results: we analyzed 251 patients (58.6% male, 41.4% female). the most often implanted device was a ddd pacemaker followed by a vvi pacemaker. mean length of hospital stay was 12.02±8.34 days. there were 54 (21.5%) positive cultures with overall 3 (1.19%) clinically apparent infections which required prolonged iv antibiotics, removal of device and reimplantation after infection resolution. in regard to microbiology, s. epidermidis (48.2%) and coagulase negative staphylococcus (29.6%) were the most often finding which is in contrast to the cultures described in the literature. the only statistically significant risk factor for positive pocket culture was male sex and presence of a urinary catheter. invasive vascular devices, previous intrahospital infection, and diabetes were not found to increase the likelihood of positive pocket culture. conclusions: positive pocket cultures after cied implant are a frequent finding mostly due to contamination and colonisation. the risk factors for such a finding differ from the usual and expected clinical circumstances. our results are consistent with those in the literature. it turns out that the most important preventive measure in cied implantation is strict aseptic procedure. introduction: intensive care patients are in constant risk of contamination due to suppression of their immune system, use of invasive procedures and medical equipment and health associated infections (hai). chlorhexidine gluconate (chg) is an antiseptic and disinfectant product. in medical research it has been found that daily chg bathing is affective in reducing levels of skin and central line related infections (climo, 2013) . it is also referred to in the recommendations of the ministry of health "prevention of septicemia due to central lines" (2011). methods: unit guide lines for patient dry bathing were written in may 2015 and thereafter began the implementation and instruction of nursing staff. quality control was inspected by observation. there was a 15 phase questioner that included several categories such as: preparation of the chg solution, staff protection actions, infusions and surgical wound dressings, bathing performance and documentation. results: a gradual rise of 97%was observed in theperformance ofdry bathing according to the unit guidelines conclusions: 97% of observed dry baths where performed according to the guide lines. points for improvement: correct care of infusions and surgical wound dressing and verify use of separate wipes for each body part. next we will examine the correlation between the use of dry baths and theextent of infections in the unit. dry baths are nowconsidered an integralpart of the daily nursing routine. they have no substantial costs, help prevent complications from infection and add to the patient's safety. introduction: despite reductions in mortality reported with sdd, concerns about bacterial resistance and alteration of microbiome limit use. a retrospective observational study was conducted into the effect of local sdd protocols on vap rates and resistance patterns. over a 2-year period, 2 regimens were used dependent on drug availability and hospital antibiotic stewardship concerns. the study was designed to review practice and identify any risks of partial implementation. methods: patients ventilated on a general intensive care were identified via clinical information systems. three periods were reviewed for adherence to sdd protocols, pre sdd (jan -feb 14), full (july -sept 15) and partial (july -sept 16). high-risk patients during both sdd periods also received iv antibiotics for 96 hours. patients admitted with pneumonia or tuberculosis were excluded from vap analysis. remaining patients' records were reviewed and the clinical pulmonary infection score (cpis) calculated for each ventilated day to identify vap rates. positive respiratory microbiological results for all patients admitted to the icu during each time period were reviewed to assess for wider changes in local resistance patterns. results: protocol adherence was assessed in 71 patients during the full sdd period and 70 during the partial ( table 1 ). the number of patients included for analysis of vap rates during each period was 38 pre sdd, 50 during full sdd and 37 during partial sdd. there were no significant changes in resistance patterns or clostridium difficule rates (table 2) . conclusions: compliance with the available enteral antibiotics was reasonable but with iv antibiotics was poor. it is accepted that alterations and non-adherence to protocols risk development of resistant bacterial strains. within our unit no decrease in vap rates was seen but reassuringly no increased rates of extended bacterial resistance were identified during the treatment periods. introduction: arterial catheters are commonly used in intensive care units (icu) and are among the most frequently manipulated vascular access devices. our aim was to evaluate the rate of arterial catheterrelated bloodstream infection and colonization. methods: this was a 12-month, prospective and monocentric cohort study, performed in a multipurpose icu. all arterial catheters, inserted in or presented to the icu, were cultured and assessed for colonization or catheter-related bloodstream infection (crbi). results: we enrolled 119 patients (63.8% males, average age 59±17 years, saps 2 42±21) of whom a total of 141 arterial catheters were analyzed for a total of 1552 catheter-days. radial arterial catheters were inserted in 88.7% (n=125), femoral arterial catheters in 7.8% (n=11) and other arterial catheters in 3.5% (n=5). signs of dysfunction were found in 28.8% and 45.5%, respectively. radial arterial catheters colonization (n=5) and crbi (n=1) occurred at a rate of 3.0 and 0.8/ 1000 catheter-days. femoral arterial catheters colonization (n=2) and crbi (n=1) occurred at a rate of 10.8 and 5.4/1000 catheter-days, respectively. mean catheter time insertion was significantly higher in colonized catheters/crbi (21±8 days; 95% ci: 14-28) when compared to arterial catheters with negative cultures (10±8 days; 95% ci: 9-12); p = 0.002). colonized lines showed acinetobacter baumannii (n=3), staphylococcus epidermidis (n=1), enterococcus spp (n=1) and pseudomonas aeruginosa (n=1). crbi were caused by staphylococcus epidermidis (n=1) and staphylococcus haemolyticus (n=1). conclusions: the incidence of radial arterial catheters colonization and crbi were lower than reported rates in literature. colonization and crbi rates were higher in femoral catheters. femoral catheters showed dysfunction more frequently. prolonged catheterization was associated with colonization and crbi. a multimodality approach to decreasing icu infections by hydrogen peroxide, silver cations and compartmentalization and applying acinetobacter as infection marker introduction: nosocomial infections at the intensive care unit (icu) represent a substantial health threat [1, 2] . icu infections are mainly attributed to the extended hospital delay which results in high morbidities and mortalities. methods: a cross sectional study was conducted at the intensive care unit, aseer central hospital, saudi arabia over 13 months period (2014) (2015) . the intervention program included the application of mist of hydrogen peroxide and silver cations, physical separation and compartmentalization of the intensive care unit. the glosair™ 400 system was used to deliver a mist of hydrogen peroxide and silver cations. hydrogen peroxide is an oxidizing agent, which kills microorganisms. results: a total of 103 strains of acinetobacter species were identified from the patients over the 13 months period (fig. 1) . the mean infection rates decreased from 14.3 in the first three months of the program to 4 in the last three month after continuous. conclusions: the program using the three procedures offered a significant decrease in infections at the icu as measured by acinetobacter count, which is one of the most hazardous nosocomial pathogens. introduction: the efficacy of ß lactam antibiotics is related to the time above mic. continuous or extended infusions can be used to increase the time above mic, especially in patients with normal or increased drug clearance. administering antibiotics by continuous infusion is not a new concept. a review in 1992 looks at the outcomes of continuous infusions [1] . more recently an improvement in mortality has been demonstrated [2] . our perception was that uptake of this low cost intervention was not common, so we undertook a survey to determine how commonly continuous infusions are used in england. methods: a telephone survey of all intensive care units in england was undertaken. questions included: -are you using continuous or extended antibiotic infusions? -which antibiotics are you using for continuous or extended infusions? -if not currently using has it been considered? data was collected over a week in june 2017. results: there was an 87% response rate. 73 (44.5%) of the units continuously infuse some antibiotics, however 71.2% of those only infuse vancomycin and not ß lactams. only 21 of the total responders (12.8%) infuse antibiotics other than vancomycin (i.e. ß lactams). conclusions: the theoretical advantage of continuous infusion of ß lactam antibiotics has been described for over 20 years. there is now evidence that this may improve survival. despite this, uptake in england has been slow. introduction: infections contribute to a significant proportion of morbidity and mortality worldwide. while many infections are successfully managed with antimicrobial therapy, rates of antimicrobial resistance (amr) are increasing. certain patient populations such as those admitted to intensive care units (icu) are at high risk. methods: we conducted a retrospective, observational study of all icu patients at a tertiary referral hospital in rwanda from january 2015 through december 2016 we collected data on diagnosis, icu length of stay, mortality and hospital length of stay, as well as microorganism, site of culture, amr and antibiotics prescribe. results: overall, 331 patients were admitted to the icu. most patients were admitted from the main operating theater (n=150, 45%).the most common admitting diagnoses were sepsis (n=113, 34%), head trauma (n= 90, 27%). a total of 268 samples were collected from 331 patients. the samples were from blood (n=110, 33%), tracheal aspirate (n=22, 7%),. the most common organisms isolated were klebsiella (n=30, 29%), acinetobacter (n=20, 19%), e.coli (n=16, 15%), proteus (n=15, 14%), citrobacter (n=8, 8%), s aureus (n=7, 7%), pseudomonas (n=5, 5%), and other (n=9, 9%). of klebsiella isolates, 100% and 76% were resistant to ceftriaxone and cefotaxime, respectively. of e.coli isolates, 86% and 71% were resistant to ceftriaxone and cefotaxime, respectively. all acinetobacter isolates were resistant to ceftriaxone and cefotaxime. conclusions: there is an alarming rate of antimicrobial resistance to commonly used antibiotics in the icu. expanding antibiotic options and strengthening antimicrobial stewardship are critical for patient care. the last three days g latten 1 , p stassen 2 1 zuyderland mc, sittard-geleen, netherlands, 2 introduction: this study provides an overview of the prehospital course of patients with a (suspected) infection in the emergency department (ed). most research on serious infections and sepsis has focused on the hospital environment, while potentially most delay, and therefore possibly the best opportunity to improve treatment, lies in the prehospital setting. methods: patients were included in this prospective observational study during a 4 week period in 2017. all patients aged 18 years or older with a suspected or proven infection were included. prehospital, ed and outcomes were registered. results: in total, 2452 patients visited the ed during the study period, of whom 440 (17.9%) patients had a (suspected) infection. (fig. 1 ) median duration of symptoms before ed visit was 3 days (iqr 1-7 days), with 23.9% of patients using antibiotics before arrival in the ed. most patients (83%) had been referred by a general practicioner (gp), while 41.1% of patients had visited their gp previously during the current disease episode. twenty-two patients (5.0%) experienced an adverse outcome (icu admission and/or 30-day all-cause mortality): these patients were less often referred by a general practicioner (gp) (59.1 vs. 84.2%, p=0.001) and were considered more urgent both by ems and in the ed. conclusions: the prehospital phase of patients with an infection provides a window of opportunity for improvement of care. patients become ill 3 days before the ed visit and 41.1% already visited their gp previously during the current disease episode, while 23.9% is currently using antibiotics. future research should focus on quality improvement programs in the prehospital setting, targeting patients and/or primary care professionals. introduction: worldwide, the prevalence of tetanus has decreased.-however, even if progress has been made in the combat to eradicate tetanus it may be a cause of admission to intensive care.the objectives of our study are to determine epidemiological,clinical and prognostic characteristics for severe tetanus in our unit. methods: we conducted a retrospective study in the medical intensive care unit of ibn rushd hospital in casablanca in morocco from 2010 to 2016.we studied the epidemiological,clinical and prognostic characteristics of the patients who were admitted for severe tetanus. results: the incidence of severe tetanus was 2.04% affecting male in 100%.41.9% were aged between 31 and 40 years old. in 85.7% there were a integumentary portal of entry. contractures were present in 69%of the cases. at intensive care unit admission, 21.4% of the patients were sedated. the anti-tetanus vaccination was never updated. according to the dakar score 28.6% of the patients were listed dakar 1, 54.8% dakar 2 and 16.6% dakar 3. for the mollaret score, the crude form was found in 44.2%, the acute generalized form was found in 32.6% and the severe form in 20.9% of the cases.mechanical ventilation was necessary in 83.3%. diazepam and baclofen were used in 92.9%, phenobarbital in76.2% and propofol in 42.85%. a serotherapy was used for all the patients and a preliminary vaccination dose for 26.9%. all the patients received antibiotics, penicillin g 33.33% and metronidazole 76.2%. the mortality was 61.9%. the length of intensive care stay was significantly higher. the need for an intubation,its duration and the occurrence of autonomic dysfunction have significantly influenced the mortality. conclusions: to improve the prognosis in these serious forms of tetanus,it is highly important to identify the warning signs and refer patients in intensive care for early and appropriate management in intensive care. introduction: bloodstream infections (bsis) are associated with increased mortality in the icu. the aim of the study was to evaluate the epidemiology and resistance patterns during the period 2013 to 2017. methods: bacteria and fungi isolated from the blood of patients hospitalized in a mixed icu during the study period were retrospectively analyzed. sensitivity testing was performed with disk diffusion (kirby-bauer) and microscan walkaway 96 plus for minimal inhibitory concentrations. results: during the study period 1198 patients were hospitalized in the icu. bsis were diagnosed in 284 cases (23.7%). the isolated microorganisms were acinetobacter baumannii (29%), klebsiella pneumoniae (15%), other enterobacteriaceae (8%), pseudomonas aeruginosa (6%), stenotrophomonas maltophilia (1%), enterococci (20%), staphylococci (8%) and candida spp. (13%). of the a. baumannii isolates, 97% were resistant to carbapenems, 9.6% to colistin, and 31% to tigecycline. of the k. pneumoniae isolates 80% were resistant to carbapenems, 70% to colistin, and 4.5% to tigecycline. of the p. aeruginosa species 44% were resistant to carbapenems and they were all susceptible to colistin. the rate of resistance to vancomycin was 56% for the e. faecium isolates, 5.5% for the e. faecalis, while the resistance to methicillin of the coagulase negative staphylococci was 90%. the most commonly isolate species of candida was c. albicans. conclusions: multi-drug resistant isolates, especially a. baumannii and enterobacteriaceae, are a serious problem in our icu. gram positive bacteria are less common, but the resistance of enterococci to vancomycin is significant. antibiotic stewardship and infection control measures should be applied in a more strict way. nosocomial sinusitis in intensive care unit patients i titov 1 introduction: nosocomial sinusitis (ns) is a complication of critically ill patients which develops 48-72 h after admission and is mostly linked but not limited to such invasive procedures as nasotracheal intubation and nasogastric tube placement. ns is often overlooked as a source of pyrexia of unknown origin, meningeal manifestations, sepsis and ventilator associated pneumonia in icu patients. ct scanning and sinus puncture are used to confirm the inflammatory process and identify the pathogen behind it. methods: a retrospective case study of 6.479 icu patients for a period of 2012-2016 was performed. we have analysed data from the ct scans of paranasal sinuses and bacteriological findings of samples obtained from sinus puncture. results: 644 (9.9%) patients were suspected of ns on the 5-7th day of stay in the icu. the ct scan confirmed pathological changes in 464 patients (7.1%). hemisinusitis was detected in 422 patients (90.9%) and pansinusitis in 41 patients (8.8%). there was also an isolated case of maxillary sinusitis in 1 patient (0.2%). the pathogenic culture was identified only in 297 (64%) samples, 34.6% of which revealed isolated bacteria and 65.4% a polymicrobial association. gram positive bacteria were detected in 16.1% of cases and gram negative in 49.5%. most cases revealed multiple antibiotic resistance. conclusions: 1. ns has proved to be largely caused by gram negative bacteria and polymicrobial associations. the use of broad spectrum antibiotics in icu may justify the presence of sterile cultures. 2.early identification of risk patients in icu as well as the use of screening ct scan may benefit timely diagnosis and adequate treatment of patients. 3 .preventive considerations include: patient's bed head elevation, the use of oral gastric tube in sedated and coma patients on ventilation, nasotracheal intubation only if indicated, removal of nasogastric tube at night, proper hygiene. conclusions: only 78 of 4,011 tb patients (2%) required critical care intervention (table 1) . those admitted to icu were older and more likely to have pulmonary, cns, miliary or abdominal tb (table 2) . mortality was high despite critical care input in a unit familiar with managing tb, and 24 hour access to infectious diseases advice within the trust, likely due to overwhelming organ dysfunction, patient frailty and advanced tb infection. rates of drug resistant tb were low and comparable to uk-wide rates over that period (5% mono-drug resistant, 2% mdr) thus less likely a contributory factor to the majority of deaths. short term antibiotics prevent early vap in patients treated with mild therapeutic hypothermia after cardiac arrest t daix 1 , a cariou 2 , f meziani 3 , pf dequin 4 , c guitton 5 , n deye 6 , g plantefève 7 , jp quenot 8 , a desachy 9 , t kamel 10 , s bedon-carte 11 , jl diehl 12 , n chudeau 13 , e karam 14 , f renon-carron 1 , a hernandez padilla 1 , p vignon 1 , a le gouge 4 introduction: patients treated with mild therapeutic hypothermia after cardiac arrests with shockable rhythm are at high risk of ventilator-associated pneumonia (vap) [1] . despite retrospective trials suggesting a benefit of short-term (48h) antibiotics in this setting [2] , it is not recommended. the primary objective was to demonstrate that systematic antibiotic prophylaxis can reduce incidence of early vap (<7 days). the impact on incidence of late vap and on day 28 mortality was also assessed. methods: multicenter, placebo-controlled, double-blinded, randomized trial. icu patients >18 years, mechanically ventilated after out-of-hospital resuscitated cardiac arrest related to initial shockable rhythm and treated with mild therapeutic hypothermia were included. moribund patients and those requiring extracorporeal life supports, with ongoing antibiotic therapy, known chronic colonization with multiresistant bacteria or known allergy to beta-lactam antibiotics were excluded. either iv injection of amoxicillin-clavulanic acid (1g/200mg) or placebo was administered 3 times a day for 2 days. all pulmonary infections were recorded and blindly confirmed by an adjudication committee. results: in intention to treat analysis, 196 patients were analyzed, (treatment group n=99; mean age 60.5±14.4 years, sex ratio=4, sofa score 8.7±3.1). global characteristics of cardiac arrest were similar (no flow= 3.5min vs 3.8min, low-flow= 21.8min vs 18.2min). 60 vap were confirmed incl. 51 early vap, 19 in treatment group vs 32 in placebo group (hr=0.546; ic 95%=[0.315; 0.946]) (fig. 1) . occurrence of late vap (4% vs 5.1%) and day 28 mortality (41.4% vs 37.5%) was not affected by the study procedure. conclusions: short-term antibiotic prophylaxis significantly decreases incidence of early vap in patients treated with mild therapeutic hypothermia after out-of-hospital cardiac arrest related to shockable rhythm and should be recommended. introduction: antibiotics are the most commonly prescribed drugs in icu.in the era of antibiotic resistance it is difficult to choose antibiotics during septic episode.the choice antibiotics mainly depends on clinical diagnosis,culture sensitivity and local flora. whether severity of illness really maters is not well known. to study antibiotic prescription pattern and whether the choice of antibiotic varies according to hemodynamic stability in patients admitted in icu.to study of microbiological isolates and their variability according to hamodynamic stability in icu patients. methods: all icu patients of more than 18 years age who received antibiotics and where cultures had been sent were included in the study.patients discharged against medical advice and where treatment had been withdrawn were excluded in this study. this prospective observational study was conducted between july 2016 to march 2017.patients were divided into stable and unstable group according to hemodynamic parameter and usage of antibiotics and microbiological isolated were correlated. icu mortality and length of stay were correlated between hemodynamically stable and unstable group. results: 786 sepsis episode were analysed. mean age was 65 years, male predominant, and average apache iv score was 58(sd25). we had 444 patients in unstable group of which 71% patients got discharged and 86% of patients got discharged in stable group. antibiotic combination therapy was used more in hemodynamically unstsble patients(p 0.3). blbli was used more in stable group. drug resistance in microbiological isolates did not reveal any statistically significant difference among stable or unstable group. conclusions: there is a tendency to administer combination antibiotics in sicker group of patients with hemodynamic instability. prevalence of microbial flora did not show any statistical difference. outcome is worse in hemodynamically unstable patients. the clinical significance of candida score in critically ill patients with candida infection h al-dorzi 1 , r khan 1 , t aldabbagh 1 , a toledo 1 , s al johani 1 , a almutairi 2 , s khalil 2 , f siddiqui 2 , y arabi 3 1 king abdulaziz medical city, riyadh, saudi arabia, 2 msd, riyadh, saudi arabia, 3 king saud bin abdulaziz university for health sciences, riyadh, saudi arabia critical care 2018, 22(suppl 1):p065 introduction: candida score (cs) is used to identify patients with invasive candidiasis in the icu, but its clinical use has not become widespread. our objective was to evaluate the clinical significance of cs in a mixed population of icu patients. methods: this was a prospective observational study of critically ill patients who had candida species growth during their stay in any of six different icus of a tertiary-care center. two intensivists classified patients as having candida colonization or invasive candidiasis according to predefined criteria. cs was calculated for each patient on the day of candida species growth as follows: 1 . see text for description point for parenteral nutrition + 1 point for surgery + 1 point for multifocal candida colonization + 2 points for severe sepsis. the receiver operating characteristic (roc) curve was plotted to assess cs ability to discriminate between invasive candidiasis and candida colonization. results: cs was 1.6±0.9 in patients with candida colonization (n=261) and 2.4±0.9 in those with invasive candidiasis (n=120) (p<0.001). however, only 38.7% of invasive candidiasis cases had cs >= 3 (compared with 8.0% of candida colonization cases; p<0.001). the roc curve (fig. 1) showed that cs had fair ability to discriminate between invasive candidiasis and candida colonization (area under the curve 0.71, 95% confidence interval 0.65 to 0.77; p<0.001). in patients with invasive candidiasis, cs was similar in hospital survivors and nonsurvivors (2.2±0.9 and 2.5±0.8, respectively; p=0.13). cs did not discriminate between survivors and nonsurvivors (area under the roc curve 0.61, 95% confidence interval 0.46 to 0.75; p<0.15). conclusions: cs was higher in patients with invasive candidiasis than those with candida colonization. however, its ability to discriminate between these patients was only fair. cs was not associated with hospital mortality. poor reliability of creatinine clearance estimates in predicting fluconazole exposure in liver transplant patients m lugano, p cojutti, f pea asuiud, udine, italy critical care 2018, 22(suppl 1):p066 introduction: invasive candidiasis (ic) is a frequent complication in liver transplant (lt) recipients, especially during the first 1-3 months after lt. fluconazole is a triazole antifungal used for prophylaxis and treatment of ic. due to its renal elimination, dose adjustments are usually based on estimated creatinine clearance (ecrcl). however, the reliability of ecrcl in predicting fluconazole clearance has never been investigated in this population. the aim of this study was to conduct a population pharmacokinetic (poppk) analysis in a cohort of lt patients who underwent therapeutic drug monitoring (tdm) in order to find out which covariates may influence fluconazole pharmacokinetics (pks). methods: this retrospective study included lt patients who were admitted to the intensive care unit of our university hospital between december 2007 and may 2016, and who were treated with intravenous fluconazole in the first months after lt. tdm of fluconazole was performed with the intent of attaining the efficacy pharmacodynamic target (auc24h/mic > 55.2). the tested covariates were: age, gender, ckd-epi ecrcl, time from lt, serum albumin and transaminases, saps ii score. poppk was carried out with pmetrics software. results: nineteen patients (mean±sd age, weight and serum creatinine of 60±8.4 years, 75±16.8 kg, 1.0±0.62 mg/dl, respectively) with a total of 89 fluconazole trough plasma concentrations were included in the poppk analysis. mean±sd fluconazole distribution volume (vd) and clearance (cl) were 27.02±10.78 l and 0.55±0.19 l/h. age and time from lt were the only clinical covariates significantly correlated with fluconazole vd and cl, respectively. conversely, ckd-epi eclcr was unable to predict fluconazole cl. conclusions: ckd-epi eclcr is unreliable in predicting fluconazole exposure in lt recipients. consistently, in this population adaptation of fluconazole dose should be based on measured crcl, and tdm may be helpful in optimizing drug exposure. outcomes of a candidiasis screening protocol in a medical icu m boujelbèn 1 , i fathallah 1 , h kallel 1 , d sakis 1 , m tobich 1 , s habacha 1 , n ben salah 1 , m bouchekoua 2 , s trabelsi 2 , s khaled 2 , n kouraichi 1 introduction: the aim is to determine the incidence, characteristics and risk factors of invasive candidiasis (ic) in critically ill patients by using a weekly screening protocol. methods: a 9 months' prospective study was conducted in a 6-bed micu. the candidiasis screening consisted of the culture of plastic swabs (from different body sites), urine and respiratory tract samples.it was conducted upon admission and on weekly basis for all the patients. decision to treat was based on clinical and microbiological features. results: 97 patients were included. the colonization rate with candida spp was 28.8%(n=28). 415 screening samples were collected with a positivity rate at 27.9%(n=118). table 1 describes the isolated candida species by site. antifungal resistance was tested in 72(62%) species. the resistance rate to fluconazole was 13.8%(n=10). the antifungal resistance of candida albicans is detailed in table 2 . 14(14.4%) patients presented an ic with a mean age and mean saps ii at 54.3 ± 18 years and 48±18.7 respectively. 7(50%) presented acute renal failure upon admission. 85.7% (n=12) of the patients needed mechanical ventilation. the median length of stay was 29 days [18.5-62.5] and the mortality rate was 42.9%(n=6). the mean sofa score upon infection was 8.5±2.79. the candida score was >= 2.5 and the colonization index was >= 0.5 in fig. 1 (abstract p065). roc curve for candida score discrimintaing between invasive candidiasis and candida colonization 92.8%(n=13) and 78.5%(n=11) of the patients respectively. only one patient had a positive blood culture. mannan antigen and anti-mannan antibodies were screened only in five patients with a positivity rate at 100%(n=5). the most isolated species was: candida albicans 64.3%(n=9). multivariate analysis showed that prior use of imipinem more than 6 days was a risk factor for ic (or=9.37, ci95[1.15 ; 75.8], p=0.03). conclusions: this study showed the ecology and epidemiology of candida species in our micu with an increased ic rate and high mortality. prior imipinem use was a risk factor for ic. introduction: icu-acquired infection is as high as 42.7 episodes per 1000 patient-days in lower-middle income countries like india (who). almost three times higher than in high-income countries [1] . candida infection is the 3rd most commonly acquired nosocomial infection in india burdening the debilitated patient with longer icu stay [2] . there are no definite guidelines on whether & when to start antifungal treatment, specific to india where ifi risk is high and diagnostic facilities are limited. currently, the intensivists across india are using antifungals, according to their clinical experience and selective application of international guidelines leading to non-uniformity of patient outcomes. in an endeavour to synchronize anti-fungal therapy and educate intensivists from small cities of india, 2 intensivists and 1 infectious disease specialist of international repute were approached to design a module on 'invasive fungal infections -when to start anti-fungals in icu [ fig. 1 ]. the ifi in india was summarised into a compact 1 hour session for dissemination of knowledge using idsa 2016 as a reference guideline. 12 intensivists from across india were trained on the module by our faculty. the module was rolled out to intensivists and pulmonologists focussing particularly on the tier-2 & tier -3 cities where avenues for learning are limited [ fig. 2 introduction: trichosporon species are fungi found in nature and human normal flora but they can be an opportunistic pathogen, introduction: this study assessed whether empiric combination antibiotic therapy directed against gram-negative bacteria is associated with lower intensive care unit (icu) mortality compared to single antibiotic therapy. methods: retrospective cohort study on prospectively collected data conducted in the icu of a tertiary care hospital in india between july2016 to march2017. all consecutive infection episodes treated with empiric antibiotic therapy and with subsequent positive culture for gram-negative bacteria were included. primary and secondary outcomes were all cause icu mortality and icu length of stay (los). outcomes were compared between infection episodes treated with single vs.combination antibiotic therapy. results: of total 214 episodes of gram-negative infections 66.4% received combination-antibiotic therapy. baseline demographic and clinical characteristics between single vs. combination therapy groups were similar (mean age: p=0.07; sex: p=0.3; mean apache iv score: p=0.07). overall icu mortality did not significantly differ between single and combination antibiotic groups (30.2% vs. 27%; p=0.7). in single antibiotic group, icu mortality was significantly higher for antibiotic-resistant compared to antibiotic-sensitive bacteria (77.8% vs. 18.5%, p=0.0002). in combination group, significantly lower icu mortality was noted if bacteria was sensitive to even one antibiotic compared to pan-resistant bacteria (21.4% vs. 63.6%, p=0.0001). icu los was similar between antibiotic-sensitive bacteria and antibiotic-resistant bacteria, both in single and combination therapy groups (single, antibiotic-sensitive vs. antibiotic-resistant: mean los±sd 14.6±12.7 vs.12.8±11days; p=0.6; combination, antibioticsensitive vs. antibiotic-resistant: 15.5±13.3 vs.11.2 days; p=0.1). conclusions: irrespective of the number of antibiotics prescribed as empiric therapy, outcome of patients solely depends on the sensitivity pattern of the bacteria isolated. pharmacokinetics of trimethoprim and sulfametrole in critically ill patients on continuous haemofiltration r welte 1 , j hotter 1 , t gasperetti 1 , r beyer 1 , r introduction: the combination of trimethoprim and sulfametrole (tmp-smt, rokiprim®) is active against multi-drug resistant bacteria and pneumocystis jirovecii. in critically ill patients undergoing continuous veno-venous haemofiltration (cvvh), however, its use is limited because of lacking pharmacokinetic data. methods: pharmacokinetics of both drugs were determined after standard doses in patients on cvvh and in critically ill patients with approximately normal renal function. quantification of tmp and smt was done by high pressure liquid chromatography (hplc) and uv detection after pre-purification by solid phase extraction. the total clearance (cltot) was estimated from arterial plasma levels and the haemofilter clearance (clhf) from plasma and ultrafiltrate concentrations. results: six patients on cvvh (3 after the first dose, 3 at steady state) and nine patients off cvvh have been enrolled (4 after first dose, 7 at steady state). after a single dose, cltot of smt was 3.5 (1.8-3.8, median [range]) and 1.7 (1.1-2.7) l/h on and off cvvh, respectively. at steady state, we observed a cltot of 1.0 (0.5-1.0) and 0.3 (0.2-0.9) l/h, respectively, on and off cvvh. steady state trough levels (cmin) of smt amounted to 52-113 mg/l in patients on cvvh and 18-145 in patients off cvvh. cltot of tmp was 4.4 (2.5-5. 3) l/h on cvvh and 5.4 (3.2-9.9) l/h off cvvh after the first dose. at steady state, its cltot amounted to 0.8 (0.4-0.8) and 1.0 (0.6-1.9) l/h on and off cvvh, respectively. cmin was 4-12 mg/l on cvvh and 3-9 mg/l in patients off cvvh. clhf accounted for 22-68% of cltot of smt and 28-72% of cltot tmp. conclusions: exposure to both antimicrobial agents is highly variable, but comparable in patients on and off cvvh. as considerable amounts of smt and tmp are eliminated by cvvh, no excessive accumulation appears to take place during treatment with standard doses. the positive impact of meropenem stewardship intervention at a brazilian intensive care unit w freitas 1 introduction: loss of colistin as a clinical option has profound public health implications. widespread use of colistin in agriculture and humans has seen the emergence of mcr-1 mediated resistance amongst south african patients [1] . we sought to describe the trends of colistin minimum inhibitory concentrations (mic) over two years using data collected by smart. methods: smart monitors the in vitro susceptibility of clinical aerobic and facultative gram-negative bacterial isolates to selected antimicrobials of importance, enabling longitudinal analyses to determine changes over time. the dataset comprised bacterial isolates from four different south african private pathology laboratories and one public sector pathology laboratory from 2015 -2016. the methods used in the study have been described elsewhere [2] . isolate proportions between years were compared using the chisquared test with yates' continuity correction. (2) (3) (4) (5) days]; 4 patients underwent renal replacement therapy. the median treatment duration (iqr) was 14 (13-14) days. in 41.6% of cases, antibiotic-therapy therapy combination (phosphomycin and colistin) was chosen. all the patients experienced a clinical response by 72/96 hours from the ceftazidime/avibactam commencing. in 8/ 9 bacteraemic patients negativization of blood culture occurred by 96 hours as well as of the rectal swab in 5/14 patients. a (b) recurred and a second treatment was given. 11/14 (78.5%) patients survived, whereas death was caused by multi-organ failure. the susceptibility test of strains showed sensitivity to ceftazidime/avibactam, whereas 100% of resistance to carbapenems, quinolones and iii/iv generation cephalosporin, tigecycline and piperacillin/tazobactam; 62.5% of susceptibility to fosfomycin and colistin; (v) less than 50% of suceptibility to aminoglicosides. conclusions: the 14 strains of kp-cp were susceptible to ceftazidimeavibactam despite the high carbapenem-resistance recorded in our icu, because od rare identification of kp-cp vim/ndl +. the preliminary data seems to confirm the efficacy and clinical utility of this antibiotic for the critically ill patients. introduction: multidrug resistant bacteria (mdr) are an increasing problem on intensive care units. lung infections caused by acinetobacter baumannii are frequently difficult to treat. phages have regained attention as treatment option for bacterial infections due to their specificity and effectivity in lysis. the aim of this preclinical study was to determine efficacy and safety of a novel phage preparation in mice. methods: mice were transnasally infected with a mdr a. baumannii strain [1] and 12 hours later treated intratracheally with a specific phage or solvent. phage acibel004 [2] was produced as suspension including efficient depletion of endotoxins. at defined time points, clinical parameters, bacterial burden in lung and bronchoalveolar lavage fluid (balf) and cell influx were determined. further, lung permeability and cytokine release were quantified and histopathological examination was performed. results: mice treated with phages recovered faster from infectionassociated hypothermia. 48 hours after infection, phage treatment led to a reduction in bacterial loads in lungs and balf. in addition, lung permeability and cytokine production were reduced in phagetreated mice. histopathological examination of the lungs showed less spreading of bacteria to the periphery in phage-treated mice, whereas cellular recruitment into the lung was unaffected. no adverse effects were observed. conclusions: for the first time a highly purified phage against a. baumannii was successfully used in vivo. the current preclinical data support the concept of a phage-based therapy against pulmonary a. baumannii infections. introduction: vap is common in critically ill patients and associated with high morbidity and mortality, especially when caused by antibiotic resistant bacteria. recently, phage therapy has emerged as a promising non-antibiotic based treatment of antibiotic resistant bacterial infections. however, proof-of-concept experimental and clinical studies are missing before its wider use in clinical medicine. the goal of this experimental study was to compare the efficacy of phage therapy versus antibiotics for the treatment of mrsa in a rat model of vap. methods: four hours after intubation and protective ventilation, rats were inoculated via the endotracheal tube with 6-9 x 10 9 cfu (ld100) of the mrsa clinical isolate aw7. the animals were subsequently extubated. two hours after bacterial challenge, rats were randomised to receive intravenously either teicoplanin (n= 8), a cocktail of 4 lytic anti-s. aureus bacteriophages (n=9) or combination of both (n=6). 5 animals served as control (no treatment). survival by 96 hours was the primary outcome. secondary outcomes were bacterial count in lungs, spleen and blood. kaplan-meier estimates of survival were done and multiple comparisons of survival rates performed using the holm-sidak method. results: treatment with either phages, antibiotics or combination of both significantly increased survival (66%, 50%, 50% respectively, compared to 0% survival for controls, p<0.05). there were no statistical differences in survival rates between either forms of treatment ( fig. 1) . treatments hinder the systemic extension of the infection into the blood and spleen without impacting bacterial counts within the lungs, but the numbers are too small to perform statistical tests (table 1) introduction: the aim of the study was comparative evaluation of the clinical and microbiological efficacy of combination of amikacin thru nebuliser aeroneb pro and standard antimicrobal therapy (amtcomb) with standard antimicrobal therapy (amtst) in treatment of ventilator-associated pneumonia (vap) and ventilator-associated tracheobronchitis (vat) caused by multi-drug resistant gram-negative bacteria. methods: in prospective two-center study with retrospective control included patients with vap and vat. in amtst group (retrospective, n=25) we used combination of meropenem 1 g every 8h iv as continuous infusion, cefoperazon/sulbactam 4 g every 12 h iv as continuous infusion and amikacin 1 g iv every 24 h. in amtcomb group (prospective, n=25) we used combination of amtst and amikacin inhalation 500 mg every 12 h thru nebuliser aeroneb pro. results: in amtcomb clinical cure rate was 84%, while in amtst 29.2% (p<0.001), clinical pulmonary infection score (cpis) on day 7 was 6 (4-7) points in amtst and 2 (0-4) points in amtcomb (p<0.001). recurrence of vap/vat was 29.2% in amtst and 12.5% in amtcomb (p=0.008). on day 7 infectious agent titer in tracheal aspirate was 10 7 (10 3 -10 8 ) cfu/ml in amtst group, while 10 3 (no growth-10 6 ) cfu/ml in amtcomb (p=0.016). microbiological eradication observed in 13 patients in amtcomb vs in 1 patient in amtst and microbiological persistance observed in 6 patients in amtcomb vs 17 patients in amtst (p=0.002). in amtcomb on 3rd day sputum was less purulent (p=0.016). amikacin nebulisation didn't led to deterioration of organ dysfunction: on day 7 there was no difference in platelet count, creatinine and bilirubin levels as compared to day 0 (p=0.102; p=0.297, p=0.532, respectively). conclusions: addition of amikacin inhalation 500 mg every 12 h thru aeroneb pro nebuliser in patients with vap and vat was more efficacious than intravenous standard antimicrobal treatment with comparable safety profile. introduction: the aim of the study was to assess the effectiveness of inhaled colistin (ic) as an adjunct to systemic antibiotics in the treatment of ventilator-associated pneumonia (vap). methods: 110 icu patients with vap were enrolled in this observational study. resolution of vap was assessed as primary endpoint; eradication of pathogens in sputum, weaning time, duration of icu stay and mortality were assessed as secondary outcomes. patients were split into 2 groups: gr.1 (n = 60) -addition of ic to systemic antibiotics without changing the basic regimen; gr. 2 (n = 50) -change in systemic antibiotics according to sensitivity. groups were comparable. ic was administered in a dose of 2 million iu tid (xselia pharmaceuticals aps, denmark). statistical analysis was performed using statistica 7.0 (m, σ, newman-keuls test; p <0.05). results: vap resolution rate was 77% in gr.1 (vs. 50% in gr. 2, p = 0.0295); eradication of pathogens from sputum by the 7th day. treatment was achieved in 80% of gr. 1 and 60% in the gr. 2 (n = 12) (p> 0.05); in gr. 1 weaning from ventilation was possible earlier than in gr. 2 -7.8±1.3 days. in gr. 1 vs. 10.9±4.5 days. in gr. 2 (p = 0.0000); in gr. 1 duration of icu stay was shorter than in gr. 2 -11.5±3.2 days vs. 17.1±2.3 days. in gr. 2 (p = 0.0000). no mortality differences were detected. conclusions: administration of inhaled colistin 2 million iu tid is effective as an adjunct to systemic antibiotics in the treatment of vap. this modified treatment promotes a more rapid resolution of vap, earlier weaning from ventilator, reduction of the duration of icu stay, with no impact on mortality. the addition of ic to systemic antibiotics should be considered as second-line regimen in vap patients. factors associated with no de-escalation of empirical antimicrobial therapy in icu settings with high rate of multi-drug resistant bacteria c routsi 1 introduction: de-escalation is recommended in the management of antimicrobial therapy in icu patients [1] . however, this strategy has not been adequately evaluated in the presence of increased prevalence of multidrug-resistant (mdr) bacteria. the aim of this study was to identify factors associated with no de-escalation in icus with high rate of mdr bacteria [2] . methods: prospective, multicenter study conducted in 12 greek icus over a 1-year period. patients with laboratory confirmed infections were included. sofa score on admission, on septic episode and thereafter every 24 h over 14 days, infection site(s), culture results, antimicrobial therapy, and mortality were recorded. only the first septic episode was analyzed. in order to assess the factors associated with no de-escalation, a multivariate analysis was performed. results: a total of 211 patients (admission sofa score 10±3) were analyzed. 43% of those had septic episode on icu admission; 57% patients had an icu-acquired. de-escalation was applied to 44 (21%) patients whereas it was not feasible in 75 patients (44 %) due to the recovery of mdr pathogens or it was not applied, although the microbiology results allowed it, in 92 patients (56 %). septic shock on the day of septic episode was present in 67% and 79% of patients with and without de-escalation, respectively, p=0.072). compared to no de-escalation, de-escalation strategy was associated with a shorter duration of shock (4 ±5 vs. 9±7 days, p<0.001) and all-cause mortality (15.4% vs. 46.4%, p<0.001). multivariate analysis showed that the variables associated with no de-escalation were: a deteriorating clinical course as indicated by an increasing sofa score (or 14.7, p<0.001) and a lack of de-escalation possibility due to recovery of mdr pathogens (or 27.3, p=0.008). conclusions: deteriorating clinical course and mdr pathogens are independently associated with no de-escalation strategy in critically ill patients. conclusions: the qsofa scale in the prognosis of sepsis does not differ significantly from the sirs criteria, but in the prognosis of mortality is significantly better than sirs. qsofa significantly worse in the prognosis of sepsis and death than the sofa scale. the international task force of sepsis-3 introduced the quick sequential failure assessment (qsofa) score to supersede the systemic inflammatory response syndrome (sirs) score as the screen tool for sepsis. the objective of this study is to prospectively access the diagnostic value of qsofa and sirs among patients with infection in general wards. methods: a prospective cohort study conducted in ten general wards of a tertiary teaching hospital. for a half-year period, consecutive patients who were admitted with infection or developed infection during hospital stay were included. demographic data and all variables for qsofa, sirs and sofa scores were collected. we recorded daily qsofa, sirs and sofa scores until hospital discharge, death, or day 28, whichever occurred earlier. the primary outcome was sepsis at 28 days. discrimination was assessed using the area under the receiver operating characteristic curve (auroc) and sensitivities or specificities with a conventional cutoff value of 2. results: of 409 patients (median age, 55 years [iqr, 40-67]; male, 225[55%]; most common diagnosis pneumonia, 234[57%]) who were identified with infection in general wards, 229(56%) developed sepsis at a median of 0 (iqr, 0-1) day, 146 patients (36%) and 371 patients (91%) met qsofa and sirs criteria at a median of 1 (iqr, 0-5) and 0 (iqr, 0-0) day, respectively. the qsofa performed better than sirs in diagnosing sepsis, with an auroc of 0.75 (95% ci, 0.71-0.79) vs 0.69(95% ci, 0.64-0.74). with a conventional cutoff value of 2, qsofa had lower sensitivity (53% [95% ci, 47%-60%] vs. 98% [95% ci, 95%-99%], p < 0.001) and higher specificity (87% [95% ci, 81%-91%] vs. 18% [95% ci, 13%-23%], p < 0.001) than sirs (table 1) . conclusions: among patients with infection in general wards, the use of qsofa resulted in greater diagnostic accuracy for sepsis than sirs during hospitalization. qsofa and sirs scores can predict the occurrence of sepsis with high specificity and high sensitivity, respectively. prognostic accuracy of quick sequential organ failure assessment (qsofa) score for mortality: systematic review and meta-analysis introduction: the purpose of this study was to summarize the evidence assessing the qsofa [1] , calculated in admission of the patient in emergency department (ed) or intensive care unit (icu), as a predictor of mortality. the hypothesis was that this tool had a good prediction performance. methods: systematic review and meta-analysis of studies assessing qsofa as prediction tool for mortality found on pubmed, ovid, embase, scopus and ebsco database from inception until november 2017. the primary outcomes were mortality (icu mortality, inhospital mortality, 30 and 90-day mortality). studies reporting sensitivity and specificity of the qsofa making it possible to create a 2x2 table were included. the diagnostic odds ratio (lndor) was summarized following the approach of dersimonian and laird using the software r ('mada' package). the summary roc curve was created using the reistma model (bivariate model). the revman 5 software was used to organize the data. results: the search strategy yielded 266 citations. of 134 unique citations, 48 met the inclusion criteria (426,618 patients). the sensitivity and specificity from each study are shown in fig. 1 . the meta-analysis of the dor was 4.838 (95% confidence interval (ci): 3.808 -6.146) and of the lndor was 1.576 (95% ic: 1.337 -1.816) (fig. 2) . the pooled area under the summary receiver operating characteristic (sroc) curve was 0.717. the summary estimative of the sensitivity was 0.55 and the false positive rate was 0.209, by bivariate diagnostic random-effects metaanalysis. the chi-square goodness of fit test rejects the assumption of homogeneity, and the fit of the model for heterogeneity was better (p-value = 0.3661). conclusions: the qsofa has a poor performance to predict mortality in patients admitted to the ed or icu. introduction: sepsis and septic shock patients are the most common cause of death in intensive care units. [1] the aim of this study is to quantify the relationship between 72 hours sequential organ failure assessment (sofa) scores change and in-hospital mortality as a treatment outcome in sepsis and septic shock patients. introduction: an outreach team, akin to a rapid response team, is made up of healthcare professionals assembled together for quick and effective reviews in managing of rapidly deteriorating or gravely deteriorated patients [1] . this study aimed to look at the variety of patient referrals in terms of their severity, patient dynamics, reasons for referral and their subsequent dispositions. methods: 258 patient records were randomly reviewed retrospectively from july to october 2017. data were collated in an excel spreadsheet for comparison and then sorted in accordance with the clinical questions and percentages calculated. results: from the 258 referrals, the severity criteria was done by calculating the national early warning score (news). it was found that 51% patients had a score of 0-4, 23% had a score of 5-6, and 26% scored more or equal to 7. 50% of patients were in the age range 61-70 years old. 78% referrals came from the emergency department (ed) where a consultant was involved in the decision of the referral; of this, 46% were referred during office hours of 8am to 5pm where there was greater manpower to aid management. 19% referrals came from inpatients on the general wards; 32% were done during office hours. 65% of referrals were transferred to ic/hd upon review; 35% were not, from whom 9 died and 7 were later admitted after procedures (2%) or because they deteriorated further (1%). for reasons for referrals and disposition decisions, see fig. 1 . conclusions: despite having no set criteria for outreach team referrals, the accuracy rate was nearly 65% admissions to ic/hd based on clinician concerns. there was only 1% re-admission rate having been re-reviewed when the patients had not been deemed suitable for ic/hd admission initially. therefore referrals were done accurately and safely with the protocol of clinician referral openness directly to ic consultants. introduction: prompt recognition of patient deterioration allows early initiation of medical intervention with reduction in morbidity and mortality. this digital era provides an opportunity to harness the power of machine learning algorithms to process and analyze big data, automatically acquired from the electronic medical records. the results can be implemented in real-time. intensix (netanya, israel) has developed a novel predictive model that detects early signs of patient deterioration and alerts physicians. in this study we prospectively validated the ability of the model to detect patient deterioration in real time. methods: the model was developed and validated using a retrospective cohort of 9246 consecutive patients admitted to the intensive care unit in the tel-aviv sourasky medical centera tertiary care facility in israel, between january 2007 and december 2015. in this study, we tested model performance in real time, on a cohort of 333 patients admitted to the same icu between june 2016 and august 2017. significant events that lead to major interventions (e.g. intubation, initiation of treatment for sepsis or shock, etc.) were tagged upon medical case review by a senior intensivist, blinded to model alerts. these tags were then compared with model alerts. [3] [4] [5] [6] . 1240 reviews occurred despite 'low news' (fig. 1) . rrt review led to cc admission in 315 (31.2%) cases; median [iqr] news 5 [3] [4] [5] [6] [7] [8] . probability of admission increased with higher news (fig. 1 ), however 82 admissions had 'low news'. of these 51 were excluded due to high news trigger in the preceding 24hrs or post-operative status. the remaining 31 (9.8%) represented genuine low news cases; age 54 [36-64], 50% male, admission apache ii 12 [8-17] and day 1 sofa 2 [1] [2] [3] [4] [5] . admission source was emergency department 29%, medical 42%, surgical 29%. diagnoses are shown in table 1 . no low news patients with sepsis were qsofa positive. cc length of stay was 2 [1] [2] [3] [4] days and icu mortality was 9.6%. conclusions: a high proportion of rrt activity occurs at low levels of abnormal physiology. despite an association between news and cc admission, news fails to trigger for approximately one in ten admitted cases. clinical concern remains an important component of the escalation of acutely ill patients. meanwhile, novel markers of deterioration should be sought and validated. introduction: although rapid response systems are known to reduce in-hospital cardiac arrest rate, their effect on mortality remains debated. the rapid response call (rrc) is a system designed to escalate care to a specialised team in response to the detection of patient deterioration. there are diurnal variations in hospital staffing levels that can influence the performance of rapid response systems and patient outcomes. the objective of this study was to examine the relationship between the time of rrc activations and patient outcome. methods: review of retrospectively collected, linked clinical and administrative datasets, at a private hospital during a 34-month period. all patients with medical emergency team activation were included. rapid response calls occurring between 18:00-07:59 were defined as 'out of hours'. results: between january 2015 and october 2017 there were 209 rrc. the trigger for rrcs activation was nurse concern (101; 38.3%), modified early warning score (80; 28.3%) and cardiac arrest (28; 13.4%). 44 rrcs were "out of hours" being the main activation trigger a modified warning score > 5. "out of hours" patients had higher icu admissions (31.7% versus 20%) and were more likely to have an inhospital cardiopulmonary arrest (or=1.4, p<0.002). conclusions: the diurnal timing of rrcs appears to have significant implications for patient outcomes. out of hours calls are associated to a poorer outcome. this finding has implications for staffing and resource allocation. and septic shock) and severe sepsis (incl. septic shock) using icd-10 codes coded as primary and secondary discharge diagnoses and procedural ops codes. we assessed incidences and discharge disposition incl. mortality. results: incidences, mortalities and discharge disposition comparing 2010 and 2015 and the mean annual increase in incidence rates are reported in tables 1 and 2 . conclusions: the annual increase in standardized sepsis incidence rates is greater than in infections, but similar to the increase in infectious disease patients with organ dysfunction, which are less prone to coding incentives than sepsis codes. an increasing number of patients is discharged to nursing homes and hospice. given the alarming increase in sepsis cases and deaths, this analysis confirms sepsis as a key priority for health care systems. introduction: patients with urgent admissions to the hospital on weekends may be subjected to a higher risk of worse outcomes, which may be due to differences in compliance to established processes. because delays to antibiotic administration is an important measure of sepsis protocol efficiency and has been associated to worse outcomes, we aimed to assess the association of the weekend effect (admissions on weekend) with timing to antibiotic administration. methods: patients included in the sepsis protocol in the emergency department (ed) of hospital sao rafael, from january 2016 to july 2017 were retrospectively evaluated. sepsis protocol is supposed to be activated to every patient with a suspected sepsis diagnosis in the ed. we evaluated the association of weekend (saturday or sunday) admission with timing to antibiotic administration. introduction: current sepsis guidelines emphasize resuscitation of hypotension to a mean arterial pressure (map) of at least 65 mmhg [1] . a map less than 90 mmhg appears to be associated with poor outcomes in postoperative patients in the intensive care unit (icu) [2] . however, extent of hypotension in critically ill septic patients during icu stay and its relationship with adverse outcomes is poorly defined. we determined the magnitude of hypotension in icu patients with a diagnosis of sepsis and its association with major complications. conclusions: reduced mortality may be supposed to be correlated to a quicker recovery of organ damage sepsis related. pcrts should be warranted in the future to corroborate these preliminary data. introduction: the pd-1/pd-l1 immune checkpoint pathway is involved in sepsis-associated immunopathy. we assessed the safety of anti-pd-l1 (bms-936559, bristol-myers squibb) and its effect on immune biomarkers and exploratory clinical outcomes in participants with sepsis-associated immunopathy. methods: participants with sepsis/septic shock and absolute lymphocyte count <=1100 cells/μ l received bms-936559 i.v. (10-900mg; n=20) or placebo (pbo; n=4) + standard of care and were followed for 90d. primary endpoints were death and adverse events (aes); secondary endpoints were monocyte (m)hla-dr levels and clinical outcomes. methods: this observational study was performed using a prospective, multi-center registry of septic shock. we compared the 28-day mortality between patients who were excluded from the new definition (defined as <2 mmol/l after volume resuscitation) and those who were not (lactate level >=2 mmol/l after volume resuscitation), from among a cohort of patients with refractory hypotension, and requiring the use of vasopressors. results: of 567 patients with refractory hypotension, requiring the use of vasopressors, 435 had elevated lactate levels, while 83 did not have elevated lactate levels (neither initially nor after volume resuscitation), and 49 (8.2%) had elevated lactate levels initially, which normalized after fluid resuscitation (fig. 1 ). thus, these 49 patients were excluded by the new definition of septic shock. significantly lower 28-day mortality was observed in these patients than in those who had not been excluded (8.2% vs 25.5%, p=0.02). conclusions: it seems reasonable for septic shock to be defined by the lactate levels after volume resuscitation, however due to small sample size further large scale study is needed. results: significant downregulation (p<0.01) of about 30 pro-and anti-inflammatory cytokines, including il-6, ip-10, tnf-a, mip-1a, mip-1ß, il-10, was documented. ifn-g effect on macrophages and dendritic cells was inhibited at the level of phosphorylated stat1. ifn-ginduced expression of cxcl10 and cxcl9 in macrophages was reduced. patients treated in vivo with higher dosages of apoptotic cells had lower cytokine/chemokine levels compared to those treated with lower levels, and in inverse correlation to agvhd staging. in vitro binding of apoptotic cells to lps was documented. conclusions: the cytokine storm is significantly modified towards homeostasis following apoptotic cell treatment. the mechanism is multifactorial and was shown to include tam receptor triggering, nfkb inhibition, and lps binding. these results together with previous studies showing significantly higher murine survival in sepsis models of lps and cecal ligation puncture suggest that apoptotic cells may be used to treat patients with sepsis. a multicenter clinical trial in septic patients is planned in 2018. moreover, the urine output significantly increased in survival group. conclusions: the present study suggests that cytokine-oriented critical care using pmma-chdf might be effective the treatment of sepsis and ards, particularly,in the treatment of ards associated with aspiration pneumonia in elderly patients. the polymyxin b immobilized fiber column direct hemoperfusion has an effect for septic shock but has no effect on sepsis: a cohort study and propensity-matched analysis k hoshino 1 introduction: overwhelming cytokine release often referred to as "cytokine storm" is a common feature of septic shock, resulting in multiple organ dysfunction and early death. attenuating this cytokine storm early by eliminating cytokines may have some pathophysiological rationale. our aim was to investigate the effects of extracorporeal cytokine removal (cytosorb) therapy on organ dysfunction and inflammatory response within the first 48 hours from the onset of septic shock. methods: patients with: sepsis of medical origin, on mechanical ventilation, noradrenaline >10mg/min, procalcitonin >3ng/ml and no need for renal replacement therapy, were randomized into cytosorb and control groups. cytosorb therapy lasted for 24 hours. in addition to detailed clinical data collection, blood samples were taken to determine il-1, il-1ra, il-6, il-8, il-10, tnf-α, pct, crp levels. introduction: blind pericardiocentesis leading to low success rate and high complication rates such as ventricular wall or oesophageal perforations, pneumothorax or upper abdominal organ injury.real time needle visualisation is allowing us to avoid this major complication [1] . methods: we presented 2 cases of acute traumatic cardiac tamponade secondary to severe chest injury. both patients presented with haemodynamic instability and echocardiographic features of pericardial tamponade. pericardiocentesis under ultrasound guidance at left parasternal area with needle directed from medial to lateral technique were performed (fig. 1) . real time needle tip visualisation done throughout the procedure (fig. 2a) . needle placement in pericardial space was confirmed with agitated saline and guidewire visualisation (fig. 2b) . pigtail catheter was inserted and blood was aspirated until the patient were haemodynamically improved. repeated ultrasound was done to confirm the absence of ultrasonographic features of tamponade and complications. results: we demonstrated a successful real time needle visualisation ultrasound guided pericardiocentesis in 2 cases acute traumatic pericardial tamponade. procedural time (time from needle piercing the skin to time needle entering the pericardium) in both cases were less than 1 minute. post procedural ultrasound confirmed no major complications. conclusions: the real time needle visualisation using ultrasound was important to reduce major complications during pericardiocentesis. the safety of the highly invasive procedure can be improved with real time needle visualisation. osman a et al. eur j emerg med (in press), 2017 introduction: diagnosis of cardiac tamponade post continuous-flow left ventricle assist devices (cf-lvads) is challenging due to missing pulsatility. recent case study of sublingually microcirculation with incident dark-field imaging (idf) provide a new improved imaging for clinical assessment of cardiac tamponade in a patient with cf-lvad. we sought to examine the changes in microvascular flow index (mfi) as a sign of cardiac tamponade following lvad implantation. methods: off-site quantitative analysis of sublingual microcirculation clips with automated vascular analyses software (ava; microvision medical©), and the velocity distributions followed during admission till discharge in patients with end-stage heart failure treated with cf-lvad complicated by cardiac tamponade. results: eleven out of thirty lvad implantations, 9 males, mean age 58 ± 10 years, april 2015 to january 2017, ((8 heart mate 3 (hm 3) and 3 heartmate ii (hm ii) (thoratec corp., ca)), were complicated by rethoracotomy due to early postoperative cardiac tamponade within 1 week. there sublingual microcirculation was examined by a novel incident dark-field imaging (idf) before and daily post-lvad implantation. pre-lvad microcirculation was typical for heart failure, characterized by slowly, sludging movement of red blood cells (rbcs), (fig. 1a arrows) . directly after implantation, a normal microcirculatory flow was seen with a high rbcs velocity (fig. 1b) . on the day of tamponade the patients were stable except for severe failure of microcirculation as reflected by drop in mfi (fig. 1c ) and congestion in venules (* in fig. 1c ). in 8 out of 11 patients there was a significant drop in mfi before tamponade was clinically recognized (p<0.05). shortly after rethoracotomy a quick restoration of microcirculatory flow has been found. conclusions: sublingual microcirculation imaging is a simple and sensitive non-invasive tool in early detection of cardiac tamponade. survey on the use of cardiovascular drugs in shock (ucards) results: a total of 827 physicians responded. as detailed in table 1 , the respondents think that dobutamine is first-line inotrope to increase cardiac pump function (n=695, 84%) and should be started when signs of hypoperfusion or hyperlactatemia despite adequate use of fluids and vasopressors in the context of low left ventricular ejection fraction are present (n=359, 43%). the most accepted target was an adequate cardiac output (n=369, 45%). the combination of noradrenaline and dobutamine was preferred to single treatment with adrenaline mainly due to possibility to titrate individually (n=366, 44%). the main reason for adding another inotrope was to use synergistic effects of two different mechanisms of action (n=229, 27%). according to respondents, phosphodiesterase-inhibitors should be used in the treatment of predominant right heart failure because of prominent vasodilatory effect on the pulmonary circulation (n=360, 44%). they also believe levosimendan is the only inotrope that does not increase myocardial oxygen demand (n=350, 42%). vasodilators are used in cardiogenic shock to decrease left ventricular afterload (n=244, 30%). there is no experience or no opinion about the use of ß-blockers in shock states (n=268, 32%). conclusions: this web-based survey provided latest trends on inotrope use in shock states which showed considerable diversity among respondents in opinions about its use. introduction: recent literature data clearly indicated that in patients with shock the resuscitation of macro-circulation often does not match with microcirculation and tissue perfusion improvement. unfortunately, the bed-side assessment of regional perfusion remains difficult, particulary in critically ill patients. in the last years thermography has been used in different medical fields but no studies have been performed on the use of this technique in critically ill patients. the aim of this study was to evaluate whether thermography is feasible and may provide useful data during resuscitation of patients with septic shock. methods: in 4 patients with septic shock we collected central systemic temperature and infrared images (flir-t640 digital camera) of limbs at 0, 3, 6 and 24 hours after shock occurrence. thermal pattern distribution of the limbs was obtained by a specific analysis of the images (thermacam™researcher p). a systemic to peripheral temperature gradient called "δ systemic-limb temperature" was calculated for each single temperature data collected. results: macrocirculatory and perfusion parameters improved in all the patients throughout the study period: mean values of noradrenaline dose decreased from 0.21 to 0.13 γ/kg/min, mean map increased from 65 to 81 mmhg and mean blood lactate decreased from 6.6 to 4.2 mmol/l. the "δ systemic-limb temperature" pattern showed an heterogenous time course in the 4 patients with a mean overall increase at 6 and 24 hours (fig. 1) . conclusions: as expected, the regional data obtained by thermography did not match with macrocirculatory and systemic perfusion parameters. the significance and the relationship between treatments and data observed will be investigated by appropriate studies. regional differences in the treatment of refractory septic shockan analysis of the athos-3 data introduction: vasodilatory shock is a common syndrome with high mortality. despite established care protocols, regional differences in treatment remain. we sought to characterize these differences using data from the recently published athos-3 study [1] . methods: individual patient data were analyzed at baseline and at 48h for regional differences in demographics, clinical characteristics, and treatment patterns, and grouped according to four geographical areas: the united states (us), canada (ca), europe (eu) and australasia (au). p-values were calculated by kruskal-wallis tests for continuous data and chi-square tests for categorical data. subsequent temporal analysis compared changes in the treatment of shock, indexed by changes in patient acuity level. results: regional differences existed with respect to bmi (p=0.0076), albumin (p<0.0001), cvp (p=0.0383), meld score (p=0.0191), apache ii score (p=0.0007) and sofa score (p=0.0076). baseline norepinephrine (ne) and ne equivalent doses were significantly higher in eu (p<0.0001 and p=0.0494, respectively), and utilization of vasopressin was correspondingly lower (p<0.0001). at baseline, stress dose steroids were utilized to a greater extent in the us and ca (p=0.0011). temporal analysis revealed differences in the utilization of vasopressin and steroids with changes in patient acuity: in eu, increasing acuity was associated with a lower utilization of vasopressin, and in ca, increased acuity was associated with a lower utilization of steroids. steroid utilization was higher with increased level of acuity in au and the us. conclusions: significant differences in the treatment of vasodilitory shock exist globally, with important implications: (a) there are introduction: levosimendan is a calcium sensitizer and katp-channel opener exerting sustained hemodynamic and symptomatic effects. in the past fifteen years, levosimendan has been used in clinical practice also to stabilize at-risk patients undergoing cardiac surgery. recently, the three randomized, placebo-controlled, multicenter studies licorn [1] , cheetah [2] and levo-cts [3] have been testing the peri-operative use of levosimendan in patients with compromised cardiac ventricular function. over 40 smaller trials conducted in the past [4] suggested beneficial outcomes with levosimendan in peri-operative settings. in contrast, the latest three studies were neutral or inconclusive. we aim to understand the reasons for such dissimilarity. methods: we re-analyzed the results of the latest trials in the light of the previous literature to find sub-settings in which levosimendan can be demonstrated harmful or beneficious. results: none of the three latest studies raised any safety concern, which is consistent with the findings of the previous smaller studies. in levo-cts, mortality was significantly lower in the levosimendan arm than in the placebo arm in the subgroup of isolated cabg patients ( fig. 1 ) [3] . the trend towards both hemodynamic and long term mortality benefits is maintained in recent meta-analyses [5, 6] including the three larger recent studies. conclusions: despite the fact that the null hypothesis could not be ruled out in the recent trials, we conclude that levosimendan can still results: 27 patients were included in levosimendan group and 36 in control group. in the whole population, weaning failure incidence and mortality was comparable between the 2 groups (respectively 24% vs 20%, pr 0, 34 and 36% vs 38%, pr=0,6). higher assistance duration, longer stay under mechanical ventilation and longer duration of stay in critical care unit were observed in levosimendan group. in the post-cardiotomy sub-group (table 1) , weaning failure was lower in levosimendan group (12% vs 29%, pr 0,9) and levosimendan was an independent protective factor from weaning failure (or 0,073, pr 0,92). positive impact of levosimendan may be explained in part by his calcium sensitizer effect and by facilitating recovery of myocardial calcium homeostasis in postcardiotomy cardiac stunning. conclusions: levosimendan failed to reduce the incidence of ecmo weaning failure, except for post-cardiotomy population. renal outcomes of vasopressin and its analogues in distributive shock: a systematic review and meta-analysis of randomized trials introduction: venous return (vr) is driven by the difference between mean systemic filling pressure (msfp) and right atrial pressure (rap) and determines the maximum ecmo flow. msfp depends on stressed volume and vascular compliance. it can be modified by absolute blood volume changes and shifts between stressed and unstressed volume. norepinephrine (ne) may increase stressed volume by constriction of venous capacitance and at the same time increase the resistance to systemic flow. we therefore studied the effects of ne on msfp, maximum ecmo flow and the ecmo pressure head (map-rap). methods: msfp was measured with blood volume at euvolemia and ne 1 to 3 (0.05, 0.125 and 0.2μg/kg/h) in a closed-chest porcine va-ecmo model (n=9, central cannulation with left atrial vent and avshunt) in ventricular fibrillation. the responses of rap and vr (measured as ecmo flow, qecmo) were studied at variable pump speeds including maximum possible speed without clinically apparent vessel collapse at constant airway pressure. results: the ecmo pump speed and qecmo showed a strictly linear relationship (r 2 0.95 to 0.995, range over all conditions) despite increased pressure head, indicating that the maximum qecmo was determined by vr alone. ne led to both increases in msfp and qecmo in a dose dependent way, indicating a rightward shift in the vr plot ( fig. 1 ) via recruitment of stressed from unstressed volume ( table 1 , fig. 2 ). this resulted in an increased msfp during ne despite decreased absolute blood volume (3.9±0.4 l vs. 3.3±0.3l, p=0.009). the reduced blood volume was associated with hemoconcentration suggesting plasma leakage. conclusions: ne shifts the vr curve to the right, allowing a higher maximum ecmo flow. the ne induced increase in msfp results from recruitment of unstressed volume to stressed volume, which may be modified by changes in vascular compliance. the effects on pump afterload were not limiting. introduction: to locate vessels for percutaneous central venous catheterizations, it may be helpful to apply not only real-time ultrasound (us) guidance but also us-assistance vein prelocation. the aim of this study was to evaluate the superiority of two us methods compared to surface landmark methods by reviewing randomized control trials (rcts). methods: as updating an earlier systematic review [1] , we searched pubmed and central in november 2017. we included rcts which compared the failure rates of internal jugular or femoral venous cannulations among 1) real-time us guidance, 2) us-assistance vein prelocation and 3) surface landmark methods. a frequentist network meta-analysis was conducted using the netmeta package on r. results: out of 1395 citations, 11 rcts (935 patients) were eligible. the number of studies comparing outcomes between real-time us guidance vs. surface landmark methods, us-assistance vein prelocation vs surface landmark methods and real-time us guidance vs us-assistance vein prelocation was 7, 3 and 1. regarding cannulation failure rate, network meta-analysis in a fix-effect model showed that a p-score was lower in the real-time us guidance than us-assistance vein prelocation (0.61 vs. 0.88), by reference to surface landmark methods, and also regarding arterial punctures, a p-score was lower in the real-time us guidance than us-assistance vein prelocation (0.64 vs. 0.83). conclusions: based on the present network meta-analysis of rcts, pscores of cannulation failure and arterial puncture were lower in the real-time us guidance, suggesting that the us-assistance vein prelocation is superior than the real-time us guidance, both of which achieve lower rates of failure and arterial puncture compared to the landmark methods. we speculates that the inferiority of real-time guidance is associated with difficulties in manipulating the needle together with an echo probe in targeting relatively smaller veins in children. introduction: we present a case report of 'shoshin beriberi' in a young female who was 'fussy with food' that developed an acutely progressive metabolic acidosis and multi-organ failure requiring intensive care support. methods: our patient was a 36-year-old british woman who presented to the emergency department (ed) with a ten-day history of diarrhea, vomiting and increasing fatigue. she had a past medical history of gastroparesis, polycystic ovary syndrome (on metformin), laparoscopic cholecystectomy and hysteropexy. she lived with her husband and two children who had viral gastroenteritis two weeks previously. results: the patient had a metabolic acidosis (ph 6.9) with raised lactate (>16) on initial blood gas in the ed. a 1.26% sodium bicarbonate infusion and hemofiltration were commenced overnight. the patient's ph and lactate remained static with an increasing work of breathing over this period. by morning she developed flash pulmonary oedema and hypotension, the first signs of acute cardiac failure. an echocardiogram displayed severely impaired left ventricular function with ejection fraction of 17%. the patient was intubated and inotropic support was commenced. it was thought that a micronutrient deficiency may have caused a rapid onset cardiac failure. pabrinex (containing 250ml of thiamine hydrochloride) was commenced and within 9 hours the patient's metabolic acidosis markedly improved ( fig. 1 ). complete reversal of the cardiac failure occurred over 96 hours. conclusions: shoshin is a rare clinical manifestation of thiamine deficiency [1] . it is an important differential diagnosis to bear in mind after excluding more common aetiologies of heart failure. especially in this case as our patient had no obvious risk factors at the time of presentation. we suggest empiric use of thiamine should be considered in treatment algorithms for young patients presenting with acute cardiac failure. the pateint had provided informed consent for publication. introduction: takotsubo syndrome (ts) is known to be an acute transient cardiac condition accompanied with acute heart failure. ts is often triggered by critical illness but that has been rarely studied in icu practice.therefore, it is known, that the use of catecholamines can directly induce ts, worsen lvot obstruction, and delay spontaneous recovery in ts patients, it is nearly impossible to avoid their administration in critically ill [1] . methods: we have analyzed medical records from 23 patients with ts, that were revealed during year 2017 in our hospital. ts was defined due to mayo criteria, including transient regional wall motion abnormalities, mildly elevated troponin level and no signs of obstructive cad on coronary angiography. results: out of 23 patients who developed ts in icu or iccu, hemodynamic instability occurred in acute phase of ts in 12 (52%) cases. 9 (39%) of patients were admitted to icu in due to septic shock (2 patients), major bleeding (1), cerebral mass lesion (1) and ards (2) and required treatment with catecholamines. general mortality rate in ts patients was 7 (30%), and 5 (55%) in critically ill ts patients. mean duration of noradrenalin infusion was 7,2 days, dobutamine infusion 4,3 days. patients with ts needed more icu resources and longer icu-stay. mortality rate was higher in ts patients (55%) vs the icu-population (28%), p = 0.02. conclusions: ts seems to be an often cause of lv dysfunction and acute heart failure in critically ill. it seems that ts could be a predictor of worse prognosis in critically ill patients. although catecholamine administration may worsen the patient prognosis and induce further ahf in critically ill patients it rearely can be avoided. introduction: previous studies on readmission following lvad implantation have focused on hospital readmission after dismissal from the index hospitalization. since there are very little data existing, the purpose of this study was to examine intensive care unit (icu) readmission in patients during their initial hospitalization for lvad implantation to determine reasons for, factors associated with, and mortality following icu readmission. methods: this was a retrospective, single center, cohort study in an academic tertiary referral center. all patients at our institution undergoing first time lvad implantation from february 2007 to march 2015 were included. patients dismissed from the icu who then required icu readmission prior to hospital dismissal were compared to those not requiring icu readmission prior to hospital dismissal. results: among 266 lvad patients, 45 (16.9%) required icu readmission. the most common reasons for admission were bleeding and respiratory failure (fig. 1) . factors found to be significantly associated with icu readmission were preoperative hemoglobin level of less than 10 g/dl, preoperative estimated glomerular filtration rate <35ml/min/1.73m2, preoperative atrial fibrillation, preoperative dialysis, longer cardiopulmonary bypass times, and higher intraoperative allogeneic blood transfusion requirements. mortality at 1 year was 30.2% in patients requiring icu readmission vs. 11.9% in those not requiring icu readmission (age-adjusted or=3.0, 95% ci 1.4 to 6.6, p=0.005). conclusions: icu readmission following lvad implantation occurred relatively frequently and was associated with significant one-year mortality. these data can be used to identify lvad patients at risk for icu readmission and implement practice changes to mitigate icu readmission. future larger and prospective studies are warranted. atrial fibrillation and infection among acute patients in the emergency department: a multicentre cohort study of prevalence and prognosis t graversgaard odense university hospital, odense, denmark critical care 2018, 22(suppl 1):p140 introduction: patients with infection presenting with atrial fibrillation (af) are frequent in emergency departments (ed). this combination is probably related to a poor prognosis compared to lone af or infection, but existing data are scarce. aim: to describe the prevalence and prognosis for af and infection individually and concomitantly in an ed setting. introduction: its afterload reducing effects make peep the treatment of choice for cardiogenic pulmonary edema. studies indicate that peep may lower coronary blood flow. its effects on left ventricular contractility is unclear. most of the surrogate measures for cardiac contractility are dependent on afterload and contractility assessment under peep may therefore be biased. we have investigated cardiac contractility under peep with the endsystolic pressure volume relationship (espvr) as a load-independent measure of contractility. methods: 23 patients scheduled for coronary angiography were ventilated with cpap and a full face mask at three levels of peep (0, 5 and 10 cmh2o) in random order. structural cardiac pathologies were excluded with echocardiography. at every peep level, left ventricular pressure volume loops (millar conductance catheter with inca system, leycom, netherlands) were obtained. the endsystolic elastance was derived from a pv-loop family under preload reduction with an amplatzer sizing balloon in the inferior caval vein. all participants gave written informed consent. the study was approved by the bernese ethics committee. results: 5 women and 18 men with an age 59±6 years were studied. ejection fraction was 70±8 % at baseline. mean espvr at peep levels of 0, 5 and 10 were 2.64±1.3, 2.56± 1.18 and 2.33±0.88 mmhg/ml (p = 0.318, repeated measurements anova). dp/dt and ejection fraction did not differ between the peep levels (p=0.138 and 0.48). conclusions: moderate levels of peep did not influence endsystolic elastance. higher peep and patients in cardiogenic shock should be investigated. introduction: we sought to assess the feasibility of 3d volumetric analysis with transthoracic echocardiography in critically ill patients. we choose a cohort typical of icu where accurate volumetric analysis is important: hypoxic, mechanically ventilated patients. 3d analysis is enticing in simplicity and wealth of data available. it is accurate in cardiology patients [1] but has not been assessed in the icu. methods: patients were imaged within 24 hours of admission. inclusion criteria: adult, hypoxic (p:f <300), mechanically ventilated, doppler stroke volume (sv) assessment possible. echocardiography: seimens sc2000 real-time volumetric analysis with standard b-mode and doppler assessment. images unacceptable if >2 segments unable to be seen in 2 volumetric planes. 3d left ventricle (lv) and right ventricle (rv) analysis with tomtec imaging and seimens acuson respectively and compared to doppler derived sv. 30% limit of agreement considered clinically acceptable [2] . imaging was optimised for volumetric analysis (20-45 vols/sec). results: 92 patients, 83 in sinus, 9 in af. no significant difference seen between doppler vs 2d simpson's biplane, 3d lv or 3d rv sv estimation. feasibility, sv values and bias are reported in table 1 and fig. 1 . limit of agreement for corrected doppler vs lv 3d sv = -48% to 55%; rv 3d sv = -62.7% to 84.3%. conclusions: 3d lv and rv volumetric analysis is feasible in majority of patients requiring mechanical ventilation, however lacks agreement with doppler derived stroke volume assessment. although images may appear sufficient, the semi-automated software appears to underestimate stroke volume. further larger studies using thermodilution are warranted. introduction: body position changes such as leg raising are used to determine fluid responsiveness. we hypothesized that the trendelenburg position increases resistance to venous return. together with abolishment of the hepatic vascular waterfall, this may limit the increase in regional blood flow. methods: inferior vena cava (ivc), portal vein (pv), hepatic, superior mesenteric (sma) and carotid artery blood flows and arterial, right atrial (ra) and hepatic (hv) and portal venous blood pressures were measured in anesthetized and mechanically ventilated pigs in supine and 30°trendelenburg positions. all hemodynamic parameters were measured during end-expiration at 5 cmh2o peep, and at inspiratory hold with increasing airway pressures (awp) of 15, 20, 25 and 30 cmh2o, respectively. paired t test was used to compare pressures and flows in different positions during end-expiration. repeated measures anova was performed to evaluate the effects of awp on hemodynamic parameters. results: trendelenburg position significantly increased ra, hv and pv blood pressures at end-expiration, while qpv and qsma remained unchanged, qha increased and qivc showed a trend to decrease (table 1 ). in both positions, all blood flows decreased with increasing awp, and the difference between ppv and qsma became smaller, indicating splanchnic blood pooling ( table 2 ). in the trendelenburg position, splanchnic blood pooling was less severe compared to supine position. conclusions: trendelenburg position tended to decrease venous return from inferior vena cava. further increases in rap by augmenting awp led to a decrease in all flows and signs of abolished hepatic vascular waterfall. passive manoeuvers to assess fluid responsiveness evoke complex hemodynamic reactions which are not fully understood. introduction: despite of preventive measures, the incidence of deep venous thrombosis (dvt) in icu patients is estimated to range from 5-31%. while clinical diagnostics is unreliable, ultrasound compression test (uct) has proven to be a highly sensitive and specific modality for the recognition of lower extremity dvt [1] . delegating this competence to icu nurses can increase uct availability and enable preventive dvt screening. therefore, we decided to conduct a clinical study to evaluate the sensitivity and specificity of uct performed by general icu nurse in icu patients compared to an investigation by icu physician certified in ultrasound. methods: prior to the study, each nurse participating in the study completed one-hour training in uct and examined 5 patients under supervision. then, icu patients without known dvt underwent uct in the femoral and popliteal region of both lower extremities performed by trained general icu nurse. on the same day, the examination was repeated by an icu physician. the results of the examinations of each patient were blinded to each other for both investigators until both tests were performed. in case of a positive test, the nurse immediately reported the result to the icu physician. the sensitivity and specificity of the test performed by general nurse was calculated in comparison with the examination by a specialist. results: a total of 80 patients were examined. both lower extremities were examined in all patients. the prevalence of dvt of 11,25% has been found. the overall sensitivity of the examination performed by general nurse was 90.0%, the specificity 100% with negative predictive value of 98.61%, positive predictive value of 100% and accuracy of 98.77%. the results of our study have shown that general icu nurses are able to perform bedside screening of dvt by compression ultrasound test with a high degree of reliability after a brief training. methods: a cytosorb® (cytosorbents, new jersey, usa) ha device was inserted within the cpb circuit in ten patients undergoing elective cardiac surgery. one hour after cpb onset, the activity of coagulation factors (antithrombin (at), von willebrand factor (vwf), factors ii, v, viii, ix, xi, and xii) were measured before and after the device. pre and post device measurements were compared using student ttest, a p value <0.05 was considered statistically significant. results: patients' mean age was 60.6 ± 21.4 years, 20% were female, the mean euroscore ii was 6.2 ± 8.1. procedures were: coronary artery bypass graft (cabg) (2/10), aortic root replacement (6/10) and cabg combined with aortic valve replacement (2/10). mean cpb duration was 161.8 ± 52.3 min. pre and post ha measurements of coagulation factors activity are presented in fig. 1 . post-device at and fii activity was significantly lower (respectively from 70.4 to 66.6, p=0.01 and from 61.5 to 57.1, p=0.03) compared to predevice measurement. there was no statistically significant difference between pre-and post-ha measurements for all other coagulation parameters conclusions: pre and post ha cytosorb® measurements for coagulation factor activity were not different except for a small decrease in at and fii activity. this might be related with intra-device consumption or adsorption. further analyses accounting for cpb fluid balance, the entire study population and timepoints are pending. introduction: the aim of this study is to evaluate changes in hemodynamics and microvascular perfusion during extracorporeal blood purification with cytosorb in patients with septic shock requiring renal replacement therapy. methods: eight adult patients with septic shock requiring continuous renal replacement therapy for acute renal failure were enrolled and underwent a 24-hour treatment with the emodasorption cartridge cytosorb. measurements were taken at baseline before starting cytosorb, after 6h (t1) and 24h (t2) and included: blood gases, macrohemodynamic parameters (picco2), vasopressor and inotropic dose, plasma levels of cytokines (interleukin [il]-1, il6, il8, il10, tumor necrosis factor alpha) and parameters of microvascular density and perfusion (sublingual sidestream dark field videomicroscopy). procalcitonin was measured at baseline and after 24h of treatment. results: a non-significant decrease in plasma levels of cytokines was observed over time. hemodynamic parameters and vasopressor requirement remained stable. the microvascular flow index increased significantly at t2, total vessel density and perfused vessel density increased at t1 and t2 ( introduction: objective renal replacement therapy (rrt) with the oxiris filter is used in sepsis septic shock with aki, but few clinical studies compare the adsorbing effect of oxiris filter on the inflammatory mediators to rrt. the aim of this study is 1-to confirm whether oxiris decreases cytokines and procalcitonin in sepsis septic shock.2-this effect is superior to rrt.3-this translates in a better cardio renal response. methods: a coohort study and a propensity-matched analysis included 73 patients admitted to three intensive care (aurelia hospital, european hospital, tor vergata -rome) with a diagnosis of septic shock.50 patients were submitted to rrt with oxiris filter and 23 patients to rrt.il 6, procalcitonin, the cardiorenal indices and sofa score were compared before (t0) and at the end of the treatments (t1). all data are expressed as mean±sd. anova one way was used to compare the changes of the variables in the time. p< 0.05 was considered statistically significant. results: of 50 patients submitted to rrt with the oxiris filter 32 could be matched to 22 septic patients who received rrt. il6 and procalcitonin decreased in the oxiris group (p< 0.01) but not in the rrt group.-map increased (p< 0.01) and noradrenaline dosage decreased in oxiris group (p< 0.01), but non in rrt group. also pao2/fio2 ratio, diuresis, sofa improved only in the in the oxiris group (p<0.05). conclusions: in sepsis/septic shock patients with aki, il6 and procalcitonin decrease more in the oxirs group then in the rrt group.this is associated with an improvement of the cardio -renal function and the clinical condition.the study confirms that rrt with oxiris filter may be useful in sepsis/septic shock when other convective/diffusive techinques fail. introduction: advos (hepa wash gmbh, munich, germany) is a recently developed ce-certified albumin-based hemodialysis procedure for the treatment of critically ill patients. in addition to the removal of water-soluble and albumin-bound substances, acid-base imbalances can be corrected thanks to an automatically regulated dialysate ph ranging 7.2 to 9.5. methods: patients treated with the advos procedure between in the department of intensive care medicine of the university medical center hamburg-eppendorf were retrospectively analyzed. overall 102 treatments in 34 critically ill patients (mean sofa score 16) were evaluated. additionally, subgroup analysis for hyperbilirubinemia, respiratory acidosis and non-respiratory acidosis were conducted. results: severe hyperbilirubinemia (>6 mg/dl) was present in 60 treatments, while 26 and 14 treatments were performed to treat respiratory (paco2>45 mmhg) and non-respiratory (paco2<45 mmhg) acidosis (ph<7.35), respectively. mean treatment duration was 16 h. advos procedure was able to correct acidosis and reduce bilirubin, bun and creatinine levels significantly. the subgroup analysis shows an average bilirubin reduction of 21% per advos multi treatment in the hyperbilirubinemia group (15.24mg/dl vs 11.77mg/dl, p<0.05). moreover, ph (7.23 vs. 7.35, p<0.001) and paco2 (65.88 vs. 53.61 mmhg, p<0.001) were corrected in the respiratory acidosis group, while in the non-respiratory acidosis group, an improvement in ph (7.19 vs. 7.37, p<0.001), hco3 (15.21 vs. 20.48, p=0.002) and base excess (-12.69 vs. -5.10, p=0.004) could be observed. there were no treatment-related adverse events during therapy. conclusions: advos is a safe and effective hemodialysis procedure, which is able to remove water soluble and protein bound markers and correct severe acidosis in critically ill patients. score for timely prescribing (stop) renal replacement therapy in intensive care unit -preliminary study of a mneumonic approach introduction: the moment of initiation of renal replacement therapy (rrt) in critically ill patients and a reason for debate, without having objective criteria that indicate it. the objective of this study was to propose a score to help identify the ideal time for the initiation of rrt, and if there is correlation between this score and intensive care unit length of stay and mortality. methods: patients admitted to the intensive care unit, > 18-yearsold, to whom rrt were indicated by the intensivist. the study protocol was approved by the hospital das forças armadas ethical committe, and written informed consent was obtained from all patients. the stop was assigned according to the presence or not of each of the items (fig. 1 ). they were classified into groups a and b according to fig. 2 , and the group change was recorded. results: 80 patients admitted to icu in the period, 2 excluded for limitation of therapeutic efforts. 78 were admitted to the study, with the mean age of 75.2 years; 64,1% males (n=50). distribution among the groups: a1 (n=1, 1.2%), a2 (31, 39.7%), a3 (5, 6.4%), b1 (6, 7.6%), b2 (35, 44.8%) e b3 (no patients). there were statistically significant correlation between group change and mortality (p 0.02), and between the stop and nephrologist agreement (p 0.01). there was no correlation between stop value and icu los (p 0,75) or stop and mortality (p 0.8). conclusions: the stop value is correlated with hemodialysis indication agreement between intensivists and nephrologists, and not correlated with icu los or mortality. the group change was correlated to increased mortality, in the study population. the significance of stop as a tool in determining the moment of initiation of renal replacement therapy remains a work in progress. introduction: liver transplant (lt) in patients with renal dysfunction presents intraoperative challenges and portends postoperative morbidity. continuous renal replacement therapy (crrt) is increasingly used for intraoperative support; however, there is a paucity of data to support this practice. methods: pilot randomized open-label controlled trial in adults receiving cadaveric lt with a modification of end-stage liver disease (meld) score >=25 and preoperative acute kidney injury (kdigo stage 1) and/or estimated glomerular filtration rate <60 ml/min/1.73m2. patients were randomized to intraoperative crrt (icrrt) or standard of care. primary endpoints were feasibility and adverse events. secondary endpoints were changes in intraoperative fluid balance, complications, and hospital mortality. analysis was intention-to-treat. results: sixty patients were enrolled, 32 (53%) were randomized (17 to icrrt; 15 to control). mean (sd) was age 49 (13) years, meld was 36 (8), 75% (n=24) had cirrhosis; 63% (n=20) received preoperative rrt; and 66% (n=21) were transplanted from icu. one patient allocated to icrrt did not receive lt. seven (41%) allocated to control crossed over intraoperatively icrrt ( (137) min, with only 3 interruptions (all due to access). icrrt fluid removal was 2.8l (range 0-14.5). fluid balance was 5.3l (2.9) for icrrt vs. 4.3l (6.1) for control (p=0.57). postoperative crrt was similar (77% vs. 50%, p=0.25). there were no differences in reexploration (p=0.36), mechanical ventilation time (p=0.87), reintubation (p=0.18), sepsis (p=0.56), or mortality (p=0.16). conclusions: in this pilot trial of high acuity lt patients, icrrt was feasible and safe. these data will inform the design of a large trial to define the role of icrrt during lt. clinicaltrials.gov: nct01575015. the uptake of citrate anticoagulation for continuous renal replacement therapy in intensive care units across the introduction: the purpose of this descriptive study is to report the trend of citrate anticoagulation uptake, used for continuous renal replacement therapy (crrt), in intensive care units (icus) across the united kingdom (uk). citrate anticoagulation has been used in the uk since 2008, but its uptake since then is unknown [1] . methods: a survey questionnaire targeted pharmacists working in uk adult icus providing crrt. invitations to participate were distributed utilising the united kingdom clinical pharmacy association online forum as a platform for access. survey administration was by self-completion and submissions were accessible over a total of six weeks. basic demographic data, icu specifications, the citrate system in use and implementation details were sought. a descriptive statistical analysis ensued. results: 70 responses were received of which 67 were analysed after duplication removal. 45 trusts, encompassing a total 67 units, in the uk confirmed use of citrate anticoagulation for crrt. units reported a mean of 71 days to implement a citrate system (range 0 to 645 days). prismaflex® (baxter) and multifiltrate (fresenius) were reported as the most commonly used citrate systems; 32 (47.8%) and 28 (41.8%) units respectively. conclusions: there are 279 icus in the uk [2] . we conclude that a minimum of 67 units (24%) use citrate anticoagulation for crrt in uk critical care centres. citrate systems of anticoagulation are becoming an increasing popular choice for regional anticoagulation, falling in line with international guidance [3] . these guidelines were introduced in 2012 which corresponds to increase national uptake. introduction: patients requiring renal replacement therapy (rrt) whilst on significant doses of vasoactive medications have often been deemed unsuitable to undergo ultrafiltration (uf). however with better understanding of the pathophysiology of renal injury [1] in intensive care patients we hypothesise that vasopressor/inotrope requirement will not significantly increase with uf or with a more negative fluid balance (fb). methods: data was retrospectively collected in a general icu/hdu of adult patients requiring acute rrt for acute kidney injury. patients on chronic dialysis were excluded. percentage change in vasopressor index and mean arterial pressure were combined to form the combined percentage change (cpc) which we used as an index of patient stability. results: 38 patients were assessed undergoing a total of 206 rrt sessions. the mean age was 57 with 23 females and 15 males. mean fb for the 24 hours from start of rrt was +651mls (range -2317 to +14850mls). using a model to correct for significant covariates and plotting 24 hour fb against cpc we found no significant effect of fb on stability p=0.98 (fig. 1 ). mean uf volume was 880mls (range 0-3009mls). there was a non linear relationship between uf and stability with moderate volumes improving but larger volumes worsening stability (fig. 2 ). this did not reach statistical significance (p=0.074) so may be due to chance but is likely due to a lack of power. conclusions: fluid balance has no effect on cardiovascular stability during rrt in our cohort but there may be a varying effect of uf depending on volume. introduction: exposure of blood to a foreign surface such as a continuous renal replacement therapy (crrt) filter could lead to activation of platelets (plt) and fibrinogen (fib) trapping. thrombocytopenia has been reported in adults on crrt but data in pediatrics are scarce. our institution uses regional citrate anticoagulation (rca) as standard of care with prefilter hemodilution and hf1000 filters (polysulfone, surface area (sa) 1.1 m2) regardless of patients' (pts) age and size. as filter sa is relatively larger in younger pts, we aimed to investigate the impact of crrt filter change on hemostasis parameters in infants on crrt in up to first three filter changes. methods: retrospective chart review results: 30 patients < 10 kg were included, age 4.3 (0.5-8) months, weight 5.4+2.4 kg, with 88 filters. metabolic disease was the most common principal diagnosis (7/30, 23%), liver failure (lf) was the most common comorbidity (12/30, 40%). all patients received prefilter continuous venovenous hemodiafiltration with minimum dose of 2000 ml/1.73m2/h. thrombocytopenia was common at crrt start (28/30, 93%). plts decreased in 74% filter changes (65/88) by 15+70% (pre vs post plt 71 (44-111) vs 50(30-83), p<0.001). fibrinogen also decreased from 201 (152-261) to 170 (134-210), p<0.001; there was no change in ptt, pt, or inr values before and after filter changes. bleeding events were seen in 13/30 (43%) of pts (8/12 of lf pts vs 5/ 18 others, p=0.04), but were not more common in pts who had decrease in plts or fib with filter changes (41% with drop in plts vs 57% without, p=0.66; 47% with drop in fib vs 75% without, p=0.58). conclusions: thrombocytopenia is common in infants on crrt. further decreases in plt and fibrinogen can be seen in with crrt filter changes if the filters are relatively large compared to patient size. bleeding events seems more related to underlying comorbidity, and less to changes in hemostatis parameters observed with filter change but would need to be confirmed with further studies. intensive monitoring of post filter ionized calcium concentrations during cvvhd with regional citrate anticoagulation: is it still required? introduction: the aim of the present study was to evaluate the role of postfilter calcium concentrations (pfca) in terms of safety and efficacy in large retrospective cohort of patients treated with cvvhd and regional citrate anticoagulation. methods: retrospective, observational study at a university hospital with 6 icus. all patients treated with rca-crrt were included in the study. results: among 1070 patients treated with rca-cvvh pfca at the start of the cvvhd was available in 987 pts. the pfca concentrations were in target range (0.25-0.35 mmol/l) in the majority of patients (70%), whereas 17% and 13% of patients had the pfca below or above the target range, respectively. in the further 72h of cvvhd treatment the propotion of patients with targeted pfca increased to 86% and remained stable. at the start of the rca-cvvhd there was a significant but weak correlation between the pfca and ionized systemic ca (ica) with a spearman rank-order correlation coefficient (rho) of 0.374 (p < 0.001). the coefficient of variation of pfca concentraions was significantly higher if compared to the coefficient of variation of ica concentration. using per protocol adaptations the incidence of a severe hypocalcemia (<0.9 mmol/l) was low and present only at first 12 hours of therapy: 4% and 2% of patients with pfca below the target range and 0.7% and 0.4% of patients with pfca in target range, at 0h and 12h respectively (p<0.001). there was no correlation between pfca concentrations and filter lifetime. the results of the present study support the previous reports about higher measurements variation of pfca compared to systemic ica (1). nevertheless due to the weak correlation of ica and pfca as well as a low number of patients with a severe metabolic complication, the results of our study question the necessity of intensive pfca monitoring during rca-crrt. present results need to be validated in further trials. introduction: in critically ill patients, occurrence of pain is frequent and usually correlates with worse outcomes, such as prolonged icu length of stay (los) and mechanical ventilation. in this regard, pain leads to sympathetic activation, inflammatory mediators and therefore, potentially to organic dysfunction. the aim of this study is to evaluate the relationship between acute pain in critically ill patients and their association with acute kidney injury (aki). methods: retrospective cohort with 6345 adults patients admitted between june 2013 and june 2016, from the icu of hospital sírio libanês hospital in sao paulo (brazil). main exclusion criteria were: length of stay < 48h, coma and previous aki. the predictor pain was obtained through daily electronic records according to numerical verbal scale (0-10). the outcome was defined as serum creatinine elevation equal to or greater than 0.3mg/dl and/or greater than 50% increase at any time after the first 48 hours in the icu. the multivariate analysis was performed by binary logistic regression through distinct groups of early or late predictive factors in relation to aki. results: after the exclusion of 3220 patients, the incidence of pain with numerical verbal scale equal to or greater than 3 points was 23.6%. the outcome occurred in 31.7% of the cohort. in the binary regression, using the more early predictive factors, sex and pain presented independent relation with the outcome -adjusted or 1.24 (1.12-1.36) and 1.63 (1.34-1.98), respectively (p <0.001). in the analysis conclusions: poor management of icu pain is associated to worse outcomes, including increased risk to aki. the search for a better pain management strategy in the icu scenario should therefore be reinforced. introduction: acute kidney injury (aki) is a common complication in hospitalised patients, strongly associated with adverse outcomes [1] . a lack of baseline incidence and outcome data limits our ability to assess local strategies aimed at improving aki care. methods: in an audit in three linked inner london hospitals we interrogated our electronic patient data warehouse (cerner millennium power insight electronic data warehouse) with a specially written query to identify cases of aki, defined by kdigo creatinine criteria, in patients aged over 18y admitted for >24h during january to june 2016. we excluded palliative care and obstetric patients. in the absence of premorbid baseline (median 7-365d pre-admission) the admission creatinine value was used. end stage renal disease (esrd) and primary sepsis diagnosis was obtained from icd10 coding. results: of 28872 admissions, we excluded 1052 with pre-existing esrd (hospital mortality 6.0%) and 8833 with fewer than one creatinine result who could not be assigned aki status (mortality 1.1%). of the remaining 18987 there were 3145 with aki (16.6%), with mortality increasing from no aki group (2.4%), to aki stage 1 (12.6%), and a further increase to aki stages 2-3 (22.4%) (p<0.001) ( table 1) . patients with aki were older (p<0.001), more likely to be medical than surgical (p<0.001), more likely to have a primary sepsis diagnosis (p<0.001) and had higher baseline creatinine (median 91 vs 79 p<0.001). no known baseline was found in 29.7% of patients with aki, but their mortality did not significantly differ to those with a baseline (14.2% vs 16.6%, p=0.093). conclusions: an electronic query identified the local burden of aki and it's associated hospital-mortality; such baseline data is essential to assess the effect of quality improvement interventions in aki prevention and care. introduction: acute kidney injury (aki) is a common condition in critically ill patients [1, 2] . loop diuretics are generally used as first line treatment. however, controlled trials show controversial results. we ought to search systematically and realize a metaanalysis on the matter. methods: an electronic search of randomized clinical trials in adult patient treated with diuretics for aki compared with standard treatment or a control group was conducted. the primary objective of the analysis was to assess recovery of renal function. secondary endpoints included time to recovery of renal function, need for renal replacement therapy (rrt), mortality in the intensive care unit (icu) and complications. introduction: increased venous pressure is one of the mechanism leading to acute kidney injury (aki) after cardiac surgery. portal flow pulsatility and discontinuous intra-renal venous flow are potential ultrasound markers of the impact of venous hypertension on organs. the main objective of this study was to describe these signs after cardiac surgery and to determine if they are associated with aki. methods: this single center prospective cohort study (nct02831907) recruited adult patients able to give consent. ultrasound studies were performed before cardiac surgery and repeated on post-operative day (pod) 0, 1, 2 and 3. abnormal portal and renal venous flow patterns are defined in fig. 1 . the association between the studied markers and the risk of new onset of aki in the following 24 hours period following an assessment was tested using logistic regression with a 95% confidence interval. clinical variables associated with the detection of the signs were tested using generalized estimating equation models. this study was approved by the local ethics committee. results: during the study period, 145 patients were included. the presence of the studied ultrasound signs is presented in fig. 2 . during the week following cardiac surgery, 49 patients (33.8%) developed aki, most often on pod 1 (71.4%). the detection of portal flow pulsatility and severe alterations in renal venous flow (pattern 3) at icu admission (pod 0) were associated with aki in the subsequent 24 hours period and was independently associated with aki in multivariable models including euroscore ii and baseline creatinine ( table 1 ). the variables associated with the detection of abnormal portal and renal patterns were associated with lower perfusion pressure, higher nt-pro-bnp and inferior vena cava measurements (table 2) . conclusions: abnormal portal and intra-renal venous patterns are associated with early aki after cardiac surgery. these doppler features must be further studied as potential treatment targets to personalize management. introduction: acute kidney injury (aki) is very prevalent after cardiac surgery in children, and associated with poor outcomes [1] . the present study is a preplanned sub-analysis of a prospective blinded observational study on the clinical value of the foresight nearinfrared spectroscopy (nirs) monitor [2] . the purpose of this subanalysis was to develop a clinical prediction model for severe aki (saki) in the first week of picu stay. methods: saki was defined as serum creatinine (scr) >/= 2 times the baseline, or urine output < 0.5 ml/kg/h for >/= 12h. predictive models were built using multivariable logistic regression. data collected during surgery, upon picu admission, as well as monitoring and lab data until 6h before saki onset, were used as predictors. relevant predictors with a univariate association with saki, were included in the models. accuracy of the models was tested using bootstraps, by auroc and decision curves. results: 177 children were enrolled, admitted to the picu of the leuven university hospitals after cardiac surgery, between october 2012 and november 2015. 5 patients were excluded. 70 children (40.7%) developed saki in the first week of picu stay. a multivariate model with 5 admission parameters (maximum lactate during surgery, duration of cpb, baseline scr, rachs1 and pim2 scores), and 4 postoperative measurements (average heart rate, average blood pressure, hemoglobin, lactate), was most predictive for saki ( fig. 1) . conclusions: the risk of saki in children after congenital cardiac surgery could be predicted with high accuracy. future models will also include medication data. these models will be compared against and combined with nirs oximetry data to investigate the independent and added predictive value of the foresight monitor. introduction: acute kidney injury (aki) occurs in over 50% of the patients in the intensive care unit (icu). the predominantly ethiology of aki is septic shock, the most common diagnosis in the icu. aki significantly increases the risk of both morbidity and mortality [1] . methods: 8 icu patients with septic shock was studied within 24 hrs from admission. 58 patients after cardiac surgery served as control group. all patients were sedated and mechanically ventilated. renal blood flow (rbf) and glomerular filtration rate (gfr) were obtained by the infusion clearance of paraaminohippuric acid (pah) and by extraction of 51cr-ethylenediamine (51cr-edta). n-acetyl-β -d-glucosaminidase (nag), was measured. results: rbf was 19% lower, renal vascular resistance 19% higher and the relation of rbf to cardiac index was 29% lower in patients with septic shock compared to the control group. gfr (32%, p=0.006) and renal oxygen delivery (rdo2) (24%) where both significantly lower in the study group (table 1) . there was no difference between the groups in renal oxygen consumption (rvo2) but renal oxygen delivery was almost 30% lower in septic shock patients. renal oxygen extraction was significantly higher in the study group than in the control group. in the study group, nag was 5.4 ± 3.4 units/mikromol creatinine more, i.e 5 times the value in patients undergoing cardiac surgery [2] . conclusions: sepsis related aki is caused by a renal afferent vasoconstriction resulting in a reduced rbf and lowered rdo2 in combination with an anchanged rvo2, this results in a renal oxygen supply/ demand mismatch. introduction: the primary aim was to determine if the addition of daily creatine kinase (ck) measurement was usefully guiding decision making in intensive care units within greater glasgow and clyde. methods: after a change to the daily blood ordering schedule to include ck, a retrospective audit was carried out covering a 5-month period within 3 intensive care units. all patients with ck >870 units/ litre were included. basic demographics, apache 2 score and admitting diagnosis were recorded. utility of ck was assessed by determining the associated diagnosis and whether the diagnosis was first considered (diagnostic trigger) due to ck level, clinical suspicion or haematuria. additionally, it was determined if and what actions had been taken based on the raised ck and associated diagnoses. results: data was collected from 01/08/2016 to 31/12/2016. 276 patients were captured with ck >870 units/litre from an average combined admission rate of 200 patients/month [1] . total male patients 191 (69.2%) and female 85 (30.8%). age range 17 to 95 years (mean 54.7). apache 2 score range 0 to 45 (mean 20.9) with estimated mean mortality of 36.7%. 176 patients (63.8%) had associated diagnoses with elevated ck including: burns 2 (0.7%), compartment syndrome 7 (2.5%), myocardial infarction 20 (7.2%), myositis/myocarditis 2 (0.7%), neuroleptic malignant syndrome 1 (0.4%), rhabdomyolysis 61 (22.1%), serotonin syndrome 7 (2.5%), surgical procedure 76 (27.5%). as outlined in fig. 1 the diagnostic trigger was the routine ck measurement in 65 patients (23.6%), prior clinical suspicion 108 (39.1%), haematuria 1 (0.4%) and unclear in 102 (36.9%). action was the correlation analysis showed the egfrs from every formula could all to some extent reflect the glomerular function or gfr accurately. the gfr (scys) formula was a quickly and accurate method for estimating gfr and may apply clinically in critically ill patients. perioperative chloride levels and acute kidney injury after liver transplantation: a retrospective observational study s choi 1 introduction: the risk of developing acute kidney injury (aki) after liver transplantation in the immediate postoperative period ranges between 17 to 95%. most studies in critically ill and surgical patients evaluated the link between chloride-rich resuscitation fluids, not serum chloride levels, and the incidence of aki. the association between preoperative chloride level or difference in perioperative chloride levels and the incidence of postoperative aki after liver transplantation were evaluated. methods: adult patients (>=18 years old) who underwent liver transplantation at seoul national university hospital between 2004 and 2015 were included in the retrospective analysis. the difference between preoperative serum chloride level and the immediate postoperative serum chloride level was defined as intraoperative chloride loading. postoperative aki within 7 days of liver transplantation was diagnosed according to the rifle criteria. patients were divided into normochloremia group (96-106 meq/l), hypochloremia group (<96 meq/l), or hyperchloremia group (>106 meq/l) according to their preoperative chloride level. intraoperative chloride loading was defined as the difference between preoperative serum chloride level and immediate postoperative serum chloride level. .03) compared to patients with preoperative normochloremia. meld scores > 11 and age >56 years were also associated with increased risk of aki. intraoperative chloride loading was not a significant risk factor for aki after liver transplantation. conclusions: preoperative hyperchloremia and hypochloremia were both associated with an increased risk of developing aki in the immediate postoperative period after liver transplantation. introduction: perioperative acute kidney injury (aki) is associated with significant morbidity and mortality [1] . certain urinary biochemical parameters seem to have a standardized behavior during aki development and may act as surrogates of decreased glomerular filtration rate (gfr) aiding in early aki diagnosis [2] . aim of this prospective observational study was the evaluation of urinary biochemical parameters as early indicators of aki in a cohort of major surgery patients. methods: 68 patients were studied. aki was defined according to akin criteria within 48 hrs after surgery [3] . at pre-defined time points (preoperatively, recovery room [rr] and on postoperative days [pod] 1 to 3) simultaneous serum and urine samples were analyzed additional studies must confirm these findings and reevaluate these simple parameters as potential aki monitoring tools. urinary liver-type fatty acid-binding protein is the novel biomarker for diagnosis of acute kidney injury secondary to sepsis t komuro, t ota shonan kamakura general hospital, kamakura, kanagawa, japan critical care 2018, 22(suppl 1):p168 introduction: acute kidney injury (aki) is the predictor of poor prognosis for the patient with sepsis and septic shock. several diagnostic criteria for aki is used on clinical settings, but useful biomarker is not known yet. urinary liver-type fatty acid-binding protein(l-fabp) is associated with kidney function and aki [1] , but that is not still discussed about aki secondary to sepsis. thus, we conducted the study of the association between urine l-fabp and aki with secondary to sepsis. (fig. 1) . the cut-off line of l-fabp was 95.71μg/g cr. conclusions: l-fabp can be the novel biomarker for diagnosis of aki. further investigation need for diagnostic value of l-fabp and usefulness of early intervention for aki used by l-fabp. introduction: biotransformation of 25-hydroxyvitamin d to active 1,25(oh) 2 d occurs primarily in the kidney. our aim was to explore whether this process was altered in patients with acute kidney injury (aki). methods: consecutive patients admitted to critical care at a tertiary hospital were recruited. the aki group comprised patients with kdigo stage ii or stage iii aki; the non-aki group were patients requiring cardiovascular or respiratory support, but with no aki. vitamin d metabolite concentrations were measured on days 0, 2 and 5. statistical analysis included comparison between groups at each time point, and longitudinal profiles of vitamin d metabolites. results: interim analysis of 55 participants (44% of the recruitment target) showed that 1,25(oh) 2 d concentrations were significantly lower in patients with aki at day 2 and day 5. considering longitudinal changes, 25-hydroxyvitamin d profiles were not different between the groups ( fig. 1 ) but there was a trend towards a longitudinal increase in 1,25(oh) 2 d in patients without aki, which was not seen in aki patients (fig. 2) . conclusions: interim analysis indicates significant differences in concentrations of 1,25(oh) 2 d, but not 25(oh)d, in critically ill patients with aki. recruitment is ongoing and further results are awaited. introduction: acute renal failure affects from 1% to 25% of patients in the intensive care units (icus)1 and it is associated with excess mortality. hydratation is a useful preventive measure but it is often controindicated in critically ill patients who, on the contrary, often benefit by a strictly conservative strategy of fluid management. fenoldopam, a selective dopamine 1-receptor agonist, increases renal blood flow and glomerular filtration rate by vasodilating selectively the afferent arteriole of renal glomerulus. the aim of our study is to compare renal effects of fenoldopam and placebo in critically ill patients undergoing a restrictive fluid management. methods: we enrolled 130 patients admitted to our icu. patients were assigned by randomization to study groups: fenoldopam (n=64) and placebo (n=66). fenoldopam was infused continuously at 0,1 mcg/kg/ min and equivalent volume for placebo during a period of seven days. creatinine, cystatin c and creatinine clearance were daily measured as markers of renal function. the incidence of aki according to rifle criteria (risk, injury, failure, loss, end stage kidney disease) was also calculated. results: patients with a negative fluid balance at the end of the week (~-5000 ml, p=0,0001) were included in the analysis, 32 in the placebo group and 38 in the fenoldopam group. there were not significant differences in the trend of creatinine, creatinine clearance, cystatin c and in the incidence of aki between the groups during the week of infusion. conclusions: a continuous infusion of fenoldopam at 0,1 mcg/kg/ min does not improve renal function and does not prevent aki in critically ill patients undergoing a strictly conservative strategy of fluid management. introduction: this study aims to evaluate the efficacy of a protocol implemented for dysphagia risk factors [1] in hospitalized patients in a cicu (coronary intensive care unit). methods: patients hospitalized in the cicu of a medium-sized hospital in presidente prudente, sp, brazil, were subjected to a survey that screened for dysphagia during the period from january of 2016 to september of 2017. patients with at least one risk factor for dysphagia were evaluated by a phonoaudiologist and are the subject of this study. the information was statistically analyzed using epi info, version 7.2.2.2 software. considering significant p <0.05 two-tailed, for logistic regressions multivariate estimated in the sample. results: for this study 1018 patients were selected, of which 57.41% were male and the mean age was 71.77 ± 10.96 years. a higher incidence of dysphagia was observed among patients who had at least one of the following risk factors: stroke (odds ratio 9.58 p<0.001); brain tumor (or 4.49 p=0.0013); chronic obstructive pulmonary disease (copd) (or 3.45 p=0.023); degenerative diseases (or 16.76 p<0.001); lower level of consciousness (or 13.62 p<0.001); ataxic respiration (or 2.24 p<0.001); aspiration pneumonia (or 7.04 p<0.001); orotracheal intubation >48h (or 13.35 p<0.001); tracheostomy (or 12.99 p<0.001); airway secretion (or 24.91 p<0.001); nasoenteral tube (or 14.9 p<0.001); gastrostomy (or 4.58 p=0.030). there was no statistical significance for age >60, traumatic brain injury, oropharyngeal surgery and unfavorable dentition. four factors appeared less than 3 times and could not be analyzed (chagas disease, human immunodeficiency virus (hiv), orofacial burn and excess saliva). conclusions: we concluded that the dysphagia triage protocol insertion was effective to identify dysphagic patients and can be used as an additional tool in the intensive care risk management. physiological bases of this age old concept, more recently applied to endotracheal intubation, have never been confirmed by current methods. we therefore decided to study the effects of an apnea oxygenation period under hfnc oxygen therapy by means of a novel modelization of the respiratory system. methods: firstly, an airway model was built with anatomical, physical and physiological attributes similar to that of a healthy subject (fig. 1) . this system reproduces the physiological evolution of intrapulmonary gases during apnea by progressively increasing co 2 levels after having cut off previous o 2 supplies (fio 2 21%). secondly, the effects of a hfnc apnea oxygenation of 50l/min with an fio 2 of 100% were analyzed by collecting intrapulmonary gas samples at regular intervals (fig. 2) . results: after 1 minute of apnea oxygenation, intrapulmonary oxygen levels remain stable at 21%. after 5 minutes, oxygen fraction reaches 33%, and increases up to 45% in 10 minutes. regarding co 2 levels, no significant modifications were observed. conclusions: a novel experimental and physiological model of the respiratory system has been developed and confirms the existence of an alveolar oxygen supply as well as the lack of a co 2 washout during hfnc apnea oxygenation. however, these effects are only observed after a delay of about 1.5 to 2 minutes. therefore, the clinical interests of this technique to reduce apnea-induced desaturation during intubation of a hypoxemic patient in the icu seem limited without adequate preoxygenation. combination of both preoxygenation and apnea oxygenation by hfnc can most likely explain positive results observed in other clinical studies. effect of 4% nebulized lignocaine versus 2% nebulized lignocaine for awake fibreoptic nasotracheal intubation in maxillofacial injuries in emergency department h abbas, l kumar king george's medical university,lucknow,india, lucknow, india critical care 2018, 22(suppl 1):p173 introduction: topical lignocaine is most commonly used pharmacological agent for anaesthetizing upper airway during fibreoptic bronchoscopy. we compare the effectiveness of two different concentrations, 2% lignocaine and 4% lignocaine, in nebulised form for airway anaesthesia during awake fibreoptic nasotracheal intubation in terms of patient's comfort and optimal intubating conditions, intubation time. methods: institutional ethics committee approved the study and written informed consent obtained; patients of either sex, between 18-55 years age with anticipated difficult airway planned for intubation were included for this study. patients were randomly allocated into two groups (a and b) based on sealed envelope method; patients and observers were blinded by using prefilled syringes of lignocaine.one group was nebulized with 10ml of 4% lignocaine(group a) and other with 10 ml of 2% lignocaine(group b) in coded syringes via ultrasonic nebuliser for 10 minutes followed by inj midazolam 0.05 mg/kg iv and inj fentanyl 1 microgram/kg iv just before the procedure. the fibreoptic broncoscope was introduced via nostril and the other nostril was used for oxygen insufflation (3-4 l/min). the fibroscope was introduced through the glottic opening and visualising tracheal rings and carina.the endotracheal tube railroaded over the fiberscope and cuff inflated. results: the primary outcome measure was patient's comfort during awake fibreoptic nasotracheal intubation. the mean patient comfort puchner scale score of group a was 1.30 ± 0.08 and of group b was 2.23 ± 0.12. the mean value of puchner scale of group b was significantly higher.the mean procedural time of group b was significantly higher (15.1%) as compared to group a (p<0.001). the no of intubations attempts did not differ between the two groups. conclusions: 4% nebulised lidocaine provided adequate airway anaesthesia and optimal intubating conditions, patient comfort, stable hemodynamics. introduction: this systematic review and meta-analysis aims to investigate whether video laryngoscopy (vl) improves the success of orotracheal intubation, when compared with direct laryngoscopy (dl). methods: a systematic search of pubmed, embase, and central databases was performed to identify studies comparing vl and dl for emergency orotracheal intubations outside the operating room. the primary outcome was rate of first pass intubation. subgroup analyses by location, device used, clinician experience, and clinical scenario were performed. the secondary outcome was rate of complications. results: the search identified 32 studies with 15,064 emergency intubations. there was no overall difference in first-pass intubation with vl compared to dl. subgroup analysis showed first-pass intubations were increased with vl in the intensive care unit (icu) (2.02 (1.43-2.85); p<0.01), but not in the emergency department or pre-hospital setting. rate of first-pass intubations were similar with glidescope® and dl, but improved with the cmac® (1.32(1.08-1.62); p=0.007). there was greater first-pass intubation with vl than dl among novice/trainee clinicians (or=1.95 (1.45-2.64); p<0.001), but not among experienced clinicians or paramedics/nurses. there was no difference in first-pass intubation with vl and dl during cardiopulmonary resuscitation or trauma. vl was associated with fewer oesophageal intubations than dl (or=0.31 (0.14-0.69); p=0.004), but more arterial hypotension (or=1.49 (1.00-2.23); p=0.05). conclusions: in summary, compared to dl, vl is associated with greater first-pass emergency intubation in the icu and among less experienced clinicians. vl is associated with reduced oesophageal intubations but a greater incidence of arterial hypotension. compared success rate between direct laryngoscope and video laryngoscope for emergency intubation, in emergency department: randomized control trial p sanguanwit, n laowattana ramathibodi hospital, bangkok, thailand critical care 2018, 22(suppl 1):p175 introduction: video laryngoscope was used as an alternative to intubate in the emergency room, designed for tracheal intubation more success [1, 2] . methods: we performed a prospective randomized controlled trial study of 158 patients who had sign of respiratory failure or met indication for intubation from july 2015 to june 2016. patients were randomly by snose technique; assigned to video laryngoscope first or direct laryngoscope first. we collect the demographics, difficult intubation predictor, rapid sequence intubation, attempt, cormack-lehane view and immediate complication. primary outcome was first attempt success rate of intubation. results: first attempt success rate of video laryngoscope was 73.1% trend to better than direct laryngoscope was 58.8%, (p=0.06), good glottic view (cormack-lehane view 1-2) of video laryngoscope was 88.5% better than direct laryngoscope 71.3%, and statistically significant (p=0.03), no statistical significant in immediate serious complication between direct laryngoscope or video laryngoscope. conclusions: compared to the success rate between using video laryngoscope or direct laryngoscope for intubation, video laryngoscope trend to better success rate, and better glottic view. 10-year cohort of prehospital intubations and rescue airway techniques by helicopter emergency medical service physicians: a retrospective database study p de jong, c slagt, n hoogerwerf radboudumc, nijmegen, netherlands critical care 2018, 22(suppl 1):p176 introduction: in the netherlands the pre-hospital helicopter emergency medical service (hems) is physician based and an adjunct to ambulance services. all four hems stations together cover 24/7 specialist medical care in the netherlands. in many dispatches the added value is airway related [1] . as part of our quality control cycle, all airway related procedures were analysed. high quality airway management is characterized by high overall and first pass endotracheal intubation (eti) success [2] . methods: the hems database was analysed for all patients in whom prehospital advanced airway management was performed in the period 2007-2017. balloon/mask ventilation, supraglottic airway (sga) devices, total intubation attempts, cormack & lehane (c&l) intubation grades, successful eti, primary and rescue surgical airway procedures and professional background were reviewed. results: in the 10-year period, there were 17075 dispatch calls. in total 8127 patients were treated in the prehospital setting by our hems. of those, 3233 required a secured airway. eti was successful in 3078 of 3148 (97.8%). in the remaining 70 patients ( fig. 1 ) an alternative airway was needed. rescue surgical airway was performed in 1.4%, 0.5 % received a rescue sga, rescue balloon/mask ventilation was applied in 0.2% of cases, 1 was allowed to regain spontaneous ventilation and in 0.1% of patients all airway management failed. hems physicians, ambulance paramedics, hems paramedics and others (e.g. german emergency physicians) had eti first pass success rates of 83.4%, 59.6%, 62.4% and 84.5% respectively (fig. 2) . difficult laryngoscopy (no epiglottis visible) was reported in 2.2% of patients (table 1) . conclusions: our data show that airway management performed by a physician based hems operation is safe and has a high overall eti success rate of 97.8%. the total success rate is accompanied by a high first pass eti success rate. introduction: incidences associated with endotracheal tubes are frequent during mechanical ventilation (mv) of intensive care unit (icu) patients and can be associated with poor outcomes for patients and detrimental effects on health care facilities. here, we aimed to identify factors associated with event occurrence due to unsafe management of endotracheal tubes (e-umet). methods: a retrospective observational study was conducted in three icus: one surgical icu, one stroke icu, and one emergency department, at a tertiary hospital in japan from 1 april 2016 to 31 march 2017. patients requiring mv and oral intubation during their icu stay were included. the primary finding was the incidence rate of e-umet (biting, unplanned extubations, and/or displacement of the endotracheal tube). the patients were divided into two groups: with or without e-umet. to investigate e-umet, potential factors possibly related to its occurrence were obtained from electronic medical records. we conducted univariable and multivariable analyses to investigate e-umet factors. results: of 410 patients, e-umet occurred in 112 (27.3%). the mean and standard deviation for age and acute physiology and chronic health evaluation (apache) ii score were 66 (17) and 25 (7), respectively. according to a multivariate logistic-regression analysis, significant risk factors associated with e-umet included patients of neurosurgery (odds ratio (or) 3.3; 95% ci, 1.51-7.46; p=0.003), sedative administration (or 2.9; 95% ci, 1.63-5.32; p<0.001), and higher richmond agitation-sedation scale (rass) scores (or 1.4; 95% ci, 1.24-1.77; p<0.001). the use of a restraint (or 0.4; 95% ci, 0.22-0.95; p=0.003) was an independent factor associated with a lower probability of e-umet. conclusions: this study suggests that risk factors associated with e-umet include neurosurgery, higher rass scores, and the administration of sedatives. patients with these factors and longer oral intubation periods might require extra care. introduction: the use of nasal high flow (nhf) as a respiratory support therapy post-extubation has become increasingly more common. nhf has been shown to be non-inferior to niv and reduces escalation needs compared to conventional oxygen therapy. clinical outcomes using nhf in patients with type ii respiratory failure (rf) is less well understood. our aim was to determine if nhf can be used successfully when extubating type ii rf patients compared to type i rf. methods: we conducted a retrospective observational study on the use of nhf as an extubation respiratory support in 56 (n=56) consecutive patients in icu over a 12-month period. primary outcome was the need for escalation in therapy (niv, intubation and palliation) post extubation. patients were categorised as high risk if they scored >=1 from: age>=75 years, bmi>=30 and >=1 medical comorbidity. results: analysis was conducted on all fifty-six (n=56) patients. type i rf group was composed of 25 (n=25) patients with a mean age of 62.7 (±sd) years. type ii rf group had 31 (n=31) patients with a mean age of 65.5 (±sd) years. in type i rf 22 patients (88%) were successfully extubated with nhf compared to 21 patients (67.7%) in type ii. in type ii rf the outcomes were more variable with a greater requirement for niv. of these patients 16% required niv, 3.2% required intubation and 12.9% received nhf therapy for palliation. a higher average bmi (30.32 vs 27.16 kg/m2) was found in unsuccessfully vs successfully extubated patients in type ii rf. in type i rf escalation of therapy was equally distributed with 4% in each category. conclusions: the use of nhf for respiratory support post-extubation may become standard practice for type i rf in critical care settings. our data suggests that nhf can be used but with caution in type ii rf and clinicians should risk stratify patients to identify those at risk of re-intubation and post-extubation respiratory failure. introduction: pathogenesis of ventilator-associated pneumonia (vap) relies on colonization and microaspiration. oral topical decontamination reduced the vap incidence from 18 to 13% [1] . the persistence of antiseptic effect in the oral cavity is questionable; we hypothesize that continuous oral antiseptic infusion may offer a better decontamination. aim of the work: we developed endotracheal tube that allows continuous oral infusion of chlorhexidine (chx), and we want to test the technique versus the conventional on bacterial colonization. (provisional patent: 62359944) methods: a two identical bio models for the upper airways were manufactured by (3dx diagnostics, usa) to adapt the modified and the ordinary endotracheal tubes (ett). the two techniques tested were using six hourly disinfection with chx (group a) versus disinfection through the 24 hours infusion technique (group b). five microorganisms plus mixed bacteria were used and each was tested for five times. normal saline was used constantly to irrigate the biomodels and ten ml aliquot was collected by the procedure end. culturing of the aliquots from decanted broth pre and post disinfection was performed. the time to apply chx by practitioner was also compared. results: there was a trend towards lower bacterial growth in group a in 5 experiments which reach statistical significance only with pseudomonas aeruginosa (p=0.045). in one experiment the growth was lower in group b (fig. 1) . additionally there was time saving advantage in group b (15±3.3 versus 5±1.2 min, p=0.01). conclusions: the novel technique got at least non inferior results, plus time saving advantage. these results may warrant future clinical trial. monitoring airways non invasive online analysing different particle flow from the airways is never done before. in the present study we use a new technology for airway monitoring using mass spectrometric analysis of particle flow and their size distribution (pexa particles in expired air). the exhaled particles are collected onto a substrate and possible for subsequent chemical analysis for biomarkers. our hypothesis was that by analysing the particle flow online, we could optimise the mechanical ventilation. our hypothesis was that a small particle flow would probably be more gentle for the lung than a large particle flow when the lung is squeezed out and the majority of all small airways are open. methods: in the present study we analyse the particle flow from the airways in vivo, post mortem and during ex vivo lung perfusion using different ventilation modes; volume controlled ventilation (vcv) and pressure controlled ventilation (pcv) comparing small tidal volumes(1) versus big tidal volumes(2) at different peep (positive end-expiratory pressure) and after distribution of different drugs in six domestic pigs. results: we found that vcv resulted in a significant lower particle flow than pcv in vivo but in ex vivo settings the opposite was found (fig. 1 ). in both in vivo and ex vivo settings we found that big tidal volume resulted in a larger particle flow than small tidal volumes.air. the opening and the closure of the small airways reflect the particle flow from the airways. we found that different ventilation modes resulted in different particle flow from the airways. we believe this technology will be useful for monitoring mechanical ventilated patients to optimise ventilation and preserve the lung quality and has a high potential to detect new biomarkers in exhaled air. introduction: malaria is a common problem in underdeveloped countries, with an estimated mortality of more than one million people per year. pulmonary involvement is one of the most serious manifestations of plasmodium falciparum malaria. non-invasive ventilation (niv) decreases muscular works and improves gas exchange by recruitment of hypoventilated alveolus. in this context, we analyze the impact of the use of non-invasive ventilation in malaria with pulmonary dysfunction. methods: it's a retrospective cohort study. we analyzed electronic records of patients who were diagnosed with malaria, with acute respiratory failure, who underwent respiratory therapy with niv between 2015-2016 within the intensive care unit (icu). the study variables were: icu mortality, length of hospital stay, niv time and outcome groups. statistical analysis was performed with the pearson correlation coefficient, with significance level of p <0.01. the statistics were performed using the bioestat 3.0 program. results: thirty-one patients were included in the study. four results were analyzed according to table 1 and fig. 1 . 94% of the patients were discharged from the hospital. pearson's correlation coefficient analysis showed statistical significance in the group (niv/discharge) in the analysis of patients hospitalized versus niv (95% ci = 0.24 to 0.83 <(p) = 0.0036). conclusions: the use of niv was positive in patients using this resource as first-line treatment of malaria in the fight against respiratory decompensation, with improvement of symptoms. introduction: cpap is used to improve oxygenation in patient with arf. we aimed to determine non-inferiority (ni) of helmet cpap to facemask in arf based on physiological (heart rate (hr) and respiratory rate (rr)) and blood gas parameters (pao2 and paco2). we also compared patients' perception in dyspnea improvement after cpap using dyspnea scale (visual analogue scale (vas)) and likert score. methods: we randomized 123 patients to helmet (n=64) and facemask (n=59) with 71.7% of arf was due to acute pulmonary edema. cpap was applied for 60 minutes. patients' physiological and blood gas parameters were recorded before and after intervention. patients then marked on dyspnea scale and likert score. ni of helmet would be declared if confidence interval (ci) of mean difference between groups (helmet's mean minus facemask's mean) in improving physiological, blood gas parameters and dyspnea scale was no worse than predetermined non-inferiority margin (nim). secondary outcome was to compare incidence of discomfort and mucosal dryness between groups. methods: this is a single center retrospective study performed in the icu of tel aviv medical center, israel, a tertiary academic referral hospital. using the electronic medical record system and intensix predictive critical care system for analysis, all patients admitted to the icu between 1.2007 and 12.2014 were assessed. respiratory deterioration in mv patients was defined as acute adjustment of fio2 increase >20% or peep increase > 5 cmh2o that persisted for at least 2 hours. the primary outcome was icu mortality. secondary outcome was length of icu stay (los). a chi square test for trends was used for the significance of mortality data and a one way anova test for los. results: 5376 mv patients were admitted to the icu with an overall mortality of 16.5%. mortality and los were tripled in patients who experienced at least one respiratory deterioration when compared to no events (33.8% vs. 9.9 %, p<0.0001 and 10.7 vs. 2.2 days, p<0.0001 respectively) (fig. 1) . increased events of respiratory deteriorations showed significant trend of increased mortality (p<0.0001). conclusions: in mv patients, a single respiratory deterioration event carries a 3 times higher mortality rate and length of stay (los). any additional event further increases both parameters. association of lung ultrasound score with mortality in mechanically ventilated patients j taculod, jt sahagun, y tan, v ong, k see national university hospital singapore, singapore, singapore critical care 2018, 22(suppl 1):p191 introduction: lung ultrasound is an important part of the evaluation of critically ill patients. it has been shown to predict recruitability in acute respiratory distress syndrome. however, little is known about the application of lung ultrasound in predicting mortality in mechanically ventilated patients. methods: observational study of mechanically ventilated patients admitted to the medical intensive care unit (icu) of a tertiary hospital (national university hospital, singapore) in 2015 and 2016. only the first icu admissions of these patients were studied. lung ultrasound was done at six points per hemithorax and scored according to soummer (crit care med 2012): normal aeration = 0; multiple, well-defined b lines =1; multiple coalescent b lines = 2; lung consolidation = 3. the lung ultrasound (lus) score was calculated as the sum of points (score range 0-36). we analysed the association of lus score with icu/hospital mortality, using logistic regression, adjusted for age and acute physiology and chronic health evaluation (apache) ii score. results: 247 patients were included (age 62.0 ± 16.2 years; 89 female [36.0%]; apache ii 29.7 ± 7.9; 88 sepsis diagnosis [35.6%]). icu and hospital mortality were 16.2% and 29.6% respectively. lus score was associated with increased icu (or 1.04, 95% ci 1.00-1.09, p=0.07) and hospital (or 1.04, 95% ci 1.00-1.08, p=0.045) mortality, adjusted for age and apache ii score. conclusions: lus score was associated with increased icu/hospital mortality and may be useful for risk stratification of mechanically ventilated patients admitted to icu. introduction: ventilator asynchrony results in morbidities and mortality. the aim of this study was to explore whether and how physicians used patient-ventilator interactions(pvi) to set mechanical ventilators(mv) in thailand. methods: thai physicians treating mv patients were asked to respond to questionnaires distributed in conferences and to e-mails sent. types of asynchronies encountered and frequency of mv adjustment guided by pvi were evaluated. in addition, correlations between physician's knowledge and 1)confidence to manage asynchronies and 2)their experience were analyzed. results: two hundred and eleven physicians answered the questionnaires. most of them were medical residents and icu specialists. 82% of them set and adjusted mv by asynchrony guidance and the majority used waveform analysis to more than a half of their patients. the most and the least common asynchronies encountered were double triggering and reverse triggering, respectively, while the most difficult-to-manage and the most easily managed asynchronies were periodic/?a3b2 show $132#?>unstable breathing and flow starvation, respectively. lack of confidence and knowledge of pvi were the major reasons of physicians who did not perform asynchrony assessment. for knowledge evaluation, more than 50% of physicians incorrectly managed asynchrony. chest and icu fellows had the greatest skills in waveform interpretation and asynchrony management with the mean score of 2.62 from the total 5, compared with specialist(2.58), medical residents(1.85), internists(1.84) and general practitioner(0.85). there were poor correlations between years' experience in mv management and the skill in waveform interpretation (r = 0.15, p=0.034) and between physician's confidence in pvi management and the clinical skill (r = 0.27, p<0.001) conclusions: the majority of thai physicians realized the importance of pvi, but the skill in asynchrony management was moderate. intensive programs should be provided to improve their clinical performance. methods: six deeply anesthetized swine underwent tracheostomy, thoracostomy and experimental plef with 10 ml/kg of radiopaque saline randomly instilled into either pleural space. animals were ventilated at vt=10ml/kg, frequency=15bpm, i/e=1:2, peep=1cmh2o, and fio2=0.5. quantitative lung computed tomographic (ct) analysis of regional aeration and global frc measurements by nitrogen wash-in/wash-out technique were performed in each of these randomly applied positions: semi-fowler's (inclined 30°from horizontal in the sagittal plane); prone, supine, and lateral positions with dependent plef and non-dependent plef (fig. 1) . results: no significant differences in frc were observed among the horizontal positions, either at baseline (p=0.9037) or with plef (p=0.58) ( fig. 2a) . however, component sector total gas volume in each phase of the tidal cycle were different within all studied positions with and without plef (p=<.01). compared to other positions, prone and lateral position with non-dependent plef had a more homogenous vt distribution among quadrants (p=.051, fig. 2b ). supine was associated with most dependent collapse (fig. 2c ) and greatest tendency for tidal recruitment (48% vs~22%, p=0.0073, fig. 2d ). conclusions: changes in body position in the setting of effusioncaused chest asymmetry markedly affected the internal distributions of gas volume, collapse, ventilation, and tidal recruitment, even when commonly used global frc measurements provided little indication of these important positional changes. of the respondents, 80% were affiliated with multidisciplinary icus, 14% with thoracic and/or cardiac icus and 6% with neuro-icus. most respondents (79%) had completed their specialist training. overall, arterial oxygen tension (pao 2 ) was the preferred parameter for the evaluation of oxygenation (fig. 1 ). the proportions of doctors' preferences for increasing, decreasing or not changing an fio 2 of 0.50 in two (out of six) patient categories at different pao 2 levels are presented in table 1 and table 2 . conclusions: this is the largest survey of the preferred oxygenation targets among icu doctors. pao 2 seems to be the preferred parameter for evaluating oxygenation. the characterisation of pao 2 target levels in various clinical scenarios provide valuable information for future clinical trials on oxygenation targets in critically ill icu patients. introduction: sonographic assessment of diaphragmatic excursion and muscle thickening fraction have been suggested to evaluate diaphragm function during weaning trial [1] . the purpose of this study is to compare these two parameters to predict extubation success. methods: this prospective study was carried out during 9 months from march to november 2017. we enrolled patients who were mechanically ventilated for more than 48h and met all criteria for extubation. the non inclusion criteria were: age < 18 years, history of neuromuscular disease or severe chronic respiratory failure. we excluded subjects who needed reintubation for upper airway obstruction, neurological or hemodynamic alteration. the scenario involves a patient expected to receive mechanical ventilation for at least 24 hours in the icu. all proportions are percentages of respondents with 95% confidence intervals. *p < 0.001 for comparisons of proportions of "no change" versus adjacent lower pao2 level (mcnemar's test) introduction: ventilator induced diaphragmatic dysfunction is known to be a contributor to weaning failure. some data suggest that assisted ventilation might protect from diaphragmatic thinning. aims of this study are to evaluate, by ultrasound (us), the change in diaphragm thickness and thickening in patients undergoing controlled and assisted mechanical ventilation (mv) and clinical factors associated with this change. methods: we enrolled patients who underwent either controlled mv (cmv) for 48 cumulative hours or 48 hours of pressure support (psv) if ventilation was expected to last for at least 5 days. patients < 18 years old, with neuromuscular diseases, phrenic nerve injury, abdominal vacuum dressing system and poor acoustic window were excluded. diaphragm thickness and thickening were measured with us as described by goligher and clinical data were collected every 48 hours until icu discharge. results: we enrolled 44 patients, 13 were excluded because they had less than 4 measurements and 2 for low quality images, leaving 29 patients for analysis. as expected, during cmv diaphragm thickening was almost absent and significantly lower than during psv (p<0,001). diaphragm thickness did not reduce significantly during cmv (p=0.201), but during psv significantly increased (p<0.048) (fig. 1 , where "day 0" represents the first day of psv). during cmv, in 10/21 patients diaphragm thickness showed a >=10% reduction. they had a significantly higher fraction of days spent in cmv (p=0.005) and longer neuromuscular blocking drugs (nbds) infusion (p=0.043). during psv, 17/26 patients showed an increase in diaphragm thickness >=10%. duration of hospital stay was significantly lower for these patients (p 0.048). differences between the two groups are reported in table 1 . conclusions: longer time spent in cmv and with nbds infusion seems associated with a decrease in diaphragm thickness. assisted ventilation promotes an increase in diaphragm thickness, associated with a reduction in the length of hospitalization. prediction of intrinsic positive end-expiratory pressure using diaphragmatic electrical activity in neutrally-triggered and pneumatically-triggered pressure support f xia nanjing zhongda hospital, southeast university, nanjing, china critical care 2018, 22(suppl 1):p199 introduction: intrinsic positive end-expiratory pressure (peepi) may substantially increase the inspiratory effort during assisted mechanical ventilation. our purpose of the study was to assess whether electrical activity of the diaphragm (eadi) can be reliably used to estimate peepi in patients undergoing conventional pneumaticallycontrolled pressure support (psp) ventilation and neutrally-controlled introduction: atelectasis develops in critically ill obese patients submitted to mechanical ventilation. the pressure exerted by the abdominal weight on the diaphragm causes maldistribution of ventilation with increased pleural pressure and diminished response to peep. our objective was to analyze the effects of peep in the distribution of ventilation in obese and non-obese patients according to bmi (obese >= 30 kg/m 2 , or non-obese: 20 to 29.9 kg/m 2 ), using electrical impedance tomography (eit). methods: we assessed the regional distribution of ventilation of surgical and clinical patients submitted to a decremental peep itration monitored by eit. we calculated the percent ventilation to the nondependent (anterior) lung regions at the highest and lowest peep applied. the highest compliance of respiratory system was consistently observed at intermediate values of peep (between those extreme values), indicating that the highest peep caused pulmonary overdistension, whereas the lowest peep likely caused dependent lung collapse results: were enrolled 37 patients, with 15 non-obese patients (25,7±2 kg/m 2 ) and 22 obese patients (32.4± 1.7 kg/m 2 ). all patients presented progressively decreased ventilation to dependent (posterior) lung regions when peep was lowered (p<0.001). obese patients consistently presented higher ventilation to the anterior lung zones (when compared no nonobese), fig. 1 introduction: lung protective ventilation is the mainstay of mechanical ventilation in critically ill patients [1] . extracorporeal co2 removal (ecco2r) can enhance such strategies [2] and has been shown to be effective in low flow circuits based on renal replacement platforms [3, 4, 5] . we show the results of a pilot study using a membrane lung in combination with a hemofilter based on a conventional renal replacement platform (prismalung™) in mechanically ventilated hypercapnic patients requiring renal replacement therapy (nct02590575). methods: the system incorporates a membrane lung (0.32 m2) in a conventional renal replacement circuit downstream of the hemofilter. 26 mechanically ventilated patients requiring renal replacement therapy were included in the study. patients had to be hypercapnic at inclusion under protective ventilation. changes in blood gases were recorded after implementation of the extracorporeal circuit. thereafter ventilation was intended to be decreased per protocol until baseline paco2 was reestablished and changes in vt and pplat were recorded. data from 20 patients were included in the final analysis. results: the system achieved an average co2 removal rate of 43.4 ±14.1 ml/min which corresponded to a paco2 decrease from 68.3 ±11.8 to 61.8±11.5 mmhg (p<0.05) and a ph increase from 7.18±0.09 to 7.22±0.08 (p<0.05) [ fig. 1 ]. after adaption of ventilator settings we recorded a decrease in vt from 6.2±0.9 to 5.4±1.1 ml/kg (p<0.05) and a reduction of pplat from 30.6±4.6 to 27.7±4.1 cmh2o (p<0.05). these effects were even more pronounced in the "per protocol" analysis [ fig. 2 ]. conclusions: low flow ecco2r in combination with renal replacement therapy provides partial co2 removal at a rate of over 40 ml/min can significantly reduce invasiveness of mechanical ventilation in hypercapnic patients. introduction: in ecco2r-crrt, efficiency of co2 removal is higher positioning the oxygenator (oxy) up-stream than down-stream the haemofilter due to higher blood flow (bf) [1] . we tested whether this effect was due to lower pre-filter pressure (pfp). methods: ecco2r-crrt circuit was tested in-vitro (n=10) with the following settings: 5 l bovine blood; bf 450 ml/min; oxy 1.81 m2 (euroset); cvvh post mode; substitution flow 2500 ml/h; uf rate function off; 1.5 m2 haemofilter (diapact®, b.braun avitum); sweep air flow 4.5 l/min. pfp was evaluated at baseline, 24, 48 and 72 hours. co2 extraction was measured at bf of 100, 300 and 500 ml/min. sweep air flow/blood ratio was 1:10. co2 was add to obtain paco2 of 80 mmhg. co2 removal rate calculation (2): co2 removal rate = (co2 ecco2r inlet-co2 ecco2r outlet)* blood flow (eq.1) co2 molar volume at 25°c [l/mol] = 24; solubility of co2 at 37°c = 0.03 mmol/(l*mmhg); hco3i = inlet hco3 concentration [mmol/l]; hco3o = outlet hco3 concentration [mmol/l]; pi co2 = inlet co2 partial pressure [mmhg]; poco2 = outlet co2 partial pressure [mmhg] equation1 becomes: co2 removal rate=24 x ((hco3i + 0.03 x pico2) -(hco3o + 0.03 x poco2)) x blood flow (eq.2) results: bf of 450 ml/min was always reached with the up-stream configuration. bf was reduced to 400 ml/min with the down-stream configuration due to high pfp alarm (table 1 ). co2 removal increased to 34.5 ±13.9 to 69.1±29.5, and 126.0±28.4 ml/min, at bf of 100, 300 and 500 ml/ min (p<0.05). conclusions: bf of 500 ml/min can be reached only with the upstream configuration due to lower circuit pfps. bf directly correlates to co2 removal efficiency. we may speculate that simultaneous use of crrt and lf-ecco2r and activation of the uf rate function with the down-stream setting may further increase pfp thus forcing to more enhanced reduction of bf and less effective co2-removal. introduction: we describe the use of a novel low-flow ecco2r-crrt device (prismalung-prismaflex, baxter healtcare gambro lundia-ab-lund, sweden) for simultaneous lung-renal support. methods: a retrospective review of patients submitted to prismalung-prismaflex due to aki associated to hypercapnic acidosis during the period may 2016 -august 2017 at prato hospital icu was performed. data collected were: demographic, physiologic, complications, outcome. data were presented as mean ± ds; anova test was used to compare changes of parameters over time; significance was set at p< 0,05. results: we identified 13 patients (mean age 71 ± 13 yr, mean sofa 12 ± 3). causes of hypercapnia were moderate ards (n=4) and ae-copd (n=9). in all patients a 13fr double lumen cannula was positioned and 350 ml/min blood-flow with 10 lt oxygen sweep-gas-flow was maintained; iv-heparin aiming to double aptt was used. haemo-diafiltration (effluent flow 35 ml/kg/hour) was delivered. in all cases prismalung-prismaflex improved respiratory and metabolic parameters (figs. 1 and 2) without any complications. all patients survived to the treatment, nevertheless 2patients (1ae-copd; 1ards) died during icu stay due to irreversible cardiac complications. in ards cases: 3 patients were successfully weaned from imv, mean duration of the treatment was 88 ± 31hours, mean duration of imv after ecco2r-crrt was 2 ± 2 days. in ae-copd cases: intubation was avoided in 3 patients at risk of niv failure, 6 patients were successfully weaning from imv, mean duration of the treatment was 79 ± 31 hours, mean duration of imv after ecco2r-crrt was 0,1 ± 0,3 days. fig. 1 (abstract p201) . 30 minutes after implementation of the combined renal replacement and ecco2r circuit a moderate decrease in paco2 (-6.5 mmhg) corresponding to a slightly higher ph (0.04) was observed conclusions: the use of prismalung-prismaflex has been safe and effective: it may be argued that it could be due to the low-blood-flow used. the positive results of this preliminary study may constitute the rational for the design of a larger randomized control trial. systemic il-18 production and spontaneous breathing trial (sbt) outcome: the effect of sepsis introduction: spontaneous breathing trial (sbt), a routine procedure during ventilator weaning, entails cardiopulmonary distress, which is higher in patients failing the trial. an intense inflammatory response, expressed by increased levels of pro-inflammatory cytokines, is activated during sbt. sepsis, a common condition in icu patients, has been associated with increased levels of the pro-inflammatory cytokine il-18. il-18 produced among others by skeletal muscles, has been associated with severe muscle wasting and maybe by icu acquired weakness. we hypothesised that il-18 increases during sbt, more evidently in sbt failures. we anticipate this response to be more pronounced in formerly septic patients fulfilling the criteria for sbt. methods: 75 sbts of 30-min duration were performed and classified as sbt failure or success. blood samples were drawn before, at the end of the sbt and 24 hours later. serum il-18 levels and other inflammatory mediators, commonly associated with distress, were determined and correlated with sbt outcome. subgroup analysis between septic and non-septic patients was performed. 2)kg/m2) were monitored for 42.0±0.9 hours. 49985 apneas were identified ranging from 10-117s (fig. 1a) . apneas were observed in 99% of patients, suggesting low predictability of respiratory insufficiency. the average mv was 73±2.4%mvpred, as patients were often sleeping or mildly sedated. we assessed the effects of each apnea on the temporally associated mv (fig. 1b) . while apneas ranging in length from 10-18s decrease mv by as much as 30%, their effect over 1min is <10%. on a 2min time scale, even 60s apneas led to lowmv just 20% of the time (fig. 1c) . conclusions: while apneas were ubiquitous, they seldom led to lowmv over clinically relevant time scales. large compensatory breaths following an apnea generally restored mv to near pre-apnea levels. nonetheless, some apneas can become dangerous when ignored, as when subsequent sedation decreases compensatory breath size. rvm data provide a better metric of respiratory competence, driving better assessment of patient risk and individualization of care. introduction: diffuse alveolar hemorrhage (dah) is an acute lifethreatening event and recurrent episodes of dah may result in irreversible interstitial fibrosis. identifying the underlying cause is often challenging but is needed for optimal treatment. lung biopsy is often performed in the diagnostic evaluation of patients with suspected dah. however, the role of lung biopsy in this clinical context is unclear. hence, we sought to identify the spectrum of histopathologic findings and underlying causes in patients with dah who underwent lung biopsy, surgical or transbronchial. methods: we identified 59 patients who underwent surgical lung biopsy (n = 25) or bronchoscopic biopsy (n = 34) in the evaluation of dah over a 19-year period from 1999 to 2017. we extracted relevant clinical pathologic and laboratory data. results: the median age in our cohort was 67 years with 51% females. serologic evaluation was positive in 47% of patients (n=28). most common histopathologic findings on surgical lung biopsy included alveolar hemorrhage (ah) with capillaritis in 11 patients of whom six had necrotizing capillaritis, followed by ah without capillaritis in 7 patients. the most common histopathologic finding on bronchoscopic lung biopsy was ah without vasculitis/capillaritis in 22 patients, followed by ah with capillaritis in 11 patients. there were no procedure related complications or mortality observed with either method of lung biopsy. the clinico-pathologic diagnoses in these patients are shown in tables 1 and 2 . conclusions: in patients with dah undergoing lung biopsy alveolar hemorrhage without capillaritis was found to be the most common histopathologic finding followed by pulmonary capillaritis. these histopathologic findings contributed to the final clinico-pathologic diagnoses of granulomatous polyangiitis and microscopic polyangiitis in a substantial portion of cases. future studies are needed to ascertain the benefits vs. risks of lung biopsy in patients with suspected dah. note that, an apnea of 30-sec will (by definition) drive mv over a 30-sec window down to 0, but will only decrease mv over a 60-sec window down to~35% mvpred and to less than 60% over a 2-min window. (c) likelihood of an apnea of specific length to decrease mv below the low mv cutoff over various time windows. note that a single 10-sec apnea has just a 25% chance to decrease mv below 40% in a 30-sec window and less than 2% chance to decrease mv below the cutoff over a 2-min window. even 60-sec apneas have just 20% chance of decreasing sustained mv over a 2-min window below the 40% mvpred cutoff (4) granulomatosis polyangitis (4) ah without capillaritis (7) antiphospholipid syndrome (1) microscopic polyangitis (1) ah with diffuse alveolar damage(4) microscopic polyangitis (3) ah with pulmonary vascular changes(1) pulmonary hypertension(1) introduction: assessing the sensitivity of the peripheral chemoreflex (spcr), we can predict the likelihood of developing respiratory and cardiovascular disorders. spcr is one of the markers of disease progression and good prognostic marker [1] . disturbed respiratory mechanics can make it difficult to evaluate. breath-holding test may be helpful in such situation, the results of this test are inversely correlated with peripheral receptor sensitivity to carbon dioxide in healthy people [2] .the aim of the study was to compare the breath-holding test to single-breath carbon dioxide test in the evaluation of the sensitivity of the peripheral chemoreflex in subjects with copd. methods: the study involved 78 patients with copd with fev1/fvc <70% of predicted, all participants were divided into two groups depending of disease severity (gold classification, 2017). in group 1 (mild-to-moderate copd, n=46) all patients had fev1>=50% and in group 2 (severe-to-very severe copd, n=32) all patients had fev1<50%. breath-holding test was performed in the morning before breakfast: voluntary breath-holding duration was assessed three times, with 10 min intervals [2] . a mean value of the duration of the three samples was calculated. the single-breath carbon dioxide test [3] was performed the next day. the study was approved by the local ethics committee. all subjects provided signed informed consent to both tests. and january 2017. the data was collected from the hospital electronic and paper notes, and data collected was mortality rate, apa-che ii score, icnarc score, type of respiratory support received and whether there was documentation of advanced decisions in case of acute deterioration. results: there were 12 patients admitted to the icu with acute respiratory failure as a complication of pulmonary fibrosis. the median apache ii score was 22 and icnarc standardised mortality ratio was 5.2. nine patients died on icu (75%) and hospital mortality was ten (83%). eight patients (67%) received high flow nasal oxygen, six (50%) received non-invasive ventilation, and two (17%) received invasive ventilation. the median time to death was 3.7 days. of 11 patients for whom paper notes were available, no patient had any documented ceiling of care or end of life decisions. conclusions: our study confirmed a very high mortality in this cohort of patients, supporting national guidance that invasive respiratory support has limited value. we advise that frank discussion with patients and their families should happen early after diagnosis, such that end of life plans are already in place in the event of acute deteriorations. introduction: arf is common in critically ill patients. we compared diaphragm contractile activity in medical and surgical patients admitted to icu with a diagnosis of arf. methods: adult medical and major abdominal laparotomic surgical patients admitted to a general icu with a diagnosis of arf were enrolled. arf was defined as a pao2/fio2 ratio<=300 mmhg/% and need for mechanical ventilation (mv) for at least 24 hours. diaphragmatic ultrasound was realized bedside when the patient was stable and able to perform a trial of spontaneous breathing. a convex probe was placed in right midaxillary line (8th-10th intercostal space) to evaluate right hemidiaphragm. diaphragmatic respiratory excursion and thickening were evaluated in m-mode on 3 consecutive breaths and thickening fraction (tf) was calculated. antropometric, respiratory and hemodynamic parameters, saps2, sofa score, duration of mv, need for tracheotomy and timing, septic state and site of infection, superinfections, icu and inhospital length of stay (los) and outcome were recorded. patients with trauma and neuromuscular disorders were excluded. p<0.05 was considered significant. results: we enrolled 30 patients: 40% medical and 60% surgical, without differences for age, sex, bmi, saps2, sofa score, sepsis and superinfections. moderate arf was prevalent in both groups. during diaphragmatic examination, no differences were recorder for respiratory rate, hemodynamic state and fluid balance. surgical patients showed a lower but not significant diaphragm excursion (1.6vs1.8cm), instead tf was significantly reduced (58vs90%,p<0.05). no differences emerged on duration of mv, but tracheotomy were higher in medical ones (30vs11%,p<0.05). icu and inhospital los do not differ between medical and surgical patients and mortality rate was respectively 17% and 22%. conclusions: in arf, surgical patients showed a lower diaphragm contractility compared to medical ones, maybe due to the combination of anesthetic and surgical effects, but with no influence on outcome. (fig. 1) . the slope of the regression line for pes/paw plots was consistently higher for slow compressions (0.98 ± 0.08), as compared to fast ones (0.84 ± 0.05). a good agreement between δ pes and δ paw (fig. 2 ) was found during slow maneuvers, but not during the fast ones. conclusions: slow chest compressions must be used when checking position/inflation of esophageal balloon. the fast maneuver produces hysteresis and underestimation of δ pes (but not in direct δ ppl). pes monitoring at high respiratory rates may be problematic. methods: 20 consecutive comatose post cardiac arrest patients were ventilated with volume assist ventilation (6 ml/kg ibw, peep 5 cm h2o) using elisa 800eit (lowenstein medical, ge). orogastric tube (nutrivent, sidam, it) was inserted, and eit vest (swisstom ag, ch) was applied in all patients. measurements were performed 60 min after admission and after 3 hrs (fig. 1) . optimal peep was defined as lower inflection point using pv curve (pv), positive ptpeep (ptp) and optimal regional stretch/silent spaces (eit) results: methods to determine peep using pv, ptp and eit were comparable in non obese patients (p=ns introduction: the driving pressure of respiratory system (dp) reflects the extent of lung stretch during tidal breathing, and has been associated with mortality in ards patients during controlled mechanical ventilation [1] . aim of this study was to examine dp during assisted ventilation, and examine if and when high dp occurs in patients in assisted ventilation with pav+. methods: critically ill patients hospitalized in the icu of the university hospital of heraklion, on mechanical ventilation in pav+ mode were studied. continuous recordings of all ventilator parameters were obtained for up to three days using a dedicated software. dp was calculated from the pav+ computed compliance (c) [2] , and the measured exhaled tidal volume (vt, dp=vt/c). periods of sustained dp above 15 cmh2o were identified, and ventilation and clinical variables were evaluated. results: sixty-two patients and 3200 hrs of ventilation were analyzed. in half of the patients, dp was lower than 12 cmh2o in 99% of the recording period, while high-dp (>15cmh2o) more than 10% of the total time was observed in 10% of patients. icu non-survivors had more time with high dp than survivors (p=0.04). periods of sustained high-dp (>15cmh2o for >1h) were observed in 9 patients. level of assist, minute ventilation, and respiratory rate were not different between the periods of high dp and the complete recordings, while vt was higher and c was lower during the high-dp period compared to the complete recording. the median compliance was below 30 ml/ cmh2o during the high-dp period, and above 50 ml/cmh2o during the complete recording. conclusions: high dp is not common, but does occur during assisted ventilation, predominantly when compliance is below 30 ml/cmh2o, and may be associated with adverse outcome. table 1 summarizes the percent of monitored time with reported data for the two devices. figure 1 depicts mv decrease following propofol and cannula dislodgement folfig. 1 (abstract p220) . bland-altman analysis demonstrated that cvp-derived δppl and δpes were correlated significantly lowing a jaw thrust. table 2) . negative (a-et) pco2 was strongly associated with good outcome and were significantly associated with overall survival (fig. 1 ) conclusions: in conclusion, the negative arterial to end-tidal co2 pressure gradient may predict patient survival in some subgroups. introduction: ards may result from various diseases and is characterized by diffuse alveolar injury, lung edema formation, neutrophil-derived inflammation and surfactant dysfunction. various biomarkers have been studied in diagnostics and prognostication of ards. the purpose of the study was to measure the expression of proinflammatory mediators like il-8 and tnf, a cellular receptor with a role in innate immunity(tlr-2),and a biomarker of fibrogenesis (mmp-7) in different phases of ards patients. methods: we studied 4 patients admitted to our icu with diagnosis of ards during the month of january 2016. six ml of blood were prospectively collected at two times: during the acute phase and in a sub-acute phase before icu discharge. blood samples were centrifuged to obtain the platelet-rich plasma and plasmatic rna (crna) was isolated from platelets.il-8, tnf, tlr-2 and mmp-7 expression in crna was determined by the droplet digital™ pcr as copies/ml. results: all patient showed a decrease in il-8, tnf, tlr2 and mmp-7 levels after the acute phase of ards (fig. 1) . patient 1 and 3 were affected by influenza a virus (h3n2), patient 2 was admitted for pneumococcal pneumonia and patient 4 was affected by legionella. adequate ethiologic treatment was promptly started in patients with bacterial infection. mean duration of mechanical ventilation was 17.5 days. all patient survived icu stay and were discharged from hospital. conclusions: il-8, tnf, tlr-2 and mmp-7 expression detected by extracted platelets rna, may be a novel tool useful for clinicians indicating persistent inflammation with resulting progressive alveolar fibrosis and impaired lung function. more data are necessary to understand the real clinical significance of this biomarkers and their role in fibroproliferation and progression of ards. introduction: although mesenchymal stem cells (mscs) transplantation has been shown to promote lung respiration in acute lung injury (ali) in vivo, its overall restorative capacity appears to be restricted mainly because of low engraftment in the injured lung. ang ii are upregulated in the injured lung. our previous study showed that ang ii increased mscs migration in an angiotensin ii type 2 receptor (at2r)dependent manner [1] . the objective of our study was to determine whether overexpression of at2r in mscs augments their cell migration and engraftment after systemic injection in ali mice. methods: a human at2r expressing lentiviral vector was constructed and introduced into human bone marrow mscs. we also downregulated at2r mrna expression using a lentivirus vector carrying at2r shrna to transduce mscs. the effect of at2r regulation on migration of mscs was examined in vitro. a mouse model of lipopolysaccharide (lps) induce ali was used to investigate the engraftment of at2r-regulated mscs and the therapeutic potential in vivo. results: overexpression of at2r dramatically increased ang ii-enhanced human bone marrow msc migration in vitro. moreover, msc-at2r accumulated in the damaged lung tissue at significantly higher levels than control mscs 24h and 72h after systematic msc transplantation in ali mice. furthermore, msc-at2r-injected ali mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti-inflammatory effects. in contrast, there were less lung engraftment in msc-shat2r-injected ali mice compared with msc-shcontrol after transplantation. thus, msc-shat2r-injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. conclusions: our results demonstrate that overexpression of at2r enhance the migration and lung engraftment of mscs in ali mice and may provide a new therapeutic strategy for the injured lung. introduction: reorganization of endothelial barrier complex is critical for increased endothelial permeability implicated in the pathogenesis of acute respiratory distress syndrome. we have previously shown hepatocyte growth factor (hgf) reduced lipopolysaccharide (lps)-induced endothelial barrier dysfunction. however, the mechanism of hgf in endothelial barrier regulation remains to be unclear. methods: recombinant murine hgf with or without mtor inhibitor rapamycin were introduced on mouse pulmonary microvascular endothelial cells (pmvecs) barrier dysfunction stimulated by lps. then, endothelial permeability, adherent junction protein (occludin), endothelial injury factors (endothelin-1 and von willebrand factor), cell proliferation and mtor signaling associated proteins were tested. results: our study demonstrated that hgf decreased lps-induced endothelial permeability and endothelial cell injury factors, and attenuated occludin expression, cell proliferation and mtor pathway activation. conclusions: our findings highlight activation akt/mtor/stat-3 pathway provides novel mechanistic insights into hgf protective regulation of lps-induced endothelial permeability dysfunction. introduction: mechanical ventilation (mv) is a life-saving intervention for critically ill patients, but may also exacerbate pre-existing lung injury, a process termed ventilator-induced lung injury (vili). interestingly, we fig. 1 (abstract p227) . fluorescein isothiocyanate-dextran or fluorescein isothiocyanate-bsa analysis of the effect of hgf on pmvecs permeability fig. 2 (abstract p227) . western blot analysis of hgf on mtor signaling pathway discovered that the severity of vili is modulated by the circadian rhythm (cr). in this study, we are exploring the role of the myeloid bmal1, a core clock component, in vili. methods: we employed mice lacking bmal1 in myeloid cells (lyzmcre-bmal1-/-) and lyzmcre mice as controls. at circadian time (ct) 0 or ct12, mice were subjected to high tidal volume mv to induce vili. lung compliance, pulmonary permeability, neutrophil recruitment, and markers of pulmonary inflammation were analyzed to quantify vili. to assess neutrophil inflammatory responses in vitro, myeloid cells from bone marrow of wt and bmal1-deficient animals were isolated at dawn zt0 (zeitgeber time 0) and dusk (zt12), incubated with dcfh-da and stimulated for 15 min with pma or pbs. neutrophil activation (ly6g/cd11b expression) and ros production (dcfh-da/ly6g+ cells) were quantified. results: injurious ventilation of control mice at ct0 led to a significant worsening of oxygenation, decrease of pulmonary compliance, and increased mortality compared to ct12. lyzmcre-bmal1-/-mice did not exhibit any significant differences when subjected to mv at ct0 or ct12. mortality in lyzmcre-bmal1-/-mice after vili was significantly reduced compared to lyzmcre controls (ct0). neutrophils isolated from control mice at zt0 showed a significantly higher level of activation and increased ros production after pma-stimulation compared to zt12. ros production of lyzmcre-bmal1-/-neutrophils did not differ from zt0 to zt12. conclusions: the lack of the clock gene bmal1 in myeloid cells leads to increased survival after injurious ventilation and to loss of circadian variations in neutrophil ros production. this suggests that the internal clock in myeloid cells is an important modulator of vili severity. introduction: hemodynamic resuscitation by means of fluids and norepinephrine (ne) is currently considered as a cornerstone of the initial treatment of septic shock. however, there is growing concern about the side effects of this treatment. the aim of this study was to assess the relationship between the hemodynamic resuscitation and the development of the ards. methods: 18 new zealand rabbits. animals received placebo (sham=6) or lipopolysaccharide (lps) with or without (edx-r, n=6; edx-nr, n=6) hemodynamic resuscitation (fluids: 20 ml/kg of ringer's lactate; and later ne infusion titrated up to achieve theirs initial arterial pressure). animals were monitored with an indwelling arterial catheter and an esophageal doppler. respiratory mechanics were continuously monitored from a sidestream spirometry. pulmonary edema was analyzed by the ratio between lung wet and lung dry weight (w/d), and the histopathological findings. results: sham group did not show any hemodynamic or respiratory changes. the administration of the lps aimed at increasing cardiac output and arterial hypotension. in the lps-nr group, animals remained hypotensive until the end of experiment. infusion of fluids in lps-r group increased cardiac output without changing arterial blood pressure, while the norepinephrine reversed arterial hypotension. compared to the lps-nr group, the lps-r group had more alveolar neutrophils and pneumocytes with atypical nuclei, thicker alveolar wall, non-aerated pulmonary areas and less lymphocyte infiltrating the interstitial tissue. in addition, the airway pressure increased more in the group lps-r, and the w/d, although slightly higher in the lps-r, did not show significant differences. conclusions: in this model of experimental septic shock resuscitation with fluid bolus and norepinephrine increased cardiac output and normalized blood pressure but worsened lung damage. obese patients have been excluded from most of the clinical trials testing the effects of peep in ards. we hypothesized that in morbidly obese patients the massive load of the abdomen/chest further increases lung collapse thus aggravating the severity of respiratory failure due to ards. methods: we performed a clinical crossover study to investigate the contribution of lung collapse to the severity of respiratory failure in ards obese patients and to determine the specific contribution of titrated peep levels and lung recruitment to changes in lung morphology, mechanics and gas exchange. patients were studied at the peep (peepicu) levels selected at our institution and at peep levels establishing a positive end-expiratory transpulmonary pressure (peepinc) and at peep levels determining the lowest lung elastance during a decremental peep (peepdec) trial following rm. results: thirteen patients were studied. at peepicu end-expiratory transpulmonary pressure was negative, lung elastance was increased and hypoxemia was present (table 1) . regardless the titration technique there was no difference in the peep level obtained. at peepinc level endexpiratory lung volume increased, lung elastance decreased thus improving oxygenation. setting peep according to a peepdec trial after a rm further improved lung elastance and oxygenation. at peedec level after a rm lung collapse and overdistension were minimized (fig. 1) . all patients maintained titrated peep levels up to 24 hours without complications. conclusions: in severely obese patients with ards, setting peep according to a peepinc trial or peepdec trial following a rm identifies the same level of optimal peep. the improvement of lung mechanics, lung morphology and oxygenation at peepdec after a rm suggests that lungs of obese ards patients are highly recruitable and benefit from a rm and high peep strategy. introduction: lung protective ventilation (lpv) strategies, principally focused around the use of tidal volumes <6 ml/kg predicted body weight (pbw) remains an enduring standard of care for ventilated patients. however, implementation of and compliance with lpv is highly variable. we used 'nudge'-based interventions to assess if these can improve lpv. methods: ventilation data analysis over 2 years (186000 hours in 685 patients) showed patients had been ventilated with a median tidal volume of 7.4 ml/kg pbw with a significant proportion receiving over 8 ml/kg pbw (fig. 1) , an effect more pronounced in female patients and those with higher bmi. interventions: 1) creation of a software tool to easily identify and monitor patients receiving tidal volumes that were too high for their pbw 2) attached laminated reference guides to each ventilator to calculate pbw 3) presentation, opportunistic education and verbal prompts to relevant clinical care staff regarding importance of lpv and use of pbw rather than actual body weight 4) incorporating checking of tidal volumes on a daily ward rounds from junior clinical members results: we collected hourly ventilation data of the patients over a 2-week period (2479 hours in 22 patients) following our interventions. there was, overall a statistically significant reduction tidal volume (p<0.001). there was improvement in the ventilation of male patients (p<0.001) but female patients endured higher tidal volumes. there was a mixed picture in different bmi grades. conclusions: reducing tidal volumes in mechanically ventilated patients can be done through a mix of behavioural and educational interventions, as well as using technological shortcuts. this helps to reduce the effort on the part of clinical staff to adhere to best practices, and ultimately improve patient outcomes. introduction: lung protective ventilation (lpv) using a tidal volume (vt) of 6-8ml/kg ideal body weight (ibw) is recommended in the intensive care unit and theatres to reduce the incidence of pulmonary complications. the aim of this audit was to assess the extent to which lpv is used in theatres in a busy district general hospital and to implement measures to promote adherence to the recommendations. methods: anaesthetists completed questionnaires for all patients undergoing general anaesthesia at northwick park hospital over 1 week. demographics, actual body weight (abw), height, american society of anesthesiologists (asa) score, and procedural information were recorded. ventilatory parameters included the ventilation mode, vt, and positive end expiratory pressure (peep (fig. 1) . significantly more females (75%) received vt >=8ml/kg than males (29%) (p<0.01) (fig. 2) . vt was independent of age, asa, bmi, ventilation mode, speciality, and patient position. conclusions: over half of the patients received vt >=8ml/kg ibw. females were more likely to be over ventilated. a likely contributing factor is the disparity between abw and ibw in this cohort. we organised staff teaching and constructed ibw charts with the appropriate corresponding tidal volumes to be displayed in all theatres to promote the use of lpv. results: there were significant differences in ards incidence between groups: ards developed in 12.4% of protective mv groups vs. 68.3% of standard mv group (p=0.0001, fisher's exact test). vap patients ventilated in a protective mode presented with lower duration of mv (12.2±4.2 days) and icu stay(16.1±3.2 days) than patients with standard mv (17.2±5.2 and 20.1±5.5 days). there were significant differences in mortality rates between patient groups: 24.1% in protective mv and 47.2% in standard mv (p=0.0043, fisher's exact test). conclusions: protective mv prevents the development of ards in vap septic patients. introduction: reduction of tidal volumes (tv) below 6 ml/kg associated with low driving pressure (dp) might improve lung protection in patients with acute respiratory distress syndrome (ards). the current study tests the combination of coaxial double lumen endotracheal tube (to reduce instrumental dead-space) and moderately respiratory rate (rr) (<80 bpm) to maintain co2 at clinically acceptable levels while using ultraprotective tv. the objective is to considerably reduce dp, which has been preconized as an index more strongly associated with survival than tv, per se, methods: 8 juvenile pigs were anesthetized, intubated and mechanically ventilated. severe lung injury (p/f<100) was induced using a double-hit model: repeated surfactant wash-out followed by injurious mechanical ventilation using low positive end-expiratory pressure and high dp (~40cmh2o) for 3 hours. then vts of 6, 4, and 3 ml/kg were used in random sequence for 30 min each, both using a standard and coaxial endotracheal tube. at each vt level, rr was adjusted to achieve paco2=60 mmhg but not exceeding 80 bpm. lung functional parameters and blood gas analysis were measured at each vt level. statistical analysis was performed using mixed linear model. results: coaxial endotracheal tube, but not the conventional tube, allowed decreasing vt to 4 and 3 ml/kg, while keeping paco2 at approximately 60 mmhg and rr<80 bpm, reducing dp of 4.0 cmh2o and 6.0 cmh2o, respectively, compared to the conventional vt of 6 ml/kg (fig. 1) . conclusions: in this ards model, coaxial tube ventilation associated with moderately high rr allowed ultraprotective ventilation (vt=3 ml/kg) and reduced dp levels, maintaining paco2 at acceptable levels. this strategy might have a significant impact on mortality of severe ards patients. the table 1 shows oxygenation and respiratory mechanics. figure 1 : echocardiographically measured right heart function. conclusions: in morbidly obese mechanically ventilated patients with ards an increase in peep by 9 cmh2o (from 12.5±1.5 cmh2o to 21.2±3.3 cmh2o) did not impair right heart function, but improved respiratory mechanics and oxygenation. introduction: mechanical ventilation can, while being lifesaving, also cause injury to the lungs. the lung injury is caused by high pressures and mechanical forces but also by inflammatory processes which are not fully understood [1] . heparin binding protein (hbp) released by activated granulocytes has been indicated as a possible mediator of increased vascular permeability in the lung injury associated with trauma and sepsis [2, 3] . we wanted to investigate if hbp levels were increased in bronco alveolar lavage (bal) fluid or plasma in a pig model of ventilator induced lung injury. methods: anaesthetized pigs were surfactant depleted by saline lavage and randomized to receive ventilation with either tidal volumes of 8 ml/kg with a peep of 8 cm h2o (controls, n=6) or 20 ml/kg with a peep of 0 cm h2o (ventilator induced lung injury (vili) group, n=6). plasma and bal samples of hbp were taken at 0,1,2,4 and 6 hours (fig. 1) . results: characteristics of pigs by study group are shown in table 1 . plasma levels of hbp did not differ significantly between pigs in the control and vili group at any time of sampling. hbp levels in bal fluid were significantly higher in the vili group after 1 (p=0.04), 2 (p=0.03), 4 (p<0.01) and 6 (p=0.02) hours of ventilation (fig. 2) . conclusions: in a model of ventilator induced lung injury in pigs, levels of heparin binding protein in bal fluid increased significantly over time compared to controls. plasma levels however did not differ significantly between groups. (fig. 2) . conclusions: this meta-analysis concluded that corticosteroid treatment in ards provided no benefit in decreasing mortality. in addition, this treatment was not associated with increasing risk of nosocomial infection. (fig. 1) . the change in the pao2/fio2 ratio was significant [rr(95%ci)=0.29(0.12-0.46), p=0.0008] (fig. 2) . finally, trial sequential analysis and grade indicated lack of firm evidence for a beneficial effect. conclusions: surfactant administration may improve oxygenation but has not been shown to improve mortality for adult ards patients. large rigorous randomized trials are needed to explore the effect of surfactant to adult ards patients. moderate to severe acute respiratory distress syndrome in a population of primarily non-sedated patients, an observational cohort study l bentsen, t strøm, p introduction: extracorporeal carbon-dioxide removal (ecco2r) might allow ultraprotective mechanical ventilation with lower tidal volume (vt) (<6 ml/kg predicted body weight), plateau (pplat) (<30cmh2o) and driving pressures to limit ventilator-induced lung injury. this study was undertaken to assess the feasibility and safety of ecco2r managed with a renal replacement therapy (rrt) platform to enable ultraprotective ventilation of patients with mild-to-moderate ards. methods: 20 patients with mild (n=8) or moderate (n=12) ards were included. vt was gradually lowered from 6 to 5, 4.5 and 4 ml/kg, and peep adjusted to reach 23<=pplat<=25 cm h2o. stand-alone ecco2r (prismalung, no hemofilter associated with the rrt platform) was initiated when arterial paco2 increased by >20% from its initial value. ventilation parameters (vt, rr, peep), respiratory system compliance, pplat and driving pressure, arterial blood gases, and ecco2r-system characteristics were collected during at least 24 hours of ultraprotective ventilation. complications, day-28 mortality, need for adjuvant therapies, and data on weaning off ecco2r and mechanical ventilation were also recorded. results: while vt was reduced from 6 to 4 ml/kg and pplat kept <25 cmh2o, peep was significantly increased from 13.4±3.6 at baseline to 15.0±3.4 cm h2o, and the driving pressure was significantly reduced from 13.0±4.8 to 7.9±3.2 cm h2o (both p<0.05). the pao2/ fio2 ratio and respiratory-system compliance were not modified after vt reduction. mild respiratory acidosis occurred, with mean ph decreasing from 7.39 ± 0.1 to 7.32 ± 0.10 from baseline to 4-ml/kg vt. mean extracorporeal blood flow, sweep-gas flow and co2 removal were 421±40 ml/min, 10±0.3 l/min and 51±25 ml/min, respectively. mean treatment duration was 31±22 hours. day-28 mortality was 15%. introduction: there is no consensus on the management of anticoagulation during extracorporeal membrane oxygenation (ecmo). ecmo is currently burdened by a high rate of hemostatic complications, possibly associated with inadequate monitoring of heparin anticoagulation. this study aims to assess the safety and feasibility of an anticoagulation protocol for patients undergoing ecmo based on thromboelastography (teg) as opposed to an activated partial thromboplastin time (aptt)-based protocol. methods: we performed a multicenter, randomized, controlled trial in two academic tertiary care centers. adult patients with acute respiratory failure treated with veno-venous ecmo were randomized to manage heparin anticoagulation using a teg-based protocol (target 16-24 minutes of the r parameter, teg group), or a standard of care aptt-based protocol (target 1.5-2 of aptt ratio, aptt group). primary outcomes were safety and feasibility of the study protocol. results: forty-two patients were enrolled, 21 were randomized to the teg group and 21 to the aptt group. duration of ecmo was similar in the two groups (9 (7-16) days in the teg group and 11 (4-17) days in the aptt group, p=0.74). heparin dosing was lower in the teg group compared to the aptt group (11.7 (9.5-15.3) iu/kg/h versus 15.7 (10.9-21.3) iu/kg/h respectively, p=0.03). safety parameters, assessed as number of hemorrhagic or thrombotic events and transfusions given, were not different between the two study groups. as for the feasibility, the teg-based protocol triggered heparin infusion rate adjustments more frequently (p<0.01) and results were less frequently in the target range compared to the aptt-based protocol (p<0.001). number of prescribed teg or aptt controls (according to study groups) and protocol violations were not different between the study groups. conclusions: teg can be safely used to guide anticoagulation management during ecmo. its use was associated with the administration of lower heparin doses compared to a standard of care apttbased protocol. methods: single-center retrospective study of patients (n=152; 45 ±11.8 years; 63% males) undergoing vv-ecmo for severe ards. the acp-score (0-4) was calculated immediately before ecmo initiation and at ecmo-day1, -day3 and -day7, as follows: pneumonia as cause of ards -1 point; driving pressure >=18cmh2o -1 point; pao2/fio2 ratio <150mmhg -1 point; paco2 >=48mmhg -1 point. results: longer duration of mechanical ventilation before vv-ecmo was associated with higher acp-scores. patients with higher acp-scores before vv-ecmo also presented longer total duration of mechanical ventilation and hospital stay. after vv-ecmo initiation, acp-scores significantly decreased from 3.0±0.74 to 1.5±0.84, 1.5 ±0.96 and 1.6±0.99 at ecmo-day1, -day3 and -day7, respectively. at ecmo-day7, patients with higher acp-scores (3-4) presented increased hospital mortality when compared with patients with lower acp-scores (0-2): 47.6 vs. 24.7%, respectively (p=0.038). at ecmo-day7, high driving pressures and low pao2/fio2 ratios were the acp-score determinants that significantly associated with increased hospital mortality. conclusions: in severe ards, vv-ecmo support allowed a significant and sustained acp-score reduction in most patients. this was achieved by artificial lung correction of low pao2/fio2, hypercapnia and elevated driving pressures. after an initial period of vv-ecmo support, patients with higher acp-scores present higher mortality rates. our results suggest that on-going adjustment of ecmo and ventilation parameters is necessary to maximize outcome. introduction: we sought to use mechanical power to describe "lung rest" in patients with acute respiratory distress syndrome (ards) supported with extracorporeal membrane oxygenation (ecmo). mechanical power describes work done by the ventilator on the patient's respiratory system over time. this concept unifies tidal volume, rate, and total pressure delivered during the ventilatory cycle into a discrete value that may be useful to guide ventilatory support. we hypothesized that initiation of ecmo led to decreased mechanical power delivered to the patient. methods: we reviewed the charts of the three medical intensive care unit patients at our institution supported with ecmo for severe ards. we collected data on plateau pressure, driving pressure, and mechanical power before initiating ecmo, then at <6 hours, 24 hours, and 72 hours after. we calculated the mechanical power delivered by the ventilator to the patient in joules per minute as 0.098 x respiratory rate x tidal volume x (peak pressure -½ x driving pressure) [1] . results: all patients were alive at discharge and at 90 days. mean pao 2 /fio 2 at ecmo initiation was 64±38, mean plateau pressure was 37±3 cm water. all patients received neuromuscular blockade at initiation of ecmo. following ecmo initiation, mechanical power decreased by an average of 58%±14% initially, by 69%±4% at 24 hours, and by 66%±17% at 72 hours (fig. 1) . by comparison, driving pressure changed by an average value of -0.3±8.0, -0.3±5.5, and -2.0±4.6 cm water over those same intervals. average plateau pressure changed by -3.3±5.7, -4.7±5.5, and -1.7±6.4 cm water during the same time period (fig. 2) . conclusions: in our limited case series, mechanical power decreased significantly following initiation of ecmo in patients with severe ards. we suggest mechanical power may be more useful than changes in driving pressure or plateau pressure when pursuing "lung rest" during ecmo. introduction: it is not clear whether acute respiratory distress syndrome (ards) is independently associated with mortality after controlling for underlying risk factor and baseline severity of illness. we attempted to assess the attributable mortality of ards by performing a systematic review and meta-analysis. methods: we systematically searched pubmed, embase, scopus and reference lists to identify observational studies reporting mortality rates of critically ill patients with and without ards. all included studies were matched for underlying risk factor. primary outcomes were all-cause in hospital-mortality and short-term mortality (combined 28 day-mortality and intensive care unit-mortality). we calculated pooled risk ratios (rr) and 95% confidence intervals (ci) with a random-effects model. our meta-analysis was registered with prospero. results: of the 3119 initially retrieved articles, 41 studies (44 cohorts) involving 58408 patients were included. the underlying risk factor was sepsis, trauma and other in 15, 18 and 11 cohorts, respectively. in-hospital mortality was higher in patients with versus without ards (31 cohorts; 54101 patients; rr 2.63, 95% ci 2.01-3.44; p<0.001). we saw a numerically stronger association between ards and inhospital mortality in trauma (rr 3.15, 95% ci 2.17-4.57; p<0.001) than sepsis (rr 1.80, 95% ci 1.24-2.63; p=0.002). short-term mortality was higher in patients with versus without ards (14 cohorts; 8040 patients; rr 1.88, 95% ci 1.27-2.78; p=0.002). ards was independently associated with mortality in approximately half of the 11 cohorts which controlled for baseline severity of illness using a multivariable analysis. conclusions: the accumulated evidence suggests that ards is independently associated with mortality after controlling for underlying risk factor; the association is stronger for trauma than septic patients. evidence is mixed as to whether ards is independently associated with mortality after controlling for baseline severity of illness. introduction: evidence is mixed as to whether acute respiratory distress syndrome (ards) is independently associated with mortality after controlling for baseline severity of illness, particularly in patients with sepsis. methods: this was an observational study comparing mortality rates of septic patients with and without ards. subjects for the present study were enrolled in 3 ongoing prospective cohorts of critically ill patients hospitalized in medical intensive care unit (icu) in the united states or south korea. ards was defined using the berlin definition for cases after 2012 and the american-european consensus conference definition for cases before 2012. sepsis was defined using the sepsis-3 definition. baseline severity of illness was assessed using a modified sequential organ failure assessment (sofa) after exclusion of the respiratory component. the primary outcome was inhospital mortality. results: of the 1024 critically ill patients enrolled in the 3 cohorts, 771 (75.3%) had sepsis and comprised the population of the present study. of the 771 septic patients, 166 (21.5%) had ards. patients with versus without ards had higher sofa score; both total (median 14 vs 11; p<0.001) and modified (11 vs 10; p<0.001). the unadjusted mortality of septic patients with ards was higher than septic patients without ards (46.7% vs 22.4%; p<0.001). after controlling for baseline modified sofa score, both moderate and severe ards remained significant predictors for in-hospital mortality [odds ratio (or) 2.90; 95% confidence intervals (ci) 1.66-5.03; p<0.001 and or 3.91; 95% ci 2.33-6.58; p<0.001, respectively]. in contrast, after controlling for baseline modified sofa score, mild ards was not associated with in-hospital mortality (or 1.04; 95% ci 0.40-2.39; p=0.94). conclusions: among critically ill patients with sepsis, moderate and severe, but not mild, ards are associated with mortality after controlling for baseline severity of illness. a multicenter study on the inter-rater reliability of heart score among emergency physicians from three italian emergency departments introduction: previous studies suggested that the heart (based on history, ecg, age, risk factors, troponin) score could be a valid tool to manage the patients with chest pain at the emergency department (fig. 1 ). our hypothesis was that there could be heterogeneity in the assignment, because of the history and ecg parameters. for this reason, our objective was to test the heart reliability. there are no published studies on this topic. methods: this is a multicenter retrospective study conducted in 3 italian eds between march and october 2017 using clinical scenarios. twenty emergency physicians were included, provided that they had undergone a course on heart score. we used 53 scenarios from a medical database with each scenario including demographic and clinical characteristics. each participant assigned scores to the scenarios using the heart. we tested the measure of interrater agreement using the kappa-statistic, the confidence intervals are bias corrected. a p-value of <0.05 was used to define statistical significance. results: the participants' assignment is shown in fig. 2 . the overall inter-rater reliability was good: kappa = 0.63 (ci 95%; 0.57 -0.72); with a good agreement between the low and high class of risk but a moderate reliability in the medium class: kappa= 0.72, 0.70 and 0.51. we have not found differences of inter-rater reliability among the senior (more than 5 yrs in ed) and junior physicians: kappa= 0.65 (ci 95%; 0.57 -0.73) and 0.60 (ci 95%; 0.51 -0-72).the heart score showed the worse value of inter-rater reliability in the history and ecg parameters : k inter = 0.37 (ci 95%; 0.33 -0.44) and 0.42 (ci 95%; 0.29 -0.50). conclusions: the heart showed a good inter-rater reliability but a fair agreement in the history parameter. the clinical experience doesn't influence the agreement in the assignment. the main limit of this study lies in using scenarios rather than real patients. introduction: the aim of the experiment was to study the efficacy of preconditioning, based on changes in inspiratory oxygen fraction on endothelial function in a model of myocardial ischemia/reperfusion injury in conditions of cardiopulmonary bypass (cpb). methods: the prospective study included 32 rabbits divided into four equal groups: hypoxic preconditioning; hyperoxic preconditioning (hyperp); hypoxic-hyperoxic preconditioning (hhp); control group. animals were anesthetized and mechanically ventilated. we provided preconditioning, then started cpb, and then induced acute myocardial infarction by ligation of left anterior descending artery. after 45 minutes of ischemia we performed 120 minutes of reperfusion. we investigated endothelial function markers (endothelin-1 (et-1), asimmetric dimethylarginine (adma), nitric oxide metabolites) at stages before ischemia (after preconditioning in study groups), after ischemia and after reperfusion. results: the level of et-1 after the stage of ischemia increased in all groups, a significant difference was between hhp and control group (p=0.006), then et-1 increased even more after the stage of reperfusion (p=0.003 hhp vs control group). the concentration of nitrite decreased after the stages of ischemia and reperfusion in comparison with the baseline in all groups. however, the level of nitrite after all types of preconditioning was higher than in the control group (p=0.016; 0.046; 0.009). the total concentration of nitric oxide metabolites in the study groups was higher than in the control group: before ischemia (after preconditioning) p=0.034; after ischemia p=0.014; after reperfusion, p=0.022. concentration of adma was lower in the hhp comparing with the control group at the stages after ischemia (p=0.006) and after reperfusion (p=0.027). conclusions: hyperp and hhp maintain endothelial function: the balance of nitric oxide metabolites and the reduction of et-1 hyperproduction in a model of myocardial ischemia/reperfusion injury in conditions of cpb. upscaling hemodynamic and brain monitoring during major cancer surgery: a before-after comparison study introduction: hemodynamic and brain monitoring are used in many high-risk surgical patients without well-defined indications and objectives. in order to rationalize both hemodynamic and anesthesia management, we implemented monitoring guidelines for patients undergoing major cancer surgery. methods: early 2014, and for all eligible patients, we started to recommend (standard operating procedure, sop) cardiac output, central venous oxygen saturation, and depth of anesthesia monitoring with specific targets (map > 65 mmhg, svv < 12%, ci > 2.5 l/min/ m 2 , scvo2 > 75%, 40 < bis < 60). eligibility criteria were pelvic or abdominal cancer surgery expected to last > 2 hours in adult patients. pre-, intra-, and post-operative data were collected from our electronic medical record (emr) database and compared before (from march to august 2013) and after (from march to august 2014) the sop implementation. results: a total of 596 patients were studied, 313 before and 283 after the sop implementation. the two groups were comparable in terms of age, asa score, duration and type of surgery, the surgical possum score was higher after than before (20 vs 18, p=0.045). the use of cardiac output, scvo2 and bis monitoring increased from 40 to 61%, 61 to 81%, and 60 to 88%, respectively (all p values < 0.05). intraoperative fluid volumes decreased (16.9 vs 15.2 ml/kg/h, p=0.002), whereas the use of inotropes increased (6 vs 13%, p=0.022). the rate of postoperative delirium (16 vs 8%, p=0.005) and urinary track infection (6 vs 2%, p=0.012) decreased, as well as the median hospital length of stay (9.6 vs 8.8 days, p=0.032). conclusions: in patients undergoing major surgery for cancer, despite an increase in surgical risk, the implementation of guidelines with predefined targets for hemodynamic and brain monitoring was associated with a significant improvement in postoperative outcome. introduction: tissue perfusion and oxygen delivery is low in patients with severe preeclampsia, which would explain multiple organ failure and death in these patients. the aim of this study was to determine the relationship between the base deficit and the risk of adverse maternal and perinatal outcomes. methods: retrospective multicenter cohort study included pregnant patients with severe preeclampsia admitted to six intensive care units at tertiary referral centers during a ten years period in colombia. clinical information was gathered from hospital medical records. the correlation of base deficit with adverse maternal outcomes was evaluated using logistic regression analysis. outcomes were maternal death, acute kidney injury, hellp syndrome, transfusion, eclampsia and extreme neonatal morbidity. results: 731 patients were included in the study, we found a total of 21 (2,8%) maternal deaths, the median calculated base deficit obtained was -5.5 meq/l. patients with base deficit greater than -8.0meq/l had significantly higher mortality rates or 3.02 (ci 1.26-7.2) p 0,013. this group of patients was also associated with a higher probability of developing a class 1 hellp syndrome or 1.7 (ci 1.02-2.82) p 0,03. a more mild alteration in the base deficit (greater than -5.0meq/l) was related to the appearance of kidney injury or 2.25 (ci 1.52-3.34) p 0.00 y complete hellp or 2.17 (ci 1.60-2.96) p 0.00. conclusions: base deficit is related to worse outcomes in patients with severe preeclampsia. according to our results, a cut-off point greater than -8meq/l, there is a higher risk of death and worse outcomes such as class 1 hellp syndrome. comparison of two different laser speckle contrast imaging devices to assess skin microcirculatory blood flow g guven, y ince, oi soliman, s akin, c ince erasmus mc, university medical center rotterdam, rotterdam, netherlands critical care 2018, 22(suppl 1):p261 introduction: laser speckle contrast imaging (lsci) is a common, non-contact and practical method used to assess blood flow of tissue surfaces. we have lack of knowledge about comparability of different lsci devices due to the arbitrary units (au) used to define blood flux. we sought to examine the linearity between skin blood flux, recorded using two different lsci devices. methods: we performed post-occlusive reactive hyperemia test (porh) on the arm and measured blood flux on the hand using two different lsci devices (moor instruments, devon, uk and perimed ab, järfälla, sweden). all volunteers were measured at baseline, during occlusion and after release of occlusion during the hyperemia phase. the third finger and fourth finger nail were selected for recording blood flux and au were used to express values. results: fifteen healthy, non-smoker male volunteers participated in this study. an excellent correlation was found between the two lsci devices (finger: r2:0.79, p<0.001 & finger nail: r2:0.68, p<0.001). data were also assessed in terms of the variability at different stages of the porh test (fig. 1a-d) . correlation of devices was still high at baseline, first minute of occlusion and in the post-occlusion hyperemia phase. however, in the period between 1 minute after start of the occlusion and the beginning of the hyperemia, correlation was lower for the whole finger (r2:0.21, p=0.002) and correlation was lost for fingernail (r2:0.05, p=0.14) between the two devices. conclusions: skin blood flux measured with two different lsci devices are linearly correlated with each other. however care should be taken when assessing patients with low blood flux such as occurs during shock and ischemic organs. introduction: the aim of this study was to evaluate the effects of hyperoxia and mild hypoxia on microcirculatory perfusion in a rat model. methods: spontaneously breathing anesthetized (isoflurane) male wistar rats (n=12) were equipped with arterial (left carotid) and venous (right jugular) cannulae and tracheotomy. rats were randomized in 3 groups: normoxiainspired oxygen fraction (fio 2 ) of 0.21; hyperoxia -fio 2 1; mild hypoxia -fio 2 0.15. the following measurements were taken hourly for 4 hours: blood gases, mean arterial pressure (map), stroke volume index (svi) and heart rate (echocardiography), skeletal muscle microvascular density (sidestream dark field videomicroscopy). results: at 1 hour, arterial o2 tension was 103±19 mmhg in normoxia, 296±60 mmhg in hyperoxia, 62±8 mmhg in mild hypoxia (p<0.001). hyperoxia induced an increase in map (from 109±13 to 129±8 mmhg at 1h, p<0.05) and a decrease in svi (from 0.67±0.1 to 0.59±0.1 ml/kg at 1h, p<0.05), while in mild hypoxia map tended to decrease and svi tended to increase (p>0.05). microvascular density decreased in hyperoxia and increased in mild hypoxia (fig. 1) . conclusions: in anesthetized rats, microvascular density decreased with hyperoxia and increased with mild hypoxia. introduction: the imbalance between oxygen (o2) delivery and o2 requirement in patients with sepsis can be assessed by central venous oxygen saturation (scvo2). the low or high scvo2 may indicate cellular hypoxia or inability to utilize the o2. this study aims to determine the relationship between high scvo2 and mortality in patients with sepsis. methods: a retrospective observational cohort study was done by collecting data (i.e., baseline characteristics, severity of infection and vasopressors) from medical records of >=15-year-old patients with sepsis and 1st scvo2 measurement within 24 hours of sepsis, who were admitted in a university hospital between 2013 and 2014. the patients were stratified by 1st scvo2 level (<70%, 70-80%, >80%) and apache-ii score (<=25, >25). the primary outcome was inhospital mortality. results: among 376 patients, those with high scvo2 (17.3%) and low scvo2 (53.7%) were associated with adjusted hazard ratios for death of 0.79 (0.54-1.15, p=0.218) and 1.16 (0.86-1.56, p=0.325), respectively, while those with normal scvo2 (29.0%) as control. when the patients were stratified by scvo2 level and apache-ii score, using patients with normal scvo2 and low apache-ii score as control, those with high scvo2 and low apache-ii score, and those with low scvo2 and low apache-ii score had adjusted hazard ratios of 0.54 (0.31-0.97, p=0.038) and 1.18 (0.79-1.76, p=0.432). for those with normal, high and low scvo2, and high apache-ii score had adjusted hazard ratios of 1.62 (1.02-2.57, p=0.041), 1.77 (1.05-2.96, p=0.031), and 1.88 (1.23-2.87, p=0.004), respectively. conclusions: the scvo2 >80% with apache-ii score >25, but not only scvo2 >80%, is independently related to increased mortality in patients with sepsis. introduction: serum lactic acid levels and scvo2 are useful predictive parameters for patients with sepsis. however, little is known the differences in the impact of lactate levels and scvo2 on the prognosis of septic patients. in this study, we investigated these differences by analysing septic patients' characteristics and prognosis. methods: this study is a post hoc analysis of data obtained from a multicentre, prospective, randomized controlled trial, which compared two fluid management strategies for septic patients requiring mechanical ventilation. we categorised patients into the following four groups: scvo2 >= 70% and lactic acid levels < 2 mmol/l (hh group); scvo2 >= 70% and lactic acid levels < 2 mmol/l (hl group); scvo2 < 70% and lactic acid levels >= 2 mmol/l (lh group) and scvo2 < 70% and lactic acid levels < 2 mmol/l (ll group). sofa score, saps ii score, lactic acid levels, scvo2 and bnp were evaluated. primary outcome was 28-day mortality, whereas secondary outcomes were the duration of mechanical ventilation, administration of crrt, duration of catecholamine therapy and length of icu stay. results: in total, 104 patients were included: hh group (n = 32), hl group (n = 31), lh group (n = 25) and ll group (n = 16). no significant differences were observed in terms of patient characteristics. further, 28-day mortality was 32% in the lh group, 28.1% in the hh group, 25% in the ll group and 13% in the hl group, and there was no significant difference in terms of mortality among the groups. furthermore, there were no significant differences in terms of secondary outcomes. on multivariate analysis using the hl group as reference, the odds ratios for 28-day mortality in the lh, hh and ll groups were 1.21 (95%ci, 0.5-5.8), 1.62 (95%ci, 0.36-7.2) and 2.0 (95%ci, 0.37-10.9), respectively. conclusions: because 28-day mortality was higher in the hh group than in the ll group, serum lactic acid levels may have bigger impact on the prognosis of septic patients. introduction: in septic shock endothelial damage can lead to failure of microcirculation and low microcirculatory oxygen saturation. in the skin this is seen as mottling and can be quantified using hyper fig. 1 (abstract p262) . changes in microvascular density spectral imaging. there is insufficient data about associations between skin oxygenation, severity of illness, biomarkers of endothelial damage and mortality in patients with septic shock. methods: this single centre observational study was performed in 24 consecutive intensive care patients with septic shock. within 24 hours of admission hyper spectral imaging of knee area skin was performed and blood was sampled for assay of biomarkers of endothelial cell damage (plasminogen activator inhibitor -1 (pai-1), soluble intercellular adhesion molecule (sicam-1), soluble vascular cell adhesion molecule (svcam-1), thrombomodulin, angiopoetin-2). nonlinear fitting of optical density spectra was used to calculate relative skin oxy/deoxy hemoglobin concentration and obtain oxygen saturation. the association between skin oxygen saturation, biomarkers, sepsis severity (apache ii, sofa) and 28-day mortality was analyzed. results: the median (iqr) age of patients was 71 years (62 to 76), and 60% were males. the median sofa and apache ii scores were 9 (7 to 12) and 24 (19 to 27) and 28-day mortality rate was 29%. 7 patients (37%) had mottling. there was a relationship between skin oxygenation, plasma biomarkers (thrombomodulin and svcam-1) and sepsis severity assessed by sofa and apache ii scores, p < 0.05. using logistic regression analysis, skin oxygenation and biomarker concentrations were not associated with 28-day mortality rate. conclusions: in our cohort of patients with septic shock, skin oxygenation and biomarkers of endothelial injury were strongly associated with initial severity of sepsis but poorly predictive of 28-day mortality. comparison between ultrasound guided technique and digital palpation technique for radial artery cannulation in adult patients: a meta-analysis of randomized controlled trials s maitra, s bhattacharjee, d baidya all india institute of medical sciences, new delhi, new delhi, india critical care 2018, 22(suppl 1):p266 introduction: possible advantages and risks associated with ultrasound guided radial artery cannulation in-comparison to digital palpation guided method in adult patients are not fully known. previous meta-analyses included both adult and pediatric patients and long axis in-plane technique and short axis out of plane technique in the same analysis, which may have incurred biases [1, 2] . methods: pubmed and cochrane central register of controlled trials (central) were searched (from 1946 to 20th november 2017) to identify prospective randomized controlled trials in adult patients where 2dimensional ultrasound guided radial artery catheterization has been compared with digital palpation guided technique. for continuous variables, a mean difference was computed at the study level, and a weighted standardized mean difference (smd) was computed in order to pool the results across all studies. for binary outcomes, the pooled odds ratio (or) with 95% confidence interval (95% ci) was calculated using the inverse variance method. results: data of 1895 patients from 10 studies have been included in this meta-analysis. overall cannulation success rate was similar between short axis out of plane technique and digital palpation [p=0.27; fig. 1 ] and long axis in-plane technique with digital palpation. ultrasound guided long axis in-plane approach and short axis out of plane approach provides better first attempt success rate of radial artery cannulation in comparison to digital palpation [p=0.01 and p=0.0002 respectively; fig. 2 ]. no difference was seen in time to cannulate between long axis and short axis technique with palpation technique. conclusions: usg guided radial artery cannulation may increase the first attempt success rate but not the over all cannulation success when compared to digital palpation technique. introduction: ultrasound guidance may improve the success rate of vascular cannulation. there is lack of data regarding the utility of usg guided arterial cannulation in critically ill patients in shock. we aim to compare the impact of using real time ultrasound guidance versus palpation method in achieving arterial catheterization in critically ill patients in hypotension. methods: a single center, prospective, randomized trial was performed among 100 critically ill patients aged >18 years, with hypotension (or requiring vasopressor infusion) and on not previous cannulated radial arteries. patients were randomized in a ratio of 1:1 to the ultrasound group or palpation group. under aseptic precautions, arterial puncture was performed using appropriate sized leader cath (vygon, ecquen, france), under real time usg guidance using short-axis out-of-plane view with bevel down. data were recorded and compared between two groups. the unpaired student's t-test or mann-whitney u test were used for continuous variables, and the uncorrected chi-squared or fisher's exact test were used for proportions. results: a total of 100 patients with hypotensive shock requiring radial artery catheterization were randomized into palpation (n = 51) and ultrasound (n = 49) groups. first pass success rate was significantly higher in ultrasound group as compared to palpation group (83% vs 41%, p<0.0001). cannulation time was significantly shorter in ultrasound group (72.9 vs 88.7,p<0.05). early complications were significantly higher in palpation group compared to ultrasound group (14.6% vs 5.2%, p<0.001). conclusions: in critically ill patients with hypotension (or requiring vasopressors), ultrasound guidance improved first pass success rate, shortened the cannulation time and reduced the rate of early complications in radial artery catheterizations. relationship between inferior vena cava diameter and variability with mean arterial pressure and respiratory effort b kalin, k inci, g gursel gazi university school of medicine, ankara, turkey critical care 2018, 22(suppl 1):p268 introduction: there is no consensus on the use of vena cava inferior (ivc) diameter and variability in the assessment of fluid response (fr) in spontaneously breathing icu patients. influence from respiratory effort, experience requirement and measurement problems are reasons for not being preferred. the aim of the study is to investigate the relationship between ivc diameter, variability and spontaneous breathing effort and hypotension measured by ultrasonography in spontaneously breathing intensive care patients methods: the maximum and minimum diameters of the ivc were measured and the collapsibility index (ci) was calculated. measurements were made in 2d mode on cineloop recordings. diaphragm thickening ratio was used as a measure of respiratory effort. correlations between respiratory effort criteria with ivc minimum diameter and ci were calculated by pearson's correlation coefficient. ivc measurement criterias, such as inspiratory diameter of < 1 cm, 25%, 40%, 45% of the ci were compared with chi square test in hypotensive and non-hypotensive patients. we took two mean arterial pressure threshold for hypotension as 60 and 70 mmhg for this calculation. results: 62 patients were included in the study. for both hypotensive threshold values, there was no significant difference in the rates of hypotensive and non-hypotensive patients with and without a minimum ivc diameter of 1 cm below. even there was no significant relationship between the ci higher than 25%, 40% and 50% and hypotension (p>0.05). in spontaneously breathing patients, a significant correlation was found between respiratory effort and ivc ci and ivc diameter < 1 cm conclusions: at the end of the study, there was a correlation between spontaneous breathing effort ivc diameter and ci in the intubed patients. additionally the result that ivc ci is not different even between hypotensive and non-hypotensive patients suggests that this method should be used with caution in predicting fr. introduction: fluid responsiveness in icu patients can be assessed using changes in pulse rate and blood pressure following administration of a fluid bolus, assisted if necessary by cardiac output (co) monitors such as the lidcoplus. this uses pulse contour analysis to estimate stroke volume (sv), with >10% change in sv following a fluid challenge (fc) signifying overall benefit. there is no evidence that the use of co monitoring improves patient outcomes and it is unclear if it improves clinical decision making. methods: a lidcoplus monitor was set up with the screen covered. a 250ml fc was administered over 2 minutes. the heart rate, systolic and mean arterial pressures were recorded before and after the fc. the clinician administering the fc was asked to decide if the patient was fluid responsive. following this decision, the sv change was revealed and the clinician asked again to assess fluid responsiveness. results: forty-five fluid challenges were studied. use of the lidco changed the decision made on 7 occasions (fig. 1) . in three patients (7%), this change in decision was appropriate and either corrected a misinterpretation of the haemodynamic data or represented a patient whose only marker of fluid responsiveness was a sv change. in four patients (9%), the lidco changed the decision inappropriately from a correct interpretation of the haemodynamic data. in six patients (13%) the sv change was ignored when it should have changed the initial decision. in the remaining 32 patients (71%) the decision made with the haemodynamic data was in agreement with the sv change and unchanged by revealing the lidco data. conclusions: the use of lidco monitoring only appropriately changed the decision made with information from basic haemodynamic monitoring in 7% of patients. this augmentation of decision making was only seen in patients whose basic haemodynamic parameters did not respond to fluid. it changed a correct decision inappropriately in 9%. overall, no improvement in the assessment of fluid responsiveness was seen. introduction: there are accumulating evidences suggesting that intraoperative blood pressure affects postoperative outcome including myocardial injury, acute kidney injury, stroke, and mortality. in a patient undergoing laryngeal microsurgery (lms), blood pressure usually rises sharply due to the stimulation on the larynx. since pulse transit time (ptt) has been reported to reflect arterial blood pressure fairly well, it has possibility to be a marker for blood pressure which reflects beat-to-beat changes in blood pressure and is less invasive than arterial catheterization. methods: intraoperative noninvasive blood pressure (nibp), electrocardiogram (ecg), and photoplethysmogram (ppg) of 26 patients undergoing lms were recorded simultaneously. ptt was defined as a time interval between the r-wave peak on ecg and the point which the maximal rising slope appears on the ppg. the mean ptt values for one minute before and after the increase in blood pressure due to the stimulation on larynx were compared. parameters of ppg such as width, height, maximal slope, minimal slope, and area were also compared. then, correlation between blood pressure and each variable was calculated. results: as the larynx was stimulated by lms, nibps have surged (systolic blood pressure, 113. 6 p<0 .001) significantly in most of the patients. systolic blood pressure and ptt were inversely correlated (r = -0.636, p < 0.001). minimum slope of ppg also showed good negative correlation with systolic blood pressure (r = -0.537, p < 0.001). conclusions: ppt showed good correlation with systolic blood pressure and may have potential to be used as noninvasive continuous blood pressure monitor during a surgery in which blood pressure changes abruptly. introduction: aim of this prospective randomized pilot study was to investigate influence of intra operative restrictive volume approach and post operative lung ultrasound (lus)on prevention and early detection of postoperative interstitial syndrome development methods: 42 cardiac patients who underwent non cardiac surgical procedure were randomly assigned for: group a-liberal volume approach or for group b-combination of restrictive intra operative volume approach and small dose of norepinephrine. all patients post operatively received <=1.5 ml/kg/h fluids, mostly crystalloids. lus was performed before surgical procedure and 24 hours after their admission in icu together with arterial blood gases measurements. the ultrasound characteristic of interstitial syndrome was development of b profile results: before surgery all patients had a profile. twenty for hours later in a group significantly higher number of patients 16/22 (72.7%) vs 3/22(13.6%) in b group,had b profile (p<0.05).at the same time there were no significant difference between the groups in amount of patients with pao2/fio2 ratio <= 270 (3 patients with positive b lines from a group vs 0 patients from group b).(p>0.05) conclusions: intra operative fluid restriction is efficient in prevention of post operative cardiogenic pulmonary edema development. lus is a simple non invasive method for early detection of interstitial syndrome even before development of signs of respiratory deterioration. introduction: the peak rate of left ventricular (lv) pressure (dp/dtmax) has been classically used as a marker of lv systolic function. since measuring lv dp/dtmax requires lv catheterization, other surrogates have been proposed using the peripheral arterial waveform. the aim of this study was to test the performance of lv and arterial (aortic and femoral) dp/dtmax for assessing lv systolic function against the gold-standard (the slope of the end-systolic pressure-volume relationship, emax) during different cardiac loading and contractile conditions. methods: experimental study in 6 pigs. lv pressure-volume data was obtained with a conductance catheter and peripheral pressures were measured via a fluid-filled catheter into the aortic, femoral, and radial arteries. emax was calculated during a transient occlusion of the inferior vena cava. the experimental protocol consisted in three consecutive stages with two opposite interventions each: changes in afterload (phenylephrine and nitroprusside), preload (bleeding and fluid bolus), and contractility (esmolol and dobutamine) (fig. 1) . measurements were obtained before and after each hemodynamic intervention. results: emax variations and lv, aortic, femoral and radial dp/dtmax changes throughout the study are shown in fig. 2 . all peripheral artery-derived dp/dtmax underestimated lv dp/dtmax. percentage changes in lv and femoral ddp/dtmax were tightly correlated (r 2 =0.77; p<0.02). both lv and femoral dp/dtmax were affected by preload changes during fluid infusion. all peripheral dp/dtmax estimations allow to detect lv systolic function changes according to emax during isolated variations in contractility. conclusions: femoral and lv dp/dtmax accurately reflected emax changes, although both were affected by preload changes during fluid administration. fig. 2 (abstract p272) . emax, lv dp/dtmax and aortic, femoral and radial dp/dtmax changes. (table 1 , fig. 1 ). concordance was <95% and radial loa was ±<30°for all devices; mean polar bias was <5°for ft only (table 2, fig. 2) . conclusions: cs, ft and pa are not interchangeable with tptd, because of inaccuracy [2] . when considering limitations they may be used for trending. introduction: about 100 years ago, the german physiologist pflüger stated that the cardio-respiratory system fulfils its physiological task by guaranteeing cellular oxygen supply and removing waste products of cellular metabolism. methods: the study was performed in early postoperative period after major abdominal surgery in 160 patients. the physical condition of patients corresponded to 3 class of asa. the median age was 46.0 (38.0-62.0) years. duration of the surgery was 6,4 (4,8-9,5) hours. surgery was performed under combined epidural anesthesia with mechanical ventilation. the study was conducted in the following stages: 1-admission from operating room; 2 -in 1-3 hours; 3 -4-7 hours; 4 -8-12 hours; 5 -after 13-24 hours after the surgery. results: depend on rate of oxygen extraction index (ero2) 4 groups were revealed: group 1 (n=44)low ero2 (<21%) followed by recovery to normal levels to stage 2-3 (ero2 = 22-32%), group 2 (n=42)normal level ero2 (2232%) in all the stages, group 3 (n=40)high levels ero2 (>33%) with recovery to normal levels to stage 2, group 4 (n=34)high ero2 (>35%) in all the stages. oxygen extraction index at admission to icu after surgery can be normal (26.25% of patients), reduced (27.5% of patients) or high (46.25% of patients). when oxygen extraction ratio is reduced metabolic recovery occurs classically after 4-7 hours; when ero2 is elevated -after 812 hours. core temperature improvement is connected with the restoration of oxygen homeostasis. so, under normal and reduced ero2 even mild central hypothermia after surgery were not observed, and at an elevated ero2 moderate hypothermia after surgery was observed with only to 4-7 hours post-surgery restoration. conclusions: maintaining an adequate tissue oxygenation is the cornerstone of metabolic response and postoperative recovery in patient after major abdominal surgery. (fig. 1) . patients with cso2<50%time above 50%h had an odds ratio of hospital survival of 0.19 (95%ci 0.38-0.91, p=0.037) (fig. 2) . conclusions: cerebral oxygen desaturation below 50% was significantly associated with outcome in patients undergoing vaecmo. in patients with cso2<50%time above 50h%, prognosis was especially poor. prospective trials are needed to evaluate if cso2 is a viable target for therapeutic interventions. introduction: during the second consensus meeting on microcirculatory analysis the exploration of novel parameters related to physiological function of the microcirculation was proposed. capillary hematocrit (chct) is a direct measure of capillary hemodilution, a potential mechanism of microcirculatory dysfunction in states of shock. our hypothesis was that by application of advanced computer vision (i) chct can be reliably measured in given capillaries, and (ii) change in chct reflects capillary hemodilution induced by cardiopulmonary bypass (cpb). methods: in 11 patients undergoing coronary artery bypass surgery 3 sublingual capillary microscopy videos were recorded before and during cpb primed with hes 130/0.4. per-capillary chct was estimated as the product of the number of red blood cells (rbc) and an assumed volume of 90nl, divided by the capillary volume including plasma gaps. rbc number was assessed by manual counting in the first frame of a given video clip, as well as using a novel advanced computer vision algorithm employing blob detection to calculate the mean per-capillary rbc number in all frames of a given video clip (fig. 1) . results: 100 capillaries were analyzed, within a total of 100 and 322000 frames using manual and algorithmic analysis. a good correlation was found between both methods for chct (r=0.79, p<0.01, fig. 2 ). cpb initiation resulted in an decrease in chct from (mean±sem) 0.23±0.02 to 0.18±0.01, p<0.001 and 0.23±0.02 to 0.18±0.01, p=0.05 in manual and algorithm. conclusions: accurate measurement of chct is possible using advanced computer vision, and it reflects hemodilution induced by initiation of cpb. chct further is a determinant of capillary delivery of oxygen. combined with the assessment of functional capillary volume, blood flow velocity, and capillary hemoglobin saturation, chct may enable direct optical quantification of capillary delivery of oxygen as an integrated functional parameter of the microcirculation. fig. 2 (abstract p277) . prognosis of patients with cso2<50%time above 50%h was poor fig. 1 (abstract p278) . detection of single erythrocytes using a novel advanced computer vision algorithm in a representative capillary ribbon extracted from a video frame of the sublingual microcirculation fig. 1 (abstract p277) . the area under cso2<50% was significantly lower in survivors introduction: cardiac function is known to be impacted by sepsis. passive leg raise (plr) is an effective method to predict fluid responsiveness (fr) or cardiac response to preload expansion. preload functional status and trending cardiac output may identify patient phenotypes with varying cardiac reserve, dysfunction and outcome. methods: patient data were analyzed from a currently enrolling prospective randomized controlled study, evaluating the incidence of fr in critically ill patients with sepsis or septic shock (fresh study, nct02837731). patients randomized to plr guided resuscitation were classified as plr+ (fluid responsive/preload dependent) if stroke volume (sv) increased >= 10% when measured with a non-invasive bioreactance device (starling sv, cheetah medical). patients were categorized into 5 different phenotypic cohorts based on changing physiology exhibited on plr and trending cardiac output over the initial 72 hours of therapy. results: a total of 269 plr assessments were performed in 31 patients. overall, 36% (96/269) of assessments indicated a patient was plr+ after receiving initial resuscitation fluid of~3l. most patients (71%) demonstrated a dynamic physiology with changing plr status occurring > 1 time over 72 hours. there were no differences among the 5 groups with respect to age, gender, or qsofa score (fig. 1) . patients in group 1 exhibited a significantly decreased icu stay (113.8 hours) compared to group 3 (271.1 hours, p=0.024) (fig. 2) . patients in group 3 exhibited significantly increased echo evidence of lv/rv cardiac dysfunction (77%), compared to group 1 (16%, p=0.02) ( table 1) . patients in group 4 exhibited 100% evidence of echo based lv/rv cardiac dysfunction. conclusions: physiological based resuscitation phenotypes identify significantly different patient groups. patients who are initially not plr+, but then become plr+ with no improved co are significantly more likely to have confirmed lv/rv dysfunction and a significantly longer icu stay. introduction: accurate measurement of a patient's intravascular volume status remains an unsolved clinical problem in the icu setting. in particular, septic and cardio-renal patients often receive volume challenges or diuresis, respectively, with little appreciation of baseline bv or the resulting response. this can lead to volume overload and/or depletion and associated increases in morbidity, mortality and hospital length of stay. methods: we tested the performance of a novel, rapid, minimally invasive technique capable of measuring pv, bv and glomerular filtration rate (mgfr) in 32 human subjects. the method consists of a single iv injection of a large (150 kda) carboxymethyl dextran conjugated to a rhodamine-derived dye and a small (5 kda) carboxymethyl dextran conjugated to fluorescein. plasma and blood volumes were quantified 15 minutes following the injection of the dye based on the indicatordilution principle. results: this phase 2b study included 16 normal subjects, 8 chronic kidney disease (ckd) stage iii and 8 ckd stage iv subjects. pv and bv varied according to weight and body surface area, with pv ranging from 2115 to 6234 mls, and both were stable for greater than six hours with repeated measurements. there was excellent agreement ( fig. 1) with nadler's formula for pv in normal subjects. a 24 hour repeat dose measurement in 8 healthy subjects showed pv variability of less than +/-5%. following an intravenous bolus of 350 ml 5% albumin solution the mean +/-(sd) measured increase in pv was 326.8 ml +/-49.9 ml post infusion (fig. 2) . conclusions: this novel bedside approach allowed for rapid and accurate determination of pv, bv, mgfr (data not shown) and dynamic monitoring following clinical maneuvers such as fluid administration, with a high level of safety, accuracy and reproducibility. this approach should assist the intensivist especially with volume administration and removal in septic and cardiorenal patients. introduction: accumulating evidence shows that fluid overload is independently associated with adverse outcome in children and adults with acute lung injury. fluid restriction initiated early in the disease process may prove beneficial, potentially by diminishing the formation of interstitial edema. the main goal of this study was to determine the short-term biophysical effects of intravenous (iv) fluid restriction during acute lung injury in relation to age. methods: infant (2-3 weeks) and adult (3-4 months) wistar rats were mechanically ventilated (mv) 24 hours after intratracheal inoculation with lipopolysaccharide to model acute lung injury. both age groups were randomized to either a normal or restrictive iv fluid regimen during 6 hours of mv. thereafter the rats were sacrificed and studied for markers of interstitial edema formation (wet-dry weight ratios), lung permeability (total protein and alpha-2 macroglobulin (a2m) in bronchoalveolar lavage; bal) and local inflammation (cell counts and cytokines in bal). results: restrictive fluid therapy was not associated with worsening of hemodynamic indices during the period of mv in either infant or adult rats. however, as compared to the normal fluid regimen, restrictive fluid therapy led to lower wet-dry weight ratios of the lungs and kidneys in adult rats (p < 0.05), but not in infants (figs. 1 and 2). no difference was found in total protein and a2m in bal between the two fluid regimens in both age groups. also, neutrophil influx in the lungs did not differ between fluid regimens in both age categories, nor did the influx of inflammatory cytokines il-6 and mip-2 in bal fluid. conclusions: there is an age-dependent effect of early fluid restriction on the formation of interstitial edema in local and distant organs in the disease process of acute lung injury. further investigation of the effects of fluid therapies in experimental models may help steering towards better treatment in critically ill patients. . 1) . in a multivariate analysis fb was independently associated with: group c (p<0.001), a history of diabetes (p=0.03), the acute physiology and chronic health evaluation iii score (<0.001) and the duration of aortic-cross clamp (p<0.001). the main findings of this study substantiated the hypothesis that the introduction of continuous fb-tracking throughout the entire care process, is associated with a significant reduction in the administration of fluids in post-cardiac surgery patients, independent of differences in their baseline characteristics. demonstrating that certain organizational changes can influence medical behavior beyond the scope of teaching and instruction, and therefore serves to provide awareness to the current issue known as 'knowledge-to-care gap'. using a protocol for fluid resuscitation: how well is it followed? introduction: positive fluid balance in icu patients has been correlated with worse outcomes [1] . consequently, we developed a protocol to guide fluid resuscitation. the protocol was introduced in 2011 and mandates that fluid responsiveness is assessed when administering fluid boluses. once a patient becomes fluid unresponsive, no further resuscitation fluid should be administered. to assess responsiveness, the protocol advises the use of haemodynamic data such as heart rate and blood pressure as well as the change in stroke volume (sv) measured by a lidcoplus monitor. after years of use and a rolling education program this protocol was felt to be well ingrained in our unit culture. we then assessed how well it was being followed. methods: staff performing fluid challenges were asked to fill out a form recording the haemodynamic and sv data measured before and after a fluid challenge. they were also asked to record their interpretation of just the haemodynamic data and then this data combined with the sv data. results: forty five forms were completed. the protocol was not followed on 16 occasions (36%). four patients who should have been assessed as responsive were deemed to be unresponsive. six patients who should have been assessed as unresponsive were assessed as being responsive. the remaining deviations from the protocol represent misinterpretation of the haemodynamic data but correct use of the sv data to reach a correct final assessment. conclusions: despite being a longstanding ingrained practice in our icu, this review suggests that the protocol for fluid resuscitation is being followed incorrectly approximately a third of the time. this could result in inappropriate under or over administration of iv fluid. we plan to review the educational programme and raise awareness of the protocol to try and improve future compliance. introduction: understanding the effects of therapeutics on the left ventricular (lv) loading conditions is of utmost importance in critically ill patients. the effective arterial elastance (ea=esp/sv, where esp is aortic end-systolic pressure and sv stroke volume) is a lumped parameter of arterial load that has been proposed as an index of lv afterload. we aimed at comparing the effects of fluid administration on esp (i.e., the lv afterload in the pressure-volume phase-plane according to the classic "cardiocentric" framework) and on ea. methods: in 30 mechanically ventilated patients, we recorded ea from the femoral peripheral systolic arterial pressure sap (ea=(0.9×femoral sap)/sv) before and after the infusion of 500-ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco-2) >=15% were defined as "responders". introduction: the respiratory variations of the inferior vena cava (ivc) diameter in mechanically ventilated patients with preload responsiveness could be explain by a higher compliance of the ivc and/or higher respiratory variations of the ivc backward pressure, i.e., the central venous pressure (cvp).we aimed at determining the respective weight of these two phenomena. methods: in 25 mechanically ventilated patients, haemodynamic, respiratory and the intra-abdominal pressure (iap) signals were continuously computerised. cvp, iap and the ivc diameter (transthoracic echocardiography) were recorded during end-inspiratory and endexpiratory occlusions, before and after the infusion of 500-ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco-2) >=15% were defined as "responders". the respiratory variations of the ivc diameter, cvp and iap were calculated as (end-inspiratory -end-expiratory values)/mean value. the compliance of the ivc was estimated by the ratio between (end-expiratoryend-inspiratory) values of ivc diameter and cvp. results: fluid administration increased cardiac index by more than 15% in 9 patients. the respiratory variations of the ivc diameter predicted fluid responsiveness (area under the roc curve: 0.799 (95%ci: 0.591-0.931), p<0.05). before fluid administration, the compliance of the ivc was not different between responders and non-responders (0.75±0.32 vs. 0.79±1.14 mm/mmhg, p=0.91), whereas the respiratory variations of the cvp were higher in responders than in nonresponders (36±24 vs. 20±10 %, p=0.03). the respiratory variations of the ivc diameter were associated with the respiratory variations of cvp (r=0.49, p=0.01) but not of iap (r=-0.12, p=0.56). conclusions: the respiratory variations of the ivc diameter rather depend on the respiratory variations of the cvp than on the ivc compliance. the iap seems to not be involved in the respiratory variations of the ivc diameter. hours and gedi measured at the same time was examined. since the dataset used in this study consists of repeated measurement data, the analysis used the general linear mixed effect model (glmm). the multivariate analysis adjusted with age, cr, and cardiac index was also conducted. results: of the 143 patients with the total bnp measurements conducted for 412 times and gedi measurements for 171 times, the median of age and saps2 were 73 (iqr 62-80) and 53 (iqr 43-67), and the hospital mortality rate was 25%. the univariable analysis and the multivariable analysis using glmm respectively found statistically significant differences, with regression coefficient at 0.03 95%ci 0.01-0.06 (p=0.02), and 0.06 95%ci 0.03-0.09 (p<0.001). conclusions: while a positive correlation between gedi and bnp was statistically identified, its effect may be minor in clinical terms, and its significant clinical difference remains unclear. introduction: fluids are a cornerstone of the management of critically ill patients who are at risk of multiple organ dysfunction syndrome. however positive fluid balance (fb) is associated with worse morbidity and mortality in this population, so fluid administration needs to be carefully titrated and the nutritional support products must be taken in consideration. objective: evaluate the impact of nutritional support in the fluid balance in a intensive care unit methods: observational prospective study, conducted in eleven portuguese icus of nine general hospitals. patients with 18 years of age or older were eligible if they were ventilated and had a length of stay (los) in icu greater than 7 days. demographic data, fluid balance along type of nutritional support used in the first 7 days and were collected from the selected patients. results: 130 patients were enrolled, 63.8% were male, the median age -64±16 (19-91), icu los -15.4±6.1 days, mortality rate of 26.9% (35). 70 % of patients were admitted for medical reasons, 31.5% had normal weight, the remaining patients were either overweight or obese. the average daily fb in the eight days was 258 ± 464 ml, being the maximum at day 1 with +1152 ml, slowly trending down reaching a neutral balance at day 4 and reaching -224 ml at day 7. in the first days the majority of the intake is due to resuscitation driven fluids, however the nutritional support contribution rises as the days passes, reaching 25% at day 4 and 35% at day 7 ( fig. 1) . regarding the administration route, the enteral route was responsible to 28,9% of fluids at day 7 compared to 6,5% of parenteral route. the nutritional support is an factor to take into account regarding fluid balance in intensive care units. in this study after the 4th day the nutritional support, it was responsible for more than 25% of the total volume that was delivered to the patient and with an higher impact with the increase in los results: we included 64 patients with mean age 65 years, 53% male, apache 28 ± 7, saps ii 56 ± 20, sofa in admission 8 ± 3, mechanical ventilation 76%, continuous renal replacement techniques 38%. the mean total volume administered during the first 7 days was 26 ± 8l with a mean dcb of 16 ± 8l and a mean fluid accumulation of 21% ± 13. regarding fluid accumulation: 17% have <10%, 35% between 10-20% and 47.5% > 20%. 28th-day mortality and icu mortality were 17% i 28% respectively. during the first week, the percentage of fluid accumulation was significantly higher in non-survivors than in survivors (28.5 ± 10.7 l vs. 18.7 ± 13.1 l, p 0.046) (fig. 1) . cumulative survival was significantly lower (logrank = 6.05, p=0.01) in patients with >20% of volume gain since the 6th day (fig. 2) . >20% volume gain in the 6th day is a independently associated variable to mortality after adjusting by age, apache and haemodialysis (or = 7.3; ci 95% 1.2-43.9; p = 0.02) ( table 2) . conclusions: in septic shock patients, fluid overload more than 20% since 6-day of evolution is associated with a higher 28th-day mortality. its early detection may influence the prognosis and survival. introduction: sepsis is defined as a life-threatening organ dysfunction due to a deregulated host response to infection [1] . fluid infusion is one of the cornerstones of sepsis resuscitation therapies. one of the major adverse effects reported is fluid overload (fo). the objective of this study was to assess influence of fo on sofa score changes from day 0 to day 5. methods: this study is a retrospective, multicenter, epidemiologic data analysis. it was performed in three french icus. all adult patients admitted for septic shock, caused by peritonitis or pneumonia and mechanically ventilated, were enrolled. delta sofa score was defined as the sofa score measured on admission minus sofa score measured on day 5. results: 129 patients met the inclusion criteria of the study. fo occurs in about 40% of the patients. cumulative fluid balance at day 5 was greater in the fo group (2.738 versus 8.715 ml, p < 0.001) ( table 1) . delta sofa score was higher in the no fo group than in the fo group (4.52 versus 2.15, p = 0.001) (fig. 1 ). there was a stepwise decrease of delta sofa score when duration of fluid overload was greater (p = 0.001) (fig. 2) . in linear modelling, association between fo status and delta sofa score was confirmed with an adjusted rr of 0.15 [0.03-0.63] (p = 0.009) ( table 2) . conclusions: 1) fo patients had more prolonged multi-organ failure during septic shock; 2) the longer the fo is the longer the more multi-organ failure last. , 100 (t120) and 160 (t180) minutes later. cardiovascular parameters were also measured at above time points. biomarker change from baseline (fold-change), indexed to hemoglobin, was compared between groups using mixed effects models (bonferroni-holm corrected p<0.05). results: minor differences in measures of shock between groups after fluid administration resolved by t120. cryst showed increased fold-change in hyaluronan compared to other groups at t20 (fwb p=0.019, hes p<0.001, gelo p<0.001), t60 (fwb p<0.001) and t120 (fwb p<0.001) (fig. 1) . gelo had increased fold-change in hyaluronan compared to other groups at t20 (hes p=0.009), t60 (fwb p<0.001) and t120 (fwb p<0.001, cryst p=0.006), as did fwb at t20 (hes p=0.008). cryst showed increased fold-change in il10 compared to other groups at t20 (hes p<0.001, gelo p=0.002), t60 (hes p=0.001, gelo p=0.005,), t120 (hes and gelo p<0.001) and t180 (hes and gelo p<0.001) (fig. 2) , of il8 at t60 (gelo p=0.006), and of kc at shock (fwb p=0.002, gelo p=0.007), t20 (fwb p=0.009, gelo p=0.007), and t120 (gelo p=0.002). conclusions: rapid large-volume crystalloid given for hemorrhagic shock was associated with increased hyaluronan, a biomarker of endothelial glycocalyx damage, and inflammation, including increased il10, il8 and kc. introduction: a bi-center randomized controlled trial has recently been published that investigates the impact of the type of fluid (crystalloid versus colloid) on patient outcome following major surgery [1] . the study used a closed-loop fluid delivery system to eliminate the clinician bias when determining when to deliver fluids. the goal of the current analysis is to compare the immediate hemodynamic response to 100 ml fluid boluses of either a crystalloid or a colloid solution. methods: patient consent was obtained prior to transferring the data from [1] to edwards lifesciences for further post-hoc analysis. the percent change in stroke volume (dsv) following each 100ml bolus was tabulated and cross-referenced to the type of fluid. the responder rate and the dsv cumulative distribution function (cdf) were determined for each type of fluid administered. a responder was defined as a dsv >= 5% for a 100ml fluid challenge. the mean dsv was compared between the two groups using a student t-test. results: from the 160 datasets reported in [1] , 119 were used in the analysis. descriptive statistics are summarized in table 1 and the cdfs are plotted in fig. 1 . more crystalloid boluses were administered. in both groups, the responder rate was around 50%. mean dsv was not significantly different between groups (p = 0.57). we observed similar responder rates and cdfs with the two fluid types, suggesting that the immediate hemodynamic response to 100 ml fluid boluses is independent from the fluid type. we therefore hypothesized that it is the longer intra-vascular persistence of the colloid that explain the lower number of boluses required to achieve the hemodynamic endpoints targeted in the clinical study [1] . fig. 1 (abstract p294) . cumulative distribution functions of delta stroke volume for crystalloid and colloid fluid boluses the reduction projected to an average annual saving of 100,272 usd ( introduction: colloids are widely used for volume resuscitation. among synthetic colloids, hydroxyethyl starch (hes) is commonly administered. in cardiac surgery, priming of the cardiopulmonary bypass (cpb) circuit with colloids minimizes resuscitation volume and results in less pulmonary fluid accumulation. however, the use of hes has been associated with a higher incidence of renal damage and a higher occurrence of coagulopathy. the aim of this study was to investigate the effect of low dose (5 -10 ml/kg) hes 6% (130/0,4) in cpb pump priming on fluid balance, blood loss, transfusion requirement and occurrence of acute kidney injury. methods: in a pre-post design, data from 1120 patients undergoing cardiac surgery with cpb were analyzed. in 560 patients, priming solution consisted of 1250 ml balanced crystalloids, 250 ml mannitol 15%, tranexamic acid 2g and 500 i.e. heparin. for the other 560 patients, 500 ml of the crystalloids were replaced with hes 6% (130/ 0.4), the other components were the same. patients were matched 1:1 with propensity score method. the primary endpoint was intraoperative fluid balance. secondary endpoints were perioperative blood loss, transfusion requirement and the occurrence of acute kidney injury. results: in total, 866 patients were analyzed. the hes group showed less positive fluid balance than the crystalloid group (p< 0.001). there was no difference in intraoperative blood loss (p=0.426) and transfusion requirement (p=0.442). the occurrence of acute kidney injury was not significantly different between the two groups (p=0,147). conclusions: low-dose administration of 5-10 ml/kg hes 6% (130/ 0.4) to cpb pump priming decreased intraoperative fluid accumulation without increasing perioperative blood loss and transfusion requirement. there was no effect on the incidence of acute kidney injury. priming cpb pumps with a low-dose of hes 6% (130/ 0.4) is an important component for a restrictive volume strategy and might safely be used in patients with preexisting renal dysfunction. introduction: most crystalloid solutions used in critically ill patients have a greater chloride (cl) concentration than plasma, which may be detrimental. replacing some cl with bicarbonate (hc03) reduces cl, but may increase partial pressure of carbon dioxide (pc02) in blood. such an increase in pc02 may be harmful [1] . the main objective was to determine if a hco3 balanced fluid resulted in increased paco2 compared to a conventional balanced fluid. methods: single center randomized controlled trial in an adult icu, comparing balanced fluid (sodium,na=142mmol/l, chloride,cl=99mmol/l, hco3=49mmol/l) vs conventional fluid (na=130mmol/l, cl=110mmol/l, hc03<=27mmol/l). university ethics committee approval:m080932. we used the absolute difference between the pco2 and 40mmhg as a comparison for the 2 fluid groups. betweengroup comparisons of pc02 from d1-d7 was done by repeated measures anova. a p value <0.05 was considered significant. results: 46 patients were allocated to the conventional group and 40 to the balanced group. at baseline the 2 groups were well matched (p>0.05) for age, weight, gender, severity of illness and organ support. there were no significant differences in pc02 between the two fluid groups, overall or at d1, d5 or d7. the balanced group showed a significant improvement in egfr (scr), between d0 and d5 (p=0.02) while the conventional group exhibited a significant decline (p=0.00). there were no significant differences between the 2 groups with respect to fluid requirements, number of positive blood cultures, icu renal replacement utilization, icu length of stay, icu mortality and 28 day mortality. conclusions: the use of a balanced fluid did not result in an increase in pco2 and appears to be safe. a beneficial effect on renal function was observed. introduction: the effects of crystalloids and colloids on macro-and microcirculation is controversial. our aim was to compare their effects on microcirculation during free flap surgery when management was guided by detailed hemodynamic assessment. methods: patients undergoing maxillo-facial tumour resection and free flap reconstruction were randomized into a crystalloid (ringerfundin, rf, n=15) and a colloid (6% hydroxyethyl starch, hes, n=15) groups. cardiac index (ci), stroke volume (svi) and pulse pressure variation (ppv) were continuously monitored by a non-calibrated device (pulsioflex -pulsion, maquet). central venous oxygen saturation (scvo2), venous-to-arterial pco2-gap (dco2), lactate levels and hourly urine output was also measured, and a multimodal, individualized approach based algorhithm was applied [1] . microcirculation was assessed by laser doppler flowmetry (periflux 5000 ldpm, perimed jarfalla, sweden). measurements were performed at baseline and from the start of reperfusion hourly for 12 hours. for statistical analysis, two-way rm anova was used. results: there was no difference between the groups regarding age, sex, length of surgery (whole population: 348 ± 69 min). patients in the rf-group required significantly more fluid in total (rf: 2581±986, hes: 1803±497 ml, p=0.011). both groups remained hemodynamically stable (ci, svi, ppv, scvo2, dco2, lactate and urine output) throughout the study. there was no difference between the rf-, and hes-groups in the laser doppler measurements neither on the control site nor in the flap (fig. 1) . conclusions: we found that when hemodynamic management is guided by a multimodal assessment and stability is maintained, there was no difference between crystalloids and colloids in macrocirculation and microcirculatory perfusion. introduction: our aim is to evaluate the impact of crystalloid fluids on immune cells. intensive care unit (icu) patients' inflammatory status can switch from an early pro-inflammatory to a late anti-inflammatory phase, which favors infections. they can receive different crystalloids, either normal saline (ns), ringer's lactate (rl) or plasma-lyte (pl). high chloride concentration present in ns has been associated with various complications [1] , whereas high doses of nacl have inflammatory effects on immune cells [2] . however, the immune consequences of crystalloids in humans are ill-defined. methods: using our comprehensive immunemonitoring platform, we assessed the immunological phenotype of peripheral blood mononuclear cells (pbmc) in humans. 11 healthy subjects received a liter of ns, rl and pl. blood samples were taken before and 6h later. pbmc phenotypes were assessed by flow cytometry and cytokine concentrations were measured by a multiplex assay. 9 off-pump cardiac surgery patients were also randomized to receive either ns, rl or pl during surgery and their stay in the icu. blood samples were drawn at various time-points. all leucocytes were analyzed in a similar fashion. we are still recruiting. results: study of healthy subject's pbmc suggested that rl reduced classical monocytes, whereas ns increased lymphocyte activation and il-17 and mip-1b levels. in cardiac surgery patients, our preliminary results suggested that rl and pl reduced classical monocytes and increased non-classical monocytes compared to ns. neutrophils were also affected differently by crystalloids, where ns seemed to activate them more. conclusions: our results suggest that crystalloids have different immune consequences. a better understanding of their immune modulation will lead to personalization of their use according to the inflammatory status of patients to restore their immune homeostasis. this randomised controlled open-label pilot study included 65 patients presenting to an emergency department with suspected infection requiring a fluid bolus. patients received either a single bolus of 10ml/kg of 0.9% nacl (isotonic group) or 5ml/kg of 3% nacl (hypertonic group). blood biomarker concentrations of glycocalyx shedding (syndecan-1, hyaluronan), endothelial activation (sicam-1, svcam-1) and inflammation (interleukin-6, -8, -10, ngal, resistin) were measured at t0 (before fluid) and 1 hour (t1), 3 hours (t3) and 12-24 hours (t24) later. changes in biomarker concentrations were compared between study groups using mixed regression models, with fold-change from t0 reported. differences in fluid volumes were compared using the wilcoxon rank sum test. significance was set at p<0.05. results: syndecan-1 concentration in the isotonic group decreased from t0 to t1 (fold-change 0.8, 95% ci 0.7-0.9), which was significantly different to the hypertonic group (fold-change 1.0, 95% ci 0.9-1.1)(p=0.012)( table 1) . interleukin-10 concentration decreased in the isotonic group from t0 to t24 (fold-change 0.1, 95% ci 0.0-0.3), which was significantly different to the hypertonic group (fold-change 0.8, 95% ci 0.3-2.6)(p=0.006). otherwise, there were no significant differences in change over time between groups for measured biomarkers. total fluid volume administered between t0 and t1 was significantly higher in the isotonic group (p<0.001) ( fig. 1) but not different for subsequent time periods. conclusions: biomarkers of glycocalyx shedding, endothelial activation and inflammation were not different between patients receiving either 0.9% or 3% saline. also, 3% nacl did not reduce administration of additional fluids. introduction: acute changes in pco2 are buffered by non-carbonic weak acids (atot), i.e., albumin, phosphates and hemoglobin. aim of the study was to describe acid-base variations induced by in-vitro pco2 changes in critically ill patients' blood and isolated plasma, compare them with healthy controls and quantify the contribution of different buffers. methods: blood samples were collected from patients admitted to the icu and controls. blood and isolated plasma were tonometered at 5 and 20% of co2 in air. electrolytes, ph, blood gases, albumin, hemoglobin and phosphates were measured. the strong ion difference (sid) was calculated [1] and non-carbonic buffer power was defined as β=-δhco3-/δph [2] . t-tests and linear regression were used for analysis. results: seven patients and 10 controls were studied. hemoglobin, hematocrit and albumin were lower in patients (p<0.001), while sid and phosphates were similar. pco2 changed from 29±4 to 108±13 mmhg, causing different blood ph variations in patients and controls (0.43±0.06 vs. 0.36±0.02, p=0.03). patients had lower blood and plasma β (20±5 vs. 30±4, p<0.001 and 2±2 vs. 4±1, p=0.03, respectively). figure 1 shows changes in [hco3-] and sid induced in blood by pco2 variations. in both populations, 82±12% of [hco3-] change was due to sid variations, while only 18±12% to changes in atot dissociation. a significant correlation between hematocrit and δsid was observed in the whole study population (fig. 2) . conclusions: the β of icu patients was lower, likely due to reduced albumin and hemoglobin concentrations. similar pco2 increases caused therefore greater ph variations in this population. electrolyte shifts, likely deriving from red blood cells [3] , were the major buffer system in our in-vitro model of acute respiratory acidosis. introduction: there is an increasing trend in the incidence of aneurysmal subarachnoid haemorrhage in hong kong and the disease carries high morbidity and mortality rate. electrolyte disturbance is one of the known complications of sah and the outcomes associated with this are not fully understood. the objective of this retrospective local study is to evaluate the pattern of electrolyte disturbances in patients with sah and their impact on the prognostic functional outcome. methods: patients with spontaneous aneurysmal sah who were admitted to icu at pamela youde nethersole eastern hospital, hong kong between 1st january 2011 and 31st december 2016 were included into this retrospective local study. collected data include demographic details, comorbidities, serum electrolyte levels (sodium and potassium) from day 1 to 11 of admission into icu, radiographic intensity of haemorrhage using fisher scale and the clinical grading of sah using wfns. prognosis of these patients was estimated using the glasgow outcome scale at 3 months after initial insult (fig. 1) . results: a total of 244 patients were included in this study. the mean age was 58, with the majority of patients being female (63.6%). the most common aneurysm location was in anterior communicating artery, though poor outcomes were shown significant in patients with posterior circulation aneurysms. whilst early-onset hyponatremia was not correlated with poor outcome, late-onset hyponatremia was associated with better outcome. logistic regression analysis identified 9 independent predictors of poor outcome (table 1) . patients who underwent interventional radiological procedure treatment was shown to have better outcome. conclusions: hypernatremia after sah is associated with poor outcome. there does not appear to be significant evidence that hyponatremia has an effect on short-term mortality or certain outcome measures such as gos, and its longer-term effects are not well characterized. fig. 1 note logarithmic transformation of los data). we found a statistically significant difference between the two groups when comparing the length of stay (p < 0.001). conclusions: dean et al demonstrated no significant difference in the mean length of stay using the same definitions of hypo and eunatraemia as in this study [1] . even though our data appears to contradict their findings, regarding the statistical significance seen, we feel that this is not significant clinically, given the very similar median times for los between the two groups; the unbalanced design may contribute to the statistical significance. fig. 1 (abstract p306) . length of stay between the two groups (note logarithmic scale for los) fig. 1 (abstract p305 ). gos at 3 months group consisted of 1477 patients with mean age 64.3 (sd 17.8) years and mean sodium 139.8 (sd 2.8) mmol/l with a median los of 3.8 (iqr 1.9 -7.1) days. we found no statistically significant difference (p = 0.0636) between the two groups when comparing the length of stay (fig. 1) . conclusions: darmon et al demonstrated prognostic consequences of an admission sodium greater than 145, eliciting hypernatraemia as a factor independently associated with 30-day mortality [1] . in contrast, our study suggests that hypernatraemia (as defined) is not associated with the length of stay, however this result is limited by the unbalanced design of this small study. introduction: our aim is to determine whether auscultation for bowel sounds helps in clinical decision making in icu patients with ileus. ileus can be the consequence of an operation, a side effect of drugs or the result of an obstruction requiring direct operative correction. although auscultation for bowel sounds is routinely performed in the icu and a well-established part of the physical examination in patients with suspected ileus, its clinical value remains largely unstudied. methods: a literature search of pubmed, embase and cochrane was performed to study the diagnostic value of auscultation for bowel sounds. results: auditory characteristics (tinkling, high pitched and rushes) were highly variable in postoperative ileus, mechanical ileus and healthy volunteers. the inter-observer variability for the assessment of the quantity, volume and pitch of bowel sounds was high, with a moderate interobserver agreement for discerning postoperative ileus, bowel obstruction and normal bowel sounds (kappa value 0.57). the intra-observer reliability of duplicated recordings for distinguishing between patients with normal bowels, obstructed bowels or postoperative ileus was 54% [1] . no clear relation between bowel sounds and intestinal transit was found (table 1) . sensitivity and positive predictive value were low: respectively 32% and 23% in healthy volunteers, 22% and 28% in obstructive ileus, and 22% and 44% in postoperative ileus ( table 2) . conclusions: auscultation with the aim to differentiate normal from pathological bowel sounds is not useful in clinical practice. the low sensitivity and low positive predictive value together with a poor inter-and intra-observer agreement demonstrate the inaccuracy of utilizing bowel sounds for clinical decision-making. given the lack of evidence and standardization of auscultation, the critically ill patient is more likely to benefit from abdominal imaging. introduction: stress ulcer prophylaxis has become a standard of care in intensive care unit (icu). however, it has been proposed that enteral nutrition (en) could play preventive role for gastrointestinal bleeding and some studies revealed no added benefit of acid suppressive drugs to patients on en. based on these backgrounds, we use proton pump inhibitor (ppi) as stress ulcer prophylaxis during starvation period, and discontinue it within 24 hours after commencing meals or en. the aim of this study is to evaluate the applicability of our protocol by reviewing the incidence of upper gastrointestinal bleeding (ugib) in our icu. methods: we conducted a retrospective observational study. all consecutive patients admitted to our icu between april 2016 and march 2017 were reviewed. patients who had ugib within 24 hours after admission, had previous total gastrectomy, or underwent upper gastrointestinal surgery were excluded. the primary outcome was the incidence of overt or clinically important ugib, and the secondary outcome was protocol adherence. we presented descriptive data as number (percentage) and median (interquartile range). results: a total of 521 patients were included. of those, 315 (60.5%) were male, median age was 73 (57-81), and median sofa score was 5 (2) (3) (4) (5) (6) (7) (8) . of all 521 patients, 16 (3.37%) had overt bleeding, and 2 (0.38%) had clinically important bleeding. both 2 patients who introduction: patients requiring operative procedures admitted under non-surgical specialties typically experience delays in treatment and fail to meet peri-operative standards with regards to the timing of operative intervention. patients admitted from medicine requiring an emergency laparotomy have an increased mortality when compared to those patients admitted from surgery (20.4% v 13.6%) [1] . methods: we undertook a retrospective case note review of patients requiring a non-elective laparotomy at our hospital during a sixmonth period in 2016. patients were identified using the emergency theatre booking system. data were gathered on admission details, peri-operative care and post-operative stay. results: two main investigators reviewed 104 patients to standardise data extraction. six patients presenting with inflammatory bowel disease were excluded from analysis. most patients (59.1%) were admitted through the emergency department; 17 (29.3%) of whom were initially admitted under medicine, with only 37.5% of these reviewed by a senior clinician prior to admission (table 1 ). there was no statistically significant difference in mortality between the medicine and surgery groups. there was a trend to increased length of stay in icu and in hospital in the medical group (table 2) . conclusions: lack of senior decision making may have a direct impact on patient care due to the inappropriate streaming of patients to medicine. the increased mean length of stay in those patients admitted to medicine may reflect a delay in surgical intervention and therefore a prolonged recovery period. we are introducing an acute abdominal pain screening and immediate action tool to improve identification of these high-risk patients and early involvement of senior decision makers. introduction: biomarkers reflecting the extent of surgical tissue trauma should be investigated in an effort to predict and prevent postoperative complications. the aim of the present study was to investigate blood concentrations of selected alarmins in patients after colorectal surgery in comparison to healthy individuals. the secondary aim was to analyze the relationship between alarmins and inflammatory biomarkers during early postoperative period. methods: the prospective, single-center, observational study consisted of non-surgical (ns) group (n=35) and surgical (s) group (n=38) undergoing colorectal surgery. serum levels of selected alarmins (s100a8 and s100a12) and inflammatory biomarkers (leukocytes; c-reactive protein, crp; interleukin-6, il-6) were analyzed. results: proteins s100a8 an s100a12 had significantly higher serum values in the s-group during all three days after the surgery. the multidimensional model taking into account age, sex, weight, group and days revealed significant differences between study groups for both proteins s100a8 and s100a12 (p<0.001, p=0.001, respectively). biomarkers (leukocytes, crp, and il-6) showed significant differences between study subgroups (p<0.001, p<0.001, and p<0.001, respectively). in s-group, moderate positive correlations were found between s100a8 and all biomarkers: leukocytes (r=0.6), crp (r=0.5), and il-6 (r=0.6). s100a12 had moderate positive correlation with leukocytes (r=0.5). levels of s100a8 also positively correlated with intensive care unit and hospital length of stay (r=0.6, r=0.5, respectively) conclusions: protein s100a8 might be considered as early biomarker of first wave of immune activation elicited by surgical injury after colorectal surgery. the increase of the alarmins is reflected by the elevation of routine inflammatory biomarkers. introduction: critical illness-induced liver test abnormalities are associated with complications and death in adult icu patients, but remain poorly characterized in the pediatric icu (picu). in the pepanic rct, delaying initiation of parenteral nutrition to beyond day 7 (late pn) was clinically superior to providing pn within 24h (early pn), but resulted in a higher rise in bilirubin. we aimed to document prevalence and prognostic value of abnormal liver tests and the impact of withholding early pn in the picu. methods: we performed a preplanned secondary analysis of 1231 of the 1440 pepanic patients aged 28 days to 17 years, as neonatal jaundice was considered a confounder. plasma concentrations of total bilirubin, alt, ast, γ gt, alp were measured systematically during picu stay. analyses were adjusted for baseline characteristics including severity of illness. results: during the first 7 picu days, the prevalence of cholestasis (>2mg/dl bilirubin) ranged between 3.8%-4.9% and of hypoxic hepatitis (>=20-fold uln for alt and ast) between 0.8%-2.2%, both unaffected by the use of pn. throughout the first week in picu plasma bilirubin concentrations were higher in late pn patients (p<0.05), but became comparable to early pn patients as soon as pn was started on day 8. plasma concentrations of γ gt, alp, alt and ast were unaffected by pn. high day 1 plasma concentrations of γ gt, alt and ast (p<=0.01), but not alp, were independent risk factors for picu mortality. day 1 plasma bilirubin concentrations displayed a ushaped association with picu mortality, with higher mortality associated with bilirubin concentrations <0.20mg/dl and >0.76mg/dl (p<=0.01). conclusions: in conclusion, overt cholestasis and hypoxic hepatitis were rare and unrelated to nutritional strategy. however, accepting a large macronutrient deficit during week 1 increased plasma bilirubin. a mild elevation of bilirubin on the first picu-day was associated with lower risk of death and may represent an adaptive stress response rather than true cholestasis. positive fluid balance is an independent risk factor for intensive care unit mortality in patients with acute-on-chronic liver failure introduction: muscle wasting is a common consequence of disuse and inflammation during admission to intensive care with critical illness. limb muscles are known to decrease in size during critical illness, but less is known about muscles of the trunk. in this study, we tracked how psoas muscle area changes at multiple levels, in a group of patients with acute severe pancreatitis. methods: paired computed tomography (ct) scans were obtained from 21 patients admitted to the royal liverpool university hospital's icu with acute severe pancreatitis. the first scan was within 3 days of admission, and the second took place between 8 to 16 days later. for each scan, three slices were identified: the top and bottom plates of l4, and the mid-point of l4 vertebral body. on each slice, the cross sectional area (csa) of the left and right psoas muscle was calculated using imagej. the difference and percentage change in csa between both scans was calculated. white cell counts and c-reactive protein results were obtained, with peak levels correlated against change in muscle size. results: combined csa of the left and right psoas muscle increased from top to bottom plates and was positively correlated with height (r=0.74, p<0.001 mid l4 level)) and weight (r=0.57, p=0.014, mid l4 level) at all three levels. at all three levels, there were significant losses of csa between the two scans (see table 1 ). crp was moderately correlated with percentage change in csa (r= -0.55, p=0.014). increasing weight on admission was associated with greater percentage losses in csa (r= -0.78, p<0.001). wcc did not correlate with change in size. in critically ill patients with acute severe pancreatitis, there are significant losses in both psoas muscles throughout the l4 level. further prospective studies are required to determine if inflammatory markers and cytokines have a role in these losses, and to determine the functional effects of these losses. introduction: the evidence for penta-therapy for hyperlipidemic severe acute pancreatitis (hl-sap) is anecdotal. the purpose of our study is to evaluate the efficacy of penta-therapy for hl-sap in a retrospective study. methods: retrospective study between january 2007 and december 2016 in a hospital intensive care unit.hl-sap patients were assigned to conventional treatment alone (the control group) or conventional treatment with the experimental protocol (the penta-therapy group) consists of blood purification, antihyperlipidemic agents, lowmolecular-weight heparin, insulin, covering the whole abdomen with pixiao (a traditional chinese medicine).serum triglyceride, serum calcium, apache ii score, sofa score, ranson score, ct severity index, and other serum biomarkers were evaluated. the hospital length of stay, local complications, systematic complications, rate of recurrence, overall mortality, and operation rate were considered clinical outcomes. results: 63 hl-sap patients received conventional treatment alone (the control group) and 25 patients underwent penta-therapy combined with conventional treatment (the penta-therapy group). serum amylase, serum triglyceride, white blood cell count, c -reactive protein, and blood sugar were significantly reduced, while serum calcium was significantly increased with penta-therapy. the changes in serum amylase, serum calcium were significantly different between the penta-therapy and control group on 7th day after the initiation of treatment. the reduction in serum triglyceride in the pentatherapy group on the second day and 7th day were greater than the control group. patients in the penta-therapy group had a significantly shorter length of hospital stay. conclusions: this study suggests that the addition of penta-therapy to conventional treatment for hl-sap may be superior to conventional treatment alone for improvement of serum biomarkers and clinical outcomes. average energy expenditure (ee) for all patients was 26 ± 4 kcal/kg (mean ± sd). there was no difference in the average ee between the patients who survived and those who died: 27 ± 1 and 25 ± 1 kcal/ kg (mean ± sd) respectively (p > 0.05). however, there was a negative correlation between ee and saps 3 score in the non-survivors groupcorrelation coefficient -0.679, p < 0.05. the energy deficit (computed by subtracting caloric intake from ee measurement) was similar among survivors and non-survivors, 5.5 ± 1 vs 6.5 ± 2 kcal/kg, respectively (mean ± sd) (p > 0.05). the patients who survived had received 21 ± 1 kcal/kg while those who died -18 ± 1 kcal/kg (mean ± sd) (p > 0.05). the provision of protein was also similar for both groups: 0.9 ± 0.1 g/kg for survivors and 1 ± 0.04 g/kg for nonsurvivors (mean ± sd) (p > 0.05). there was no statistically significant correlation between provision of calories and protein and outcomes such as length of hospital and icu stay or duration of mechanical ventilation. conclusions: average energy expenditure in critically ill patients with acute severe pancreatitis roughly equals to aspen estimation of 25 kcal/kg and does not differ among survivors and non-survivors. outcomes such as survival, length of hospital and icu stay and duration of mechanical ventilation were unaffected by caloric nor protein provision in this sample. introduction: disturbances in gastrointestinal motility are common in critically ill patients receiving enteral nutrition. slow gastric emptying (ge) is the leading cause of enteral feeding intolerance (efi), which compromises nutritional status and is associated with increased morbidity and mortality. this phase 2a study evaluated the efficacy, safety and tolerability of acute tak-954 (previously td-8954), a selective agonist of the 5 hydroxytryptamine receptor 4 (5ht4), compared with metoclopramide in critically ill patients with efi. methods: this was a double-blinded, double-dummy study conducted in mechanically ventilated patients with efi (>200 ml gastric residual volume) randomized to receive either intervention (tak-954 0.5 mg over 1 hour and 0.9% saline 10 ml injection qid) or control (0.9% saline over 1 hour and metoclopramide 10 mg injection qid). within 1 hour of the first dose, patients received a test meal of 100 ml ensure® and ge was measured using scintigraphy. primary objectives were to evaluate the safety and tolerability of tak-954 and its effect on ge (% retention at 180 mins) vs control. results: a total of 13 patients (intervention, n = 7; control, n = 6) were studied. the median ages were 47 and 57 years in these groups, respectively. post-treatment, a 2-fold greater number of patients had normal gastric retention (<13% at 180 mins) in the intervention group vs the control group (6 vs 3; fig. 1 ). in the intervention and control groups, (table 1) . no aes led to treatment discontinuation. conclusions: a greater proportion of patients receiving tak-954 had normal gastric retention after a single dose compared with those receiving metoclopramide. treatment with tak-954 was not associated with an increase in aes. these results support further evaluation of tak-954 in critically ill patients with efi. method to assess gastric emptying in the fed state in enterally tube fed patients: comparison of the paracetamol absorption test to scintigraphy j james 1 introduction: the paracetamol absorption test (pat) is the most common and practical approach for assessing gastric emptying (ge) in critically ill patients. however, current methods require that paracetamol be administered to an empty stomach, removing gastric contents and depriving patients of feeding for several hours. the objective of this study was to develop methods to assess gastric emptying in these patients without interrupting feeding. methods: gastric emptying was assessed in the fed state using pat and scintigraphy in 12 healthy volunteers. paracetamol 1g in 30ml was ingested immediately before consumption of a test meal of 250ml ensure plus containing 375kcal, 15.6g protein, and 12.3g fat plus 4mbq of 99mtc-dpta as a scintigraphic agent. comparisons were made between paracetamol absorption and the time to 25% and 50% gastric emptying by scintigraphy at baseline and after administration of ulimorelin 600μg/ kg, a prokinetic agent known to enhance gastric emptying. blood samples for paracetamol were collected for up to 4h post administration. values for normal gastric emptying were based on the 95% confidence intervals for pk parameters. sensitivity and specificity were assessed by receiver operating characteristic (roc) analysis before and after treatment. results: the pat correlated with scintigraphy and pk parameters for normal emptying were determined. cmax and auc2 were the most sensitive and specific parameters for assessing ge with lowest variability and areas under the roc curve of 0.8981 and 0.8889, respectively. a 2h sampling period appeared sufficient to distinguish normal from abnormal emptying. conclusions: the pat can be used to distinguish normal versus abnormal ge in the fed state. under the conditions used, patients can receive up to 250ml enteral feeding over a 2h test period (125 ml/hr). this method can be used to distinguish normal from abnormal gastric emptying in enterally tube fed patients without interrupting feedings. introduction: for mechanically ventillated critically ill patients, the effect of full feeding on mortality is stil controversial. we aimed to investigate the relationship of energy intakes with 28-day mortality, and nutritional risk status influenced this relationship. methods: this prospective observational study was conducted among adult patients admitted to icu and required invasive mechanical ventilation (imv) for more than 48 h. data on baseline characteristics and the modified nutritional risk in critically ill [mnutric] score was collected on day 1. energy intake and nutritional adequacy was recorded daily until death, discarge or until twelfth evaluable days. patients were divided into 2 groups: a)received < 75% of prescribed energy b) received >= 75% of prescribed energy. results: 150 patients (65% male, mean age 51.0±15.3 years, mean body mass index 27.9±6.2 kg/m2, mean mnutricscore 5.8± 1.7) were included. in the univariate analysis, mnutri̇c score was associated with 28-day mortality. in the multivariable logistic regregression analysis, mnutric score(odds ratio, or 1.65, ci 1.20-1.70, p < o.oo1) was associated with 28-day mortality. nutritional adequacy was assessed, median nutritional adequacy was 0.40 (0.17-0.75). in patients with high mnutri̇c score (5-9), received >= 75% of prescribed energy was associated with a lower predicted 28-day mortality; this was not observed in patients with low mnutri̇c score (0-4). conclusions: nearly 60 % of imv required patients admitted to icu were at nutritional risk, mnutri̇c score is associated with 28-day mortality. energy adequacy of >= 75% of prescribed amounts were associated with decreased mortality in patients with a high mnutri̇c score. results: patients included in the study were asa iv. four patients died in the first few days after surgery (2÷16 days). mean length of stay in icu was 5.2 ±3.4 days. univariate analysis showed a correlation between hypoalbuminemia and the onset of mof (p = 0.004); reduction of the lymphocyte count and risk of mof (p = 0.008). sofa score showed a significant correlation with occurrence of pneumonia (p = 0.035) and mof (p = 0.04). including the 30-day mortality among confounders, albumin and lymphocyte count were the strongest predictors of mof. length of stay in icu and ventilation days did not have statistical significance. bmi showed no predictive value of any outcome. conclusions: our sample was poor but results of our study seem to indicate malnutrition as an independent risk factor for elderly patients undergoing emergency surgery. early multidisciplinairy screening of dysphagia at admission to the emergency departmenta pilot study d melgaard, l sørensen, d sandager, a christensen, a jørgensen, m ludwig, p leutscher north denmark regional hospital, hjørring, denmark critical care 2018, 22(suppl 1):p324 introduction: dysphagia increase the risk of aspiration pneumonia, malnutrition, dehydration and death. this combined with the fact that patients with dysphagia have a longer stay in the hospital makes early prognosis and appropriate treatment important. knowledge about effect of early dysphagia screening is limited. the aim of this study is to examine the prevalence of dysphagia in the emergency department (ed) population. methods: this study included consecutively hospitalized patients in 10 days from 2pm-10pm at the ed of north denmark regional hospital. the screening took place within 2 hours of admission. inclusion criteria were any of the following: age ≥65 years, neurological disorders, alcoholism, copd, pneumonia, dyspnoea, diabetes or unexplained weight loss. a nurse screened patients with a water test and with signs of dysphagia tested by an occupational therapist with the v-vst and the meof-ii. results: of 140 eligible patients (56% male, median age 75 years) 95 (68%) were screened. it was impossible to screen 12 patients (9%) to limited time and 30 patients (21%) due to poor health condition and 5 patients (4%) declined participation. the prevalence of dysphagia in the study population was 16% (15 patients). results from the water test were confirmed with v-vst and meof-ii. in patients with lung related diseases or circulatory diseases was the prevalence respectively 25% and 24%. patients, not screened due to poor health condition, were tested during hospitalisation and the prevalence of dysphagia was 75% in this group of patients. conclusions: the prevalence in ed patients was 16%. patients transferred to other departments due to poor health condition had a prevalence of 75%. it is possible to screen patients in the ed. the water test is a useful screening tool in an acute setting. introduction: to improve protein and energy delivery in a nutrition delivery bundle was introduced to a level 3 icu. greater protein and energy intake is associated with improved outcomes in the critically ill [1] [2] [3] [4] , but only 50% of prescribed protein and energy is delivered in icus worldwide [5, 6] . methods: percentage of target protein and energy delivery was measured via participation in the international nutrition survey (ins) before and after a "nutrition delivery bundle" was introduced by the icu dietitian. the nutrition delivery bundle involved all stakeholders in icu nutrition care (fig. 1) and included the following quality improvement measures: increased icu dietetic staffing, update of icu enteral feeding protocol with staff education, use of higher protein formulations, earlier patient nutrition assessment, daily calculation of percentage nutrition delivery, increased nutrition communication through more regular discussion of patient care with medical team, expansion of choice of nasojejunal tube available, 6 monthly reporting of key nutrition performance indicators, improved resources for cover dietitian(s) when icu dietitian on leave (fig. 2) . results: prior to a nutrition delivery bundle being introduced the mater misericordiae university hospital (mmuh) icu achieved 59% of protein and 62% of energy targets over the first 12 admission days of 20 consecutive mechanically ventilated patients in icu >72hrs enrolled in the international nutrition survey. this increased to 75% of protein and 79% of energy targets in 2014 (table 1) . conclusions: a 27% improvement in protein and energy delivery to critically ill patients was seen after the introduction of a dietitian-led nutrition delivery bundle. introduction: the critically ill polytrauma patient with sepsis presents with variable energetic necessities characterized by a proinflammatory, pro-oxidative and hypermetabolic status. one of the challenges the icu doctor faces is adapting the nutritional therapy based on the individual needs of each patient. through this paper we wish to highlight the trend of energy needs in the case of critically ill polytrauma patients with sepsis by using non-invasive monitoring of respiratory gases based on indirect calorimetry (ge healthcare, helsinki, finland). methods: this is a prospective observational study carried out in the anesthesia and intensive care unit "casa austria", emergency county hospital "pius brinzeu", timisoara, romania. we monitored vo2, vco2, energy demand (ed), and specific clinical and paraclinical data. we measured energy demand values monitored by direct calorimetry with values calculated based on standard formulas. results: 21values have been recorded in the study. the mean vo2 was 3.3 ± 0.4 ml/min/kg, the mean vco2 was 2.3 ± 0.3 ml/min/kg. in regard with energy demand, the mean ed obtained through direct calorimetry was 2393.2 ± 912.9 kcal/day, and those obtained by using mathematic formulas were 1988.6 ±1100 kcal/day (p < 0.05). moreover, statistically significant differences have been observed regarding the mean difference between energy demand determined using indirect calorimetry and that determined mathematically, respectively between the enteral and parenteral administered ed. conclusions: continuous monitoring of the energy demand in critically ill patients with sepsis can bring important benefits in regard with the clinical prognosis of these patients through the individualization and adaption of intensive therapy for each patient. introduction: cachexia is defined as a complex metabolic syndrome associated with underlying illness, characterized by loss of muscle with or without loss of fat. in cancer cachexia, reduction in muscle size has been demonstrated to be an independent risk factor for mortality. loss of muscle in icu patients is rapid and extensive and is also associated with mortality risk, but methods to measure muscle mass in these patients are lacking. surrogate methods (dexa, ct, ultrasound, total body water) do not measure muscle mass directly methods: the d3-creatine (d3-cr) dilution method takes advantage of the fact that 98% of cr is found in muscle and that muscle mass can be assessed by cr pool size. cr is transported into muscle against a concentration gradient and irreversibly converted to creatinine (crn), which is excreted in urine. a single oral dose of d3-cr is transported to skeletal muscle, and measurement of d3-crn enrichment in a spot urine sample provides an accurate estimate of skeletal muscle mass. results: the method has been validated in preclinical and clinical studies; in a large longitudinal observation study in older men, d3-cr muscle mass was strongly associated with habitual walking speed, risk of falls, and incident mobility limitation; dexa failed to show these relationships. the d3-cr method is being used in a nicu study to measure changes in muscle mass in neonates (gates foundation grant). further, this method has been incorporated into a trial assessing the treatment effects of a ghrelin agonist in icu patients with enteral feeding intolerance (nct02784392). in this trial, the d3-cr dose is delivered intravenously and a spot urine sample is collected at baseline and postdose. conclusions: the d3-cr method provides a non-invasive, accurate way to assess therapeutic agents that may mitigate the loss of skeletal muscle mass; it is of particular utility in clinical settings where changes in muscle mass are consequential, such as muscle loss during an icu admission. introduction: vitamin c, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation, which affects most intensive care unit (icu) patients. while many observational studies have demonstrated that critical illness is associated with low levels of vitamin c, randomized controlled trials (rcts) of high-dose vitamin c, alone or in combination with other antioxidants, yielded contradicting results. the purpose of this systematic review and meta-analysis is to evaluate the clinical effects of vitamin c when administered to various populations of icu patients. methods: eligible trials: rcts comparing vitamin c, by enteral or parenteral routes, to placebo in icu patients. data collection and analysis: we searched medline, embase, and the cochrane central register of controlled trials. after assessing eligibility, data was abstracted in duplicate by two independent reviewers. overall mortality was the primary outcome; secondary outcomes were infections, icu length of stay (los), hospital los, and ventilator days. pre-specified subgroup analyses were conducted to identify more beneficial treatment effects. results: pooling 9 rcts (n=1322) reporting mortality, vitamin c was not associated with a lower risk of mortality (risk ratio [rr]: 0.84, 95 % confidence interval [ci]: 0.48-1.37, p=0.44, i2=59%). in a subgroup analysis, trials of lower quality (n= 5) were associated with a reduction in mortality (rr 0.50, 95% ci 0.32, 0.77, p= 0.002), whereas high quality trials (n= 4) were not. no statistical difference existed between subgroups (p= 0.22). in addition, no effect was found on infections, icu or hospital length of stay, and ventilator days. conclusions: current evidence does not support the hypothesis that vitamin c supplementation improves clinical outcomes of icu patients. introduction: the protein intake for patients who met adequacy for energy was assessed within our cardiothoracic intensive care. nutritional support should aim to provide at least 80% of calorie requirements to achieve nutritional adequacy with suggested protein requirements of 1.2-2 g/kg/day [1] . guidelines highlight the difficulty achieving the correct protein:energy ratio from nutritional support to meet this target especially in the obese population. methods: the audit was registered with clinical governance. data was collected prospectively from patients requiring tube feeding for three or more days from january 2016 -october 2017 (table 1 ). data included type and volume of feed and calories from other sources. patients who met adequacy for energy (fig. 1) introduction: patients admitted to the intensive care unit (icu) are usually at high risk of malnutrition [1, 2] . the purpose of our study was to compare the accuracy of nutric score, nrs 2002 and sga in predicting los-icu, los-hosp and in-hospital mortality. methods: a total of 348 consecutive patients admitted between march to june 2016 in a mixed (medical/surgical) icu were assessed on day of admission using the three screening tools to classify them into high-risk and low-risk of malnutrition. day 1 apache 2 scores and demographic data were recorded. los-icu, los-hosp inhospital mortality and secondary outcomes studied were need for supplemental nutritional support, need for ventilation and need for dialysis in high-risk and low-risk patients by each nutrition assessment tool. results: of the 348 patients studied, 221 (63.5%) were males and 127 (36.5%) were females. 67.87% males and 71.65% females were found to be at a high risk of malnutrition by at least one of the scores. the mean apache 2 score for patients at high risk (using any one screening tool) was 15.11 (sd 6.10) and 8.04 for the low risk group (sd 3.34; p <0.01). the nrs 2002 and sga demonstrated statistically significant correlation(p=0.001) for length of icu stay for both the high risk and low risk group whereas only the nrs 2002 correlated significantly for the length of hospital stay(p=0.002). mortality was significantly higher in high risk patients identified using all 3 scores. conclusions: there was a wide difference in the percent of patients identified as high-risk using each of the 3 scores. introduction: nitrogen balance (nb) may be an important tool in the nutritional management of critically ill patients. cancer patients present a special challenge regarding nutrition, due to its peculiar characteristics related to neoplasia and adjuvant treatments. objectives: to evaluate nb in patients with solid cancer in the postoperative period in the icu, analyzing the correlation between nb and the mortality outcome in the icu. methods: retrospective cohort study. we evaluated adult patients (>18 years) admitted to the icus of two different hospitals, with diagnosis of current cancer in postoperative period (elective or emergency surgeries). patients were excluded if the diagnosis of cancer was not confirmed. nb (measured through analysis of dietary protein intake subtracted from 24-hour urinary urea plus an estimate of nonurinary losses) was calculated on the 1st, 3rd and 5th icu day. nb was measured only while the patient was in the icu. results: during the study period, 125 patients were included (mean age 58.1, mean apache 17.4, 65.6% male). admission apache ii and abdominal-site surgery were predictors of mortality. the nb of all patients was negative on the 1st icu day. in the patients who survived, nb of the 3rd and 5th day remained stable (negative), whereas in patients who died nb was more positive (fig. 1) . there was no difference in the amount of protein ingested on the 1st day between survivors and deceased patients. conclusions: among adult patients with solid cancer in the postoperative period in the icu, nb was persistently negative in the survivors between 1st and 5th icu day, but among the patients who died nb tended to be more positive on the 3rd day. nb monitoring could allow a more adequate individualization of nutritional management in this group of patients. fig. 1 (abstract p335) . nitrogen balance in 1st, 3rd and 5th icu day introduction: nutritional therapy plays an important role in the treatment of critically ill patients. caloric and protein goals are defined, and artificial nutrition tailored to the targets which are related to outcome [1] . questions rise about the mean caloric and protein needs of patients, once discharged from icu, and the evolution of body weight, and nutritional adequacy. the aim is to know the ratios between caloric needs and intake of patients with a minimum stay at icu of 5 days. methods: after evaluation of 146 critically ill patients, 12 patients were prospectively followed during their entire hospitalization. data concerning nutritional needs, prescriptions and delivery were collected from the electronic medical file. nutritional calculations of oral intake were done by nubel. ratios were made during the entire stay and body weight was followed up. results: in 5 female and 7 male patients, median age 63.5 years (range 26-84 year), estimated body weight of 74.8 ± 21 kg and actual body weight of 73.3± 17 kg, a mean caloric need of 1795 ± 479 kcal/ day and an effective delivery of 1348 ± 508 kcal/day was observed. body weight increased in two patients and decreased in 10 (83%). in ten out of twelve patients, underfeeding was present. one patient with a caloric need of 1125 kcal/day received a mean caloric load of 230 kcal/day (20.4%). conclusions: the overall observed evolution in body weight was negative in most of the patients. nutritional adequacy was low after icu discharge and never reached target. introduction: severe burn injury can create a rapid-onset, sustained proinflammatory condition that can severely impair all major organs. this massive systemic response has been documented clinically by associated biomarker measurements including dramatic elevations in cytokines such as il-6. the severity of multi-organ injury and subsequent development of other systemic complications in burn patients have been well-correlated with il-6 levels, including the increased risk of sepsis/multi-organ failure and associated morbidity and mortality. considering that estrogen is a powerful and easy to use anti-inflammatory agent, an experimental burn model was created to test the potential value of parenteral 17β-estradiol (e2) as a feasible and inexpensive early intervention to mitigate the the profound pro-inflammatory response associated with severe thermal injury. methods: male rats (n = 28) were assigned randomly into three groups: 1) controls/no burn (n = 4); 2) burn/placebo (n = 12); and 3) burn/e2 (n = 12). burned rats received a 40% 3°tbsa dorsal burn, fluid resuscitation and one dose of e2 or placebo (0.5 mg/kg intra-peritoneal) 15 minutes post-burn. eight animals from each of the two burn groups (burn/placebo and burn/e2) were sacrificed at 30 minutes (sham group at 7 days only), with four each of the two burn groups sacrificed at 45 days. tissue samples from 9 major organs and serum were obtained and analyzed by elisa for il-6 at each of these intervals. results: in the burned rats, 17β-estradiol decreased the organ levels of il-6 significantly as measured at both early (30 min.) and late (45 day) phases post-burn (figs. 1 & 2 . also, sham animal levels were comparable to the estradiol group, conclusions: experimentally, a single, early post-burn dose of estrogen significantly mitigates the associated detrimental inflammatory response in all major organs up to 45 days. in turn, this may present a promising potential therapy to decrease the widespread multipleorgan dysfunction seen in severe burn injury patients. early, single-dose estrogen increases levels of brain-derived neurotrophic factor (bdnf), a neurotrophin for neuronal survival and neurogenesis following indirect brain inflammation caused by severe torso burns introduction: prior studies have found that patients with severe burns may suffer significant neurocognitive changes. while frequently attributed to psycho-social issues, we have found a substantial, rapid and sustained (30 min -45 day) increase in rat brain inflammatory markers (for example, il-6) following remote torso burns that is blunted by a single post-burn dose of estrogen. brain-derived neurotrophic factor (bdnf), one of the most active neurotrophins, protects existing neurons and encourages the growth and differentiation of new neurons and synapses. as estrogens not only blunt inflammation but also exert an influence on cns growth factors, we hypothesized that 17β-estradiol (e2) might affect levels of bdnf in the post-burn rat brain. methods: male rats (n = 44) were assigned randomly into three groups: controls/no burn (n = 4); burn/placebo (n = 20); and burn/e2 (n = 20). burned rats received a 40% 3°tbsa dorsal burn, fluid resuscitation and one dose of e2 or placebo (0.5 mg/ kg intraperitoneally) 15 minutes post-burn. eight animals from each of the two burn groups (burn/placebo and burn/e2) were sacrificed at 24 hours and at 7 days, respectively (sham group at 7 days only), with four each of the two burn groups sacrificed at 45 days. brain tissue samples were analyzed by elisa for bdnf. results: mean levels of bdnf were significantly elevated within 24 hours and continued to increase up to 45 days post-injury in burned animals receiving the 17β-estradiol (>300 pcg/mg) as compared with the placebo-treated burned animals (<160 pg/mg) and controls (<120. pcg/mg). see fig. 1 . conclusions: early, single-dose estrogen administration following remote severe burn injury significantly elevated levels of bdnf in brain tissue. this finding may represent an extremely novel and important pathway to enhance both neuroprotection and neuroregeneration in burn patients. the value of cortisol in patients with the infection and multiple organ dysfunction. s tachyla, a marochkov mogilev regional hospital, mogilev, belarus critical care 2018, 22(suppl 1):p339 introduction: hormones changes in patients with infection and multiple organ dysfunction is a topic that hasn't been adequately studied. goal of study: to establish the value of cortisol in patients with infection and multiple organ dysfunction. methods: after approval the ethics committee of the mogilev regional hospital a prospective observational study was performed. the study included 181 patients aged 18 to 87 years. all patients were hospitalized in the intensive care unit with the infection and multiple organ dysfunction. patients with endocrine diseases and receiving glucocorticoids were excluded. cortisol levels were measured on admission and during the course of treatment by radioimmunoassay. in group l (n = 16) patients had a low levels of cortisol, in the m group (n = 96) -normal cortisol, in group h (n = 69) -high cortisol. results: cortisol level was in l-group 91.9 (8.28, 131.7) nmol/l, in mgroup 410.9 (292.8; 504.7) nmol/l, in h-group 934.2 (763, 6; 1495.5) nmol/l. it is found that the mortality was higher in the groups l -43.8% (p = 0.33) and h -47.8% (p = 0.03), than in the m-group -31.3%. the mgroup odds ratio equals 2.02 at 95% confidence interval 1.06 -3.82 when compared with the h-group. in the m-group in survivors patients (n = 36) showed a decrease cortisol with 1281 (1033.8, 1702.5) nmol/l to 912.3 (801.5, 1068.8) nmol/l (p = 0.01). while the no survivors patients (n = 33) showed increase cortisol with 732 (657.1, 749.2) nmol/l to 1491.2 (1000; 1600) nmol/l (p = 0.008). thus itself cortisol level is not a marker of mortality. receiver operating curve analysis for cortisol was performed: area under the curve equals 0.56 at 95% confidence interval of 0.47 -0.65 (p = 0.19), sensitivity 48.4%, specificity 70.6%. conclusions: in patients with infection and multiple organ dysfunction may be observed disorders in cortisol levels. these disorders require correction to prevent the increased mortality. introduction: the hypothalamic-pituitary-adrenal (hpa) axis is a key regulator of critical illness. cortisol and adreno-corticotrophic hormone (acth) are pulsatile, which emerges from the feed forwardfeedback of the two hormones [1] . different genes are activated by continuous or pulsatile activation of the glucocorticoid receptor, even when the total amount is the same [2] . we aimed to characterise the acth and cortisol profiles of patients who were critically ill after cardiac surgery and assess the impact of inflammatory mediators on serum cortisol concentrations. methods: 20 patients with >2 organ system failure, >2 days after cardiac surgery were recruited. total cortisol was assayed every 10 min, acth every hour and il1, il2, il4, il6, il8, tnf-α every 4 hours. cortisol binding globulin (cbg) was assayed at 0 and 24hrs. the relationship between cortisol and the inflammatory mediators was quantified in individual patients using a mixed regression model. results: all profiles showed pulsatility of both cortisol and acth and there was concordance between the two hormones (see fig. 1 ). one patient died after 23 hours (see fig. 2 ). this patient lost pulsatility and concordance of cortisol and acth. mean cbg was 26.89μ g/ml at the start of sampling and 28.13μ g/ml at the end. there was an association between il6 (p=0.0002), il10 (p<0.0001), il4 (p=0.029) and serum cortisol levels. there was no association between the other mediators and cortisol. conclusions: cortisol and acth are both pulsatile in critical illness. because pulsatility emerges from the interaction between the two hormones[2]the premise of a 'disconnect' between the pituitary and adrenal gland is refuted. il6, il10 and il4 may have roles in the control of cortisol during critical illness. introduction: elevation in plasma cortisol is a vital response to sepsis and partially brought about by reduced cortisol breakdown in which bile acids (bas) may play a role. vice versa, cortisol can also upregulate bas. we hypothesized a central role for the hepatic glucocorticoid receptor (hgr) in cortisol and ba homeostasis and in survival from sepsis. methods: in a mouse model of sepsis, we documented hgr expression and investigated the impact of hepatocyte-specific shrnaknockdown of gr on markers of corticosterone (cort), ba and glucose homeostasis, inflammation and survival. we also compared hgr expression in human septic icu and elective surgery patients. results: in mice, sepsis reduced hgr expression with 21% (p=0.04), elevated plasma cort, bas and glucose and suppressed a-ringreductases. also in human patients, sepsis reduced hgr expression (p<0.01), further suppressed by treatment with steroids (p=0.04). in septic mice, further and sustained hgr-inhibition increased mortality from 12% to 60% (p<0.01). at 30h, hgr-inhibition prevented the rise in total plasma cort, but did not affect a-ring-reductases expression. however, it further reduced cort binding proteins, resulting in elevated free cort equal to septic mice without modified hgr. after 3 days of hgr-inhibition in sepsis, total and free cort were comparable to septic mice without modified hgr, now explained by further reduced a-ring-reductase expression, possibly driven by higher hepatic ba content. hgr-inhibition blunted the hyperglycemic sepsis response without causing hypoglycemia, markedly increased hepatic and circulating inflammation markers and caused liver destruction (p<0.05), the severity of which explained increased mortality. conclusions: in conclusion, sepsis partially suppressed hgr expression, which appears to upregulate free cort availability via lowered cort binding proteins and a-ring-reductases. however, further sustained hgr suppression evoked lethal excessive liver and systemic inflammation, independent of cort availability. introduction: cortisol levels have been found to be increased in sepsis patients, and high cortisol levels have been correlated with increased mortality. the purpose of this project is to assess the association of plasma cortisol levels with severity of coagulopathy in a population of patients with sepsis and clinically confirmed dic. methods: citrated, de-identified plasma samples were collected from 52 adults with sepsis and suspected dic at the time of icu admission. platelet count was determined as part of standard clinical practice. pt/inr and fibrinogen were measured using standard techniques on the acl-elite coagulation analyzer. cortisol, d-dimer, pai-1, cd40l, nlrp3, and microparticles were measured using commercially available elisa kits and were performed. dic score was calculated using isth scoring algorithm. results: cortisol showed significant variation based on dic status (kruskal-wallis anova, p < 0.0001). patients with non-overt dic and overt dic exhibited significantly elevated cortisol levels compared to healthy controls (p < 0.0001 for both groups). cortisol levels showed dic based variations. patients with sepsis and overt dic had elevated cortisol compared to patients with sepsis and no dic (p = 0.0069) (fig. 1) . correlations were evaluated between cortisol and hemostatic markers platelets, fibrinogen, inr, d-dimer, and pai-1 as well as with the inflammatory marker, nlrp3 and the platelet markers cd40l and microparticles. cortisol conclusions: cortisol showed a significant association with hemostatic status in a population of patients with sepsis and welldefined coagulopathy. cortisol levels were significantly elevated in patients with overt or non-overt dic compared to healthy individuals and in patients with overt dic compared to those with sepsis without dic. introduction: in most cases presenting with hypoglycemia in emergency departments (eds), the etiology of the hypoglycemia is almost identified. however, about 10% of cases, the etiology of hypoglycemia cannot be determined. methods: this is a 2-year prospective observational study. a total of 232 patients were transported to our ed with hypoglycemia. after the investigation, a rapid acth loading test (synthetic 1-24 acth 250 μg iv.) was performed on 21 patients with unexplained hypoglycemia; i.e., 250 μg acth was administered intravenously and blood specimens were collected before loading, at 30 min and 60 min after acth administration. we adopted a peak serum cortisol level < 18 μg/dl or a delta cortisol of < 9 μ g/dl for the diagnosis of adrenal insufficiency. results: among the patients, 163 of 232 (70.3%) were using antidiabetic drugs, 15 (6.5%) were using hypoglycemia-relevant drugs, 12 (5.2%) suffered from digestive absorption failure including malnutrition, 10 (4.3%) had been consuming alcohol, 9 (3.9%) suffered from malignancy, and 2 (0.9%) suffered from insulin autoimmune syndrome. initially, an etiology was unknown in 21 of 232 (9.1%) patients. rapid acth test revealed the adrenal insufficiency in 19 (8.2%) among them. administration of hydrocortisone in adrenal insufficiency patients promptly improved hypoglycemia. in those patients, serum sodium level was lower (na; 134 vs. 139 meq/l, p<0.001) and serum potassium level was higher (k; 4.7 vs. 3.9 meq/l, p<0.001) than in the other hypoglycemic patients, respectively. there was no significant difference in baseline plasma glucose level on ed between the groups of patients (28 vs. 26 mg/dl, p=0.34). conclusions: the probability of adrenal insufficiency was much greater than that of the better-known insulinoma as a cause of hypoglycemia. when protracted hypoglycemia of unknown etiology is recognized, we recommend that the patient is checked for adrenal function using the rapid acth loading test. introduction: sepsis caused have showed serious alternations of thyroid hormones releasing, causing a nonthyroidal illness syndrome. the aim of the study was to measure thyroid hormone levels in septic patients and analyse its relation with clinical state and outcome. methods: prospective study in a cohort of 150 consecutive septic patients. we studied thyrotropin (tsh), free triiodothyronine fraction (ft3) and free thyroxin fraction (ft4) serum levels, apache ii and sofa score. statistical analysis was performed using spss 15.0. results: we analysed 150 episodes of sepsis (16%) and septic shock (ssh) (84%), the median age of the patients was 64 (inter-quartile range, 48.7-71) years; the main sources of infection were: respiratory tract (39%) and intra-abdomen (30%); 70.7% had medical diseases. apache ii score was 25 [21-30], sofa score was 10 [7.75-11] and 28day mortality was 22.7%. our data shown 18.3% with low levels of tsh (<0.2uui/ml), 20.3% had low levels of ft4 (<0.75 ng/dl) and 71.4% low levels of ft3 (<2 pg/ml). the tsh (0.89 vs. 1.46 uui/ml) and ft3 (1.3 vs 1.8 pg/ml) concentration of ssh group were significantly lower than those of sepsis group, whereas ft4 (1.10 vs 1.18 ng/dl) it was not statistically significantly. correlation of ft3 to apa-che ii (r = −0.342, p = 0.035) and sofa score (r = −0.409, p = 0.017). the profile of death patients were men (64.7%, n =22), with significantly older (63 vs. 57 years; p=0,049), as well as clinical severity scores, apache ii (29.8 vs. 24.1; p<0.001) and sofa (12.1 vs 8.9; p<0,001). non-survivors had significantly lower tsh 0.85 vs. 1.4 uui/ ml; p=0.042, and ft3 1.2 vs. 1.39 pg/ml, p=0.031, however ft4 did not show statistical significance 0.42 vs. 0.58ng/dl, p=ns. conclusions: conclusions: most of our septic patients present an altered thyroid function. our data suggest that tsh and specially ft3 may be used as a marker of disease severity and a mortality predictor. observational study to evaluate short and long-term bone metabolism alteration in critical patients. introduction: reduction of bone mineral density and/or muscle mass can be short and long-term complications in critical patients admitted in intensive care unit (icu). the study aims to evaluate, during a 12-month period, the following parameters: 1) the alterations of bone metabolism and quantitative and qualitative parameters of bone tissue, 2) the proportion of subjects with bone fragility, and 3) the identification of specific risk factors. methods: an observational-longitudinal monocentric study is being conducted in adult patients hospitalized in icu. the evaluations performed at baseline, 6 and 12 month visits include analysis of biochemical and instrumental exams. results: a specific clinical-care pathway was created between bone metabolic diseases unit and icu, in order to perform specific anamnestic collection, biochemical analysis of bone metabolism, and instrumental exams. 31 patients were enrolled and evaluated at the baseline visit. biochemical exams, performed within 72 hours of hospitalization, showed that 64% (n:20) of subjects had a deficit of 25ohvitamind <20 ng/dl, associated with normal corrected serum calcium levels and of these 42% (n:13) had high pth levels. bone alkaline phosphatase was increased in 26% (n:8) of patients. conclusions: critical patients are "fragile" subjects, which should be monitored with a short and long-term follow-up. the creation of a clinical pathway that includes specialists of bone metabolism may be a virtuous way to identify patients who report bone mass loss and increased fracture risk. this study will allow to implement the knowledge regarding specific risk factors of bone fragility and the most appropriate therapeutic choices as prevention and treatment. a retrospective analysis of predictors for length of intensive care stay for patients admitted with diabetic ketoacidosis a fung, tl samuels, ae myers, pg morgan east surrey hospital, redhill, uk critical care 2018, 22(suppl 1):p346 introduction: diabetic ketoacidosis (dka) is one of the most common metabolic causes of admission to the intensive care unit (icu). the incidence of dka is quoted as between 4.6-8 episodes per 1000 patients with diabetes mellitus (dm) [1] . we aim to establish the factors that affect length of stay (los) on icu. methods: we undertook an analysis of patients admitted to icu over the last 7 years with a primary diagnosis of dka. we assessed whether there was an association between the following factors and an increased length of icu stay: age, gender, body mass index (bmi), systolic blood pressure, heart rate, sodium, potassium, haemoglobin and ph. these factors were assessed using multiple linear backward stepwise regression. results: overall, 94 admissions were identified over the time period from the ward watcher database. the median los was 2.4 days (iqr 1.3 -4.7). our analysis demonstrated that length of icu stay (alpha level <0.05) was significantly associated with bmi, low systolic blood pressure, and the presence of hyponatraemia or hypernatraemia. conclusions: we found the variables that affect the los for patients presenting to our unit with dka are bmi, elow systolic bp, low sodium and high sodium. we intend to extend this work to include survival analysis with the same subgroup of patients. maximal glycemic gap is the best glycemic variability index correlated to icu mortality in medical critically ill patients t issarawattna, r bhurayanontachai prince of songkla university, songkla, thailand critical care 2018, 22(suppl 1):p347 introduction: several evidences shown a correlation of glycemic variability (gv) and icu mortality. however, there have been no report of the correlation between various parameters of gv and mortality in medical icu patients. the aim was to determine the correlation between various parameters of gv and medical icu mortality, as well as, to identify the best gv index to predict icu mortality. methods: a retrospective chart review was then conducted in medical icu at songklanagarind hospital. the patient characteristics, causes of admission, apache ii, blood glucose within the first 24 hours of icu admission and icu mortality were recorded. glycemic variability parameters including maximal glycemic gap, standard deviation, coefficient of variation and j-index of blood glucose were calculated. the correlation of those gv index to icu mortality was determined. the roc and auroc of each gv index were then compare to identify the best gv index to predict icu mortality. results: of 538 patients, 442 patients (82.2%) were survived ( table 1 ). all gv indexes were significantly higher in non-survival group (p < 0.05) ( table 2 ). maximal glycemic gap was independently correlated to icu mortality and give a highest auroc compared to others gv. (maximal glycemic gap auroc 0.69 (95%ci 0.64-0.75 vs. coefficient of variation auroc 0.68 (95%ci 0.62-0.74) vs standard deviation auroc 0.67 (95%ci 0.61-0.73) vs j-index auroc 0.63 (95%ci 0.57-0.7), (p< 0.001) (fig. 1) . conclusions: maximal glycemic gap independently correlated to icu mortality and was the best gv to predict icu mortality in medical critically ill patients. reliability of capillary blood glucose measurement for diabetic patients in emergency department h ben turkia, s souissi, a souayeh, i chermiti, f riahi, r jebri, b chatbri, m chkir regional hospital of ben arous, ben arous, tunisia critical care 2018, 22(suppl 1):p348 introduction: acute glycemic disorders should be early diagnosed and treated in emergency department (ed), especially hypoglycemia. can capillary blood glucose (cg) replace plasmatic glucose (pg). the objective of this study was to compare capillary blood glucose with venous blood glucose methods: patients with type 2 diabetes were included. we realize a capillary blood glucose with a glucose meter (acu-check active-roche) and a concomitant determination of venous blood glucose with laboratory machine (synchrony cx3 delta system beckman coulter). a correlation study (pearson correlation) between the two measurements was evaluated and linear fitting equation was established. the concordance was checked with bland and altman method. results: during the 4 months of the study, 258 patients were included. the average age was 55+/-19 years old, with a sex ratio =1. majority of patients (70%,n=182) had type 2 diabetes and 58% was treated with insulin. we found an excellent correlation between the two techniques with a pearson correlation coefficient r= 0.96.topredict the pg from cg, we can use this equation: pg(g/l)=0.9979 cg(g/l)+ 0.08128 (r2=0.9207 ; p=0.0001). we noticed a good concordance between the two techniques especially in case of hypoglycemia and moderate hyperglycemia (fig. 1) . however, 11 releases were noted with a pg higher than 4g/l. conclusions: in ed, the measurement of capillary glucose can exempt from venous blood glucose especially in case of hypoglycemia and moderate hyperglycemia. is frequently found in critically ill patients in icu, especially patients who are treated for a long time. this study aims to analyse the comparison between length of stay and dvt incidents in critically ill patients. methods: a cross-sectional study was employed. we include all patients who were 18 years or older and were treated in icu of dr soetomo public hospital for at least 7 days. data were collected from june 2016 until june 2017. the patients were examined with sonosite usg to look for any thrombosis in iliac, femoral, popliteal, and tibial veins and well's criteria were also taken. results: thirty patients were included in this study. this study shows that length of stay is not the only risk factor for dvt in patients treated in icu. in our data, we found out that the length of treatment did not significantly cause dvt. other risk factors such as age and comorbidities in patients who are risk factors may support the incidence of dvt events. the diagnosis of dvt is enforced using an ultrasound performed by an expert in the use of ultrasound to locate thrombus in a vein. conclusions: length of treatment is not a significant risk factor for dvt. several other factors still need to be investigated in order for dvt events to be detected early and prevented. [2] was used to retrospectively study trends and outcomes of cancer patients admitted to the icu between 2002 and 2011. logistic regression analysis was performed to assess predictors of 28-day and 1-year mortality. results: out of 41,468 icu admissions, 1,100 hemato-oncological, 3,953 oncological and 49 patients with both a hematologic and solid malignancy were analyzed. hematologic patients had higher critical illness scores, while oncological patients had similar apache-iii and sofa-scores. in the univariate analysis, cancer was strongly associated with mortality (or 2.5, table 1 ). over the 10-year study period, 28-day mortality of cancer patients decreased by 30% (fig. 1) . this trend persisted after adjustment for covariates, with cancer patients having significantly higher mortality (or=2.49, 95%ci: 2.3, 2.7). between 2002 and 2011, the adjusted 28-day mortality decreased by 8% every year. over the decade, 1-year mortality decreased by 27%. having cancer was the strongest individual predictor of 1-year mortality in the multivariate model (or=4.40, 95%ci: 4.1, 4.8) (fig. 2) . conclusions: between 2002 and 2011, the number of cancer patients admitted to the icu increased steadily and significantly, while longitudinal clinical severity scores remained overall unchanged. although hematological and oncological patients had higher mortality rates than patients without cancer, both 28-day and 1-year mortality decreased significantly over the study period. introduction: sepsis was redefined in 2016 with the introduction of an increase in sequential organ failure assessment δsofa) score of >= 2 and the quicksofa (qsofa) as screening tools for sepsisrelated mortality. however, the implementation of these criteria into clinical practice has been controversial and the applicability for hematological patients is unclear. methods: we therefore studied the diagnostic accuracy of different sepsis criteria for sepsis and mortality according to definition criteria in a retrospective analysis of hematological patients in an academic tertiary care hospital. patient characteristics and variables were collected in icuand non-icu patients to determine the systemic inflammatory response syndrome (sirs), δsofa and qsofa. by applying the definition of sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection" [1] as reference, the scores were evaluated. in patients with sepsis who died, 5/22 were sirs-negative, 4/24 δsofa-negative and 14/20 qsofa-negative ( fig. 1 and table 2 ). conclusions: in conclusion, these findings suggest that criteria proposed in the sepsis-3 definition might have limitations as screening fig. 2 (abstract p351) . results of the logistic regression analysis for (a) 28-day and (b) 1-year mortality. all covariates were statistically significant except for white race in the 1-year mortality model. ***p-value<10-16, **p-value<0.001, *p-value<0.01 fig. 1 (abstract p351) . longitudinal change in 28-day mortality for cancer patients (yes) compared with controls (no) over the 10-year study period. mortality in the cancer group decreased from 36% to 25% (-30%), while mortality in the control group decreased from 14 to 12% (-21%). enoxaparin pharmacokinetics in patients with augmented renal clearance, preliminary results of a single center study introduction: augmented renal clearance (arc) has being described in some groups of critically ill patients. the aim was to investigate the impact of arc on the pharmacokinetics of enoxaparin. methods: this is a prospective study in a surgical and medical intensive care unit (icu) carried out from august to november 2017. patients <65 years old, under prophylactic treatment with enoxaparin and normal plasma creatinine, were included. anti-xa activity was measured at second day under treatment. creatinine clearance was calculated from urine sample collected during 24-hours. arc was defined by a creatinine clearance >=130 ml/min/1.73 m2. results: thirteen patients aged 43 years old (±16.4) were included. six patients developed arc and 5 of them were in therapeutic range. seven patients did not develop arc and 6 of them were in therapeutic range. there was no differences between the two groups in achieving therapeutic range (fisher test, p=0.5). we did not observe thromboembolic events. conclusions: we found no relationship between arc and therapeutic failure in patients under prophylactic treatment with enoxaparin. introduction: this study reviewed argatroban use in patients in a tertiary hospital critical care unit. argatroban is a direct thrombin inhibitor approved for use in proven or suspected heparin-induced thrombocytopenia (hit) in patients with renal dysfunction. methods: this was a retrospective cohort study in a medical and surgical icu in a tertiary teaching hospital. data was collected for adult patients treated with argatroban for proven or suspected hit april-august 2016, excluding patients requiring ecmo. we scored patients using the 4t score and compared this to an elisa immunoassay optical density score which quantifies the pf4/h antibody level. also noted was use of continuous haemodialysis and organ failure using the sequential organ failure assessment (sofa), scoring >=3 defines failure. results: 16 patients were treated with argatroban for proven or suspected hit. 15/16 patients had a positive elisa. there was no relationship between 4t score and elisa optical density (fig. 1) . infusions were commenced at either the manufacturer recommended dose of 2 μg/kg/min or a reduced dose of 0.5 μg/kg/min. patients receiving the reduced dose had a median of 2 organs failing compared to 1 in the standard regimen. the time taken to the first aptr in range was longer with the reduced dose regimen, however, the time to a stable aptr was less (table 1 ). in 2 patients the dose of argatroban never stabilised. 1 died and 1 was very sensitive to argatroban and required cessation of the infusion for interventions. in the reduced regimen group, there were 2 episodes of bleeding, 1 minor pr bleed in a patient with 3 organs failure and 1 upper gi bleed. conclusions: in this population of icu patients the 4t score did not correlate with the elisa optical density score, as found previously. patients with multi-organ failure mostly received the reduced starting dose. however, the bleeding events were still confined to this group. this correlates with previous studies that organ dysfunction necessitates a dose reduction for argatroban. results: the mean age in our study group was 54±22 years. the effects of tpe on standard coagulation were increased aptt (24±2 to 36 ± 6 s, p=0.005) and decreased fibrinogen levels (286±76 to 242 ±48 mg/dl, p=0.008). a non-significant decrease in platelet count was observed (160333±23091 to 151133±22244/mm 3 , p=0.662). on rotem parameters tpe was associated with increased ct in extem (57±8 to 73±12 s, p=0.030) and intem (156±15 to 194 ±52 s, p=0.003) and increased maxvt on extem (90± 27 to 128 ± 37 s, p=0.031) and intem (177±17 to 225±71 s, p=0.003). all other rotem parameters changed non-significantly. the decrease observed in fibrinogen levels was not associated with a decrease in fibtem mcf (15±2 to 14±2 mm, p=0.414). conclusions: our results demonstrate that tpe is associated with minimum changes in clot kinetics initiation that do not result in either pro-or anti-coagulant changes. therefore, tpe with fresh frozen plasma can be safely used in normal subjects. introduction: acutely ill patients are prone to critical illness anaemia, a multifactorial condition with potential contribution of iatrogenic anaemia defined as lowered hb due to large/frequent venepunctions. decline in hb is most pronounced in the first 3 days of icu stay. it correlates with the need for rbc transfusion, but the impact on patient outcome is uncertain. the aim of this study was to determine impact of phlebotomy on change in hb (δhb), and correlation of δhb with need for transfusion, presence of central venous catheter (cvc) and patient outcome. conclusions: critical illness anaemia is an unexplained phenomenon. impact of phlebotomy is hard to unequivocally determine since there are many confounders. the change in hb levels during icu stay correlates with the need for transfusion that could cause immunomodulation and potentially adverse outcome. every effort should be made to maintain adequate hb levels and lower the risk of iatrogenic anemia. introduction: anemia is prevalent in critically ill traumatic brain injury (tbi) patients and red blood cell (rbc) transfusions are often required. over the years, restrictive transfusion strategies have been advocated in the general critically ill population. however, considerable uncertainty exists regarding optimal transfusion thresholds in critically ill tbi patients due to the susceptibility of the injured brain to hypoxemic damages. methods: we conducted an electronic self-administered survey targeting all intensivists and neurosurgeons from canada, australia and the united kingdom working caring for tbi patients. the questionnaire was developed using a structured process of domains/items generation and reduction with a panel of experts. it was validated for clinical sensibility, reliability and content validity. results: the response rate was 28.6% (217/760). when presented with a scenario of a young patient with severe tbi, a wide range of transfusion practices was noted among respondents, with 47% favoring rbc transfusion at a hemoglobin level of 7g/dl or less in the acute phase of care, while 73% would use this trigger in the plateau phase. multiple trauma, neuromonitoring data, hemorrhagic shock and planned surgeries were the most important factors thought to influence the need for transfusion. the level of evidence was the main reason mentioned to explain the uncertainty regarding rbc transfusion strategies. conclusions: in critically ill tbi patients, transfusion practices and hemoglobin thresholds for transfusion are said to be influenced by patients' characteristics and the use of neuromonitoring in critical care physicians and neurosurgeons from canada, australia and the uk. equipoise regarding optimal transfusion strategy is manifest, mainly attributed to lack of clear evidences and clinical guidelines (1-year) . no significant associations were found between ffp:rbc ratio and mortality rates. patients with higher apache ii score received more platelet transfusions and mortality rates were higher in those who received platelets:rbc ratio >1. on multivariate analysis, higher apa-che ii score was an independent predictor of increased mortality. conclusions: the compliance with the recommended 1:1:1 ratio of blood products was poor. there was no association between transfusion ratios and mortality after adjusting for apache ii score. introduction: the lack of evidence-based medicine supporting the transfusion decision is illustrated by the wide range of blood product use during first-time coronary artery bypass grafting (cabg). use of red blood cells (rbc) ranges from 3 to 83 percent, while the use of platelets range from 0 to 40 [1] . approximately 20 percent of cabg patients suffer abnormal bleeding, with platelet dysfunction thought to be the most common culprit [2] . methods: the objective of this study was to evaluate the use of allogeneic blood and blood products among patients undergoing first-time cabg over the past 15years. the first 50 patients who underwent cabg (on-pump and off-pump) from 1 st of march each year were included for analysis. the percentage of patients receiving rbc, fresh frozen plasma (ffp), platelet and cryoprecipitate during the first 48 hours intra-and postoperatively were analysed. linear regression analysis was performed in each group. results: our analysis shows that the use of rbc decreased over the last 15 years, in contrast to the use of the other 3 investigated products. (see fig. 1 ) the increase of platelets was the most pronounced with a direction coefficient of 0.022 and had the least variability (r 2 =0.59). (see fig. 2 ) the decrease in rbc was less obvious than the rise in platelet use (direction coefficient of 0.015) and had a higher variability (r 2 =0.32). the consumption of ffp and cryoprecipitate stayed constant (direction coefficient of 0.004 and 0.001 respectively). the higher incidence of semi-urgent cabg in recent years, which involves continuation of anti-platelet therapy until the day before surgery, can be an explanation for our observed increased use of platelets. the observed decrease in rbc transfusion over the past 15 years might be due to rising awareness of complications associated with red cell transfusion. introduction: red blood cells (rbc) transfusion is frequently required in cardiac surgery and is associated with increased morbidity and mortality rates. the aim of this study is to identify predictors of rbc transfusion for patients undergoing cardiac surgery, emphasizing the use of bioelectrical impedance analysis (bia). methods: this was a retrospective study of patients who underwent elective cardiac surgery between years 2013 and 2014 in a tertiary reference center. patients' demographic and clinical variables, preoperative bia measurements and postoperative data were analyzed. the univariate and multivariate logistic regression analyses were used to identify the predictors of postoperative rbc transfusion. all of the calculations were performed with ibm spss v. 24. introduction: red blood cells (rbc) transfusion is a common intervention in cardiac surgery and is associated with higher mortality rates and predisposes serious adverse events. the aim of this study was to determine whether red blood cells (rbc) transfusion is linked to long-term results after cardiac surgery. methods: this observational retrospective study included all of the patients who underwent any of the sts defined elective cardiac surgery types from 2013 to 2014. we evaluated 3-5 year all-cause mortality rates and secondary postoperative outcomes defined by the sts risk prediction model. patients were categorized according to whether they received rbc transfusions postoperatively; long-term results were compared using cox-regression analysis and kaplan-meier method. introduction: transfusion of packed red cells (prcs) is an important treatment option for patients requiring intensive care but, like all treatments, it is not without risk. these patients, although may be more sensitive to anaemia, are also at increased risk of transfusionrelated complications. we conducted an audit of blood prescribing and administering practices in our intensive care unit. methods: audit proformas were placed in blood prescribing forms for a 1-month period. all transfusions of prcs were logged over this time, and transfusion triggers, post-transfusion haemoglobin (hb) and whether hb was checked between units was recorded, in addition to other supplementary information. results: over a 1-month period, 25 transfusion events were recorded, with an average age of the transfused patients of 60 years old (range 35 -87 years). 76% of transfusion events were for low hb, 8% for bleeding and in 16% of cases the indication was not documented. for patients transfused for a low hb, the mean transfusion trigger was 75 g/l (range: 66 g/l -86 g/l). only 12% had a transfusion trigger of 70g/l or less, and a further 12% who were transfused for a low hb had a hb of 80g/l or more. 36% of transfusion events involved transfusing 2 or more units and, in only 22% of these cases the hb was checked between units. excluding the two bleeding patients, the mean increase in hb following a single unit transfusion was 11.4 g/l (range 2 g/l -18 g/l), whilst in patients transfused two units, the average increase in hb was 10 g/l per unit transfused (range 7 g/l -14.5 g/l), suggesting single unit transfusions may have greater hb yields. conclusions: our audit demonstrated variability in transfusion triggers and progress needed with administering practices when transfusing multiple units of blood in the non-bleeding patient. we have since implemented measures to meet guidelines in both prescribing prcs with restrictive triggers and in the administration and assessment of hb between units, and will be re-auditing. introduction: there is a perceived increased risk of bleeding in cirrhosis patients undergoing invasive procedures. this lead to a high rate of empirical prophylactic transfusion, which has been associated to increased complications and cost. the best strategy to guide transfusion in these patients remains unclear. our aim was to compare three strategies to guide blood component transfusion prior to central venous catheterization (cvc) in critically ill cirrhosis patients. methods: single center, randomized, double-blinded, controlled clinical trial conducted in brazil [1] . all cirrhosis patients admitted to the icu with indication for a cvc were eligible. participants were randomized 1:1:1 to three transfusion strategies based on: (1) standard coagulation tests (sct), (2) rotational thromboelastometry (rotem) and (3) restrictive. the primary outcome was proportion of transfusion of any blood component prior to cvc. secondary outcomes were incidence of major and minor bleeding, icu length of stay (los), and 28-day mortality. analysis was intention-to-treat. results: 57 participants (19 in each group) were enrolled between september 2014 and december 2016. most were male (64.9%) and listed for liver transplantation. the study ended after reaching efficacy in first interim analysis. there was no significant difference in baseline characteristics among groups. regarding primary endpoint, there was 14 (73.7%), 13 (68.4%), and 3 (15.8%) events in sct, rotem and restrictive groups, respectively (p <0.001). there was no difference between sct and rotem groups (p >0.99). overall 28-day mortality was 33.3% and was similar between groups. icu los did not differ between groups. there was no major bleeding. overall minor bleeding occurred in 10.53% with no difference between groups. conclusions: a restrictive strategy is safe and effective in reducing the need of blood component transfusion prior to cvc in critically ill cirrhosis patients. a rotem-based strategy was no different from transfusion guided by sct. introduction: desmopressin (ddavp) is a vasopressin analogue which improves platelet function. its general use as a haemostatic agent is still controversial. the aim of study was to evaluate the effect of prophylactic desmopressin in blood coagulation in patients undergoing heart valve surgery. methods: prospective, randomized, double-blind clinical trial performed at the heart institute of the university of são paulo. a total of 108 adult patients undergoing heart valve surgery were enrolled from february 2015 to november 2016. immediately after cardiopulmonary bypass weaning and heparin reversal, patients were randomized in ratio 1:1 to intervention group: ddavp (0.3 μg/kg) or control group. blood samples were drawn at three different times, at baseline (t0), 2 hours (t1) and 24 hours (t2) after study medication. blood coagulation and perioperative bleeding were analysed using laboratorial tests and thromboelastometry, chest tube drainage and requirement of allogenic transfusion within 48 hours. results: a total of 54 patients were allocated to intervention and 54 to control group. blood levels of factor viii at t2 (236. 5 conclusions: prophylactic use of desmopressin in heart valve surgery does not influence coagulation and thromboelastometric parameters. identifying the impact of hemostatic resuscitation on development of multiple organ failure using factor analysis: results from a randomized trial using first-line coagulation factor concentrates or fresh-frozen plasma in major trauma (retic study) p innerhofer 1 introduction: to clarify how hemostatic resuscitation affects occurrence of multiple organ failure. methods: analysis of secondary endpoints of the retic study [1] (coagulation factors, activated protein c (apc), thrombin generation, rotem parameters, syndecan-1, thrombomodulin (tm) and d-dimer) measured at randomization, and after patients had received ffp or coagulation factor concentrates (cfc) at admission to icu, 24 and 48 hours thereafter. we used factor analysis to reduce the highly interrelated variables to a few main underlying factors and analysed their relation to mof before and after hemostatic therapy. results: the factors concentration, clot and hypoperfusion representing trauma-induced coagulopathy (table 1) were comparable between groups at baseline (fig. 1) and only high hypoperfusionscore predicted mof, while after therapy a low clot-score also predicted mof. only the changes of the clot-score independently affected occurrence of mof (p=0.0002, adjusted or 3.40, ci 2.46-4.71), while changes of concentration (p= 0.8979, adjusted or 0.96, ci 0.68-1.34) and hypoperfusion (p=0.8098, adjusted or 1.06, ci 0.84-1.33) did not. a lower clot-score occurred after ffp transfusion than use of cfc, mainly through persistent thrombocytopenia (platelet count r2-4 ffp vs cfc p<0.02) (fig. 2) . the higher concentration-score after ffp did not affect mof and ffp had no beneficial effect on fibrinolysis, syndecan-1, tm or apc. conclusions: hemostatic resuscitation should augment the factor clot, which is feasible with early fibrinogen administration but not with ffp. the found platelet-saving effect of early fibrinogen administration is important as platelets play a major role in inflammation and transfusion of platelets did not correct thrombocytopenia. introduction: the trauma induced coagulopathy clinical score (ticcs) was developed to be calculable on the site of injury with the objective to discriminate between trauma patients with or without the need for damage control resuscitation (dcr) and thus transfusion [1] . this early alert could then be translated to in-hospital parameters at patient arrival. base excess (be) and ultrasound (fast) are known to be predictive parameters for emergent transfusion. we emphasize that adding this two parameters to the ticcs could improve its predictability. methods: a retrospective study was conducted in the university hospital of liège. based on the available data in the register (from january 1st 2015 to december 31st 2016), the ticcs was calculated for every patient. be and fast results were recorded and points were added to the ticcs according to the ticcs.be definition (+3 points if be < -5 and + 3 points in case of a positive fast). emergent transfusion was defined as the use of at least one blood product in the resuscitation room. the capacity of the ticcs, the ticcs.be and the trauma associated severe hemorrhage (tash) to predict emergent transfusion were assessed. results: a total of 328 patients were included in the analysis. 46 (14 %) needed emergent transfusion. the probability for emergent transfusion grows with the ticcs.be value (fig. 1) . positive predictive values (ppv) and negative predictive values (npv) of the three scores are displayed in table 1 . conclusions: our results confirm that be and fast results are relevant parameters that can be added to the ticcs for better prediction of the need for emergent transfusion after trauma. fig. 1 (abstract p367) . probability for emergent transfusion with ticcs.be values. fig. 2 (abstract p366) . boxplots show available measurements of extrinsically activated clot firmness at 10 min (exa10), fibrin polymerization at 10 min (fiba10) and platelet count at baseline (r1) and after therapy at admission to icu, 24 and 48 hours thereafter (r2 to r4) for the cfc (blue, n=46) and the ffp (yellow, n=42) group as well as for patients without (white, n=40) and with (grey, n=48) multiple organ failure. table 1 ) for the cfc (blue, n=46) and the ffp (yellow, n=42) group, as well as for patients without (white, n=40) and with (grey, n=48) multiple organ failure. each factor is given at the measurement time point baseline (r1) and following haemostatic resuscitation at admission to icu, 24 and 48 hours thereafter (r2 to r4). introduction: the management of the critically ill polytrauma patient is complex and is often a challenge for the intensive care team. the objectives of this study is to analyze the oxidative stress expression in polytrauma cases as well as to evaluate the impact of antioxidant therapy on outcomes. methods: this prospective study was carried out in the clinic for anaesthesia and intensive care "casa austria", form the "pius brînzeu" emergency county hospital, timisoara, romania, with the approval of the hospital's ethics committee. clinicaltrials.gov identifier nct03095430. the patients' selection criteria included an injury severity score (iss) of 16 or higher, and age of 18 or higher. 67 patients were eligible for the study. they were divided in two groups, group a (antioxidant free, control, n=32), and group b (antioxidant therapy, study group, n=35). the antioxidant therapy consisted in continuous iv administration of 7500 mg/24 h of vitamin c until discharge from icu. the patients included in the study presented with similar characteristics, and no statistically significant differences were shown between group a and b regarding age (p > 0.05), sex (p > 0.05), iss upon admission (p > 0.05), percentage of patients admitted in the icu more than 24 hour post-trauma (p > 0.05), and associated trauma (p > 0.05). among patients in group b statistically significant differences were identified regarding the incidence of sepsis (p < 0.05), multiple organ dysfunction syndrome (p < 0.05), mechanical ventilation time (p < 0.05), and mortality (p < 0.05). no statistically significant differences were shown regarding the time spent in the icu (p > 0.05). conclusions: following this study we can state that the administration of substances with a strong antioxidant character has positive influences on the outcome of critically ill patients, decreasing the incidence of secondary pathologies as well as mortality rates. icc increased by 22.62%, icd increased by 17.57%, slightly increased ma, and ircl was nearly in the normal range. conclusions: rapid and accurate diagnosis of the coagulation system by lpteg method at different stages of traumatic disease allows for more accurate selection and adjustment of the therapy, which allows improving the prognosis of the disease. introduction: evidence for tranexamic acid (txa) in the pharmacologic management of trauma is largely derived from data in adults [1] . guidance on the use of txa in pediatric patients comes from studies evaluating its use in cardiac and orthopedic surgery. there is minimal data describing txa safety and efficacy in pediatric trauma. the purpose of this study is to describe the use of txa in the management of pediatric trauma and evaluate efficacy and safety endpoints. methods: this retrospective, observational analysis of pediatric trauma admissions at hennepin county medical center from august 2011 to november 2017 compares patients who did and did not receive txa. the primary endpoint is survival to hospital discharge. secondary endpoints include surgical intervention, transfusion requirements, length of stay, thrombosis, and txa dose administered. results: there were 35 patients [<=] 16 years old identified for inclusion using a massive transfusion protocol order. twenty patients (57%) received txa. baseline characteristics and results are presented as median (iqr) unless otherwise specified, with statistical significance defined as p < 0.05. patients receiving txa were more likely to be older, but there was no difference in injury type or injury severity score (iss) at baseline (table 1) . there was no difference in survival to discharge, need for surgical intervention, or thrombosis (table 2) . patients who did not receive txa had numerically higher transfusion requirements and longer length of stay, but these did not reach significance. conclusions: txa was utilized in 57% of pediatric trauma admissions at a single level i trauma center, more commonly in older patients. though limited by observational design, we found patients receiving txa had no difference in mortality or thrombosis. introduction: the risk of venous thromboembolism (vte) in trauma is greatly increased and one of the leading causes of morbidity and mortality after an accident [1] . prophylactic measures to prevent vte primarily consist of anticoagulants. in instances in which anticoagulation is contraindicated or inadequate, inferior vena cava (ivc) filters can be used [2] . however, insertion of ivc filter as a prophylactic measure is controversial as filter-related complications are well documented and increase with treatment time [3] . the objectives of our study were to evaluate ivc filter insertion indications and filter related complications in pelvic trauma patients. methods: 250 patients with pelvic fractures were operated during the study period 1/01/2011-31/12/2015. all patients who received ivc filter during the period were included into analysis. relevant data was collected from electronic patient journal. results: thirty four patients received retrievable filters during the study period (22 males and 12 females) ( table 1) . median age of patients was 59 years (range, 21-80). the predominant indication (79%) was prophylactic insertion. the median indwell time was 26 days (range 1-410 days). despite ivc filter insertion one patient experienced lung embolism and another -dvt. in eleven cases ivc filters were tried to be removed at the treating hospital. in two cases filter extraction was unsuccessful and in another two cases filters were left in place due to ivc thrombosis. conclusions: majority of ivc filters were inserted outside guidelines [4] and proportion of prophylactic indications is significantly higher (80% vs 24%) than seen in registry studies [5] . filter related complications were observed in 18% of patients. more restrictive approach to prophylactic ivc insertion should be exercised. the impact of preinjury antiplatelet and anticoagulant pharmacotherapy on outcomes in patients with major trauma admitted to intensive care unit ( conclusions: patients on preinjury anticoagulants and antiplatelet agents showed an increased mortality; this may be the result of the greater incidence of bleeding, the older age and more comorbidities in this groups. is enzymatic debridement better in critically burned patients? introduction: early debridement of burned tissue reduces infection rate, icu stay and mortality. the use of proteolytic enzymes such as bromelain allows a faster, more effective and selective debridement of denatured tissue, preserving and exposing healthy tissues, reducing debridement times compared to standard of care. methods: retrospective observational study performed in the critical burn unit (march 2016 to september 2017) including 27 patients >18 years old with a total body surface area (tbsa) burned > 15% and < 75%, or > 65 years old with a tbsa burned > 10%, who underwent enzymatic debridement. mean and standard deviation were used for normal quantitative variables and median and interquartile range in the opposite case. qualitative variables were presented by absolute and relative frequencies. results: mean age was 47.6 ± 17.8 years old, 74% males, apache ii 11 (ri 5-18), absi 7 (ri 5-9). median tbsa burned was 29% (ri 18-50%), 21% (ri 16-39) were deep dermal or full thickness. time until debridement was 21 hours (ri 8-35). 7.4% (n=2) had incomplete debridement after first application, 33% (n=9) received regional anesthesia, 91% (n=25) didn't need blood transfusion. 25% of patients who didn't have vasopressors prior debridement, needed the use of it with a mean dose of 0,6mcg/kg/min. 25% of patients with vasopressors prior treatment, required an increase of dose by a mean of 0.9 mcg/kg/min. median icu stay was 19 days. mortality was 22%. conclusions: topical bromelain allows a fast start of tissue debridement with a low rate of failure. the need for fasciotomy and blood transfusion was very low. topical treatment involved a fast and simultaneous debridement of the tbsa burned, generating an inflammatory response that in some cases required vasopressors. 837.539.15/10307). the bche activity was measured by using point-ofcare-test system (securetec detektions-systeme ag, neubiberg, germany). levels of the routine inflammation biomarkers, i.e. c-reactive protein (crp) and the white blood cell count (wbcc), were measured during the initial treatment period. measurements were performed at the admission, followed by 12, 24 and 48-hour time points. injury severity score (iss) was used to assess the trauma severity. results: the observed reduction in the bche activity was in accordance with the change in the crp concentration and the wbcc. the bche activity measured at the hospital admission negatively correlated with the length of the icu stay in patients with polytrauma (r = -0.5, spearman's rank correlation coefficient). conclusions: the bche activity might be used as an early indicator for the magnitude of the systemic inflammation following polytrauma. moreover, the bche activity, measured at the hospital admission, might predict the patient outcome and therefore prove useful in early identification of the high-risk patients. pharmacological interventions for agitation in traumatic brain injury: a systematic review introduction: among tbi complications, agitation is a frequent behavioural problem [1] . agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. pharmacological treatments are often considered for agitation management following tbi. however, the benefit and safety of these agents in tbi patients as well as their differential effects and interactions are uncertain. methods: the major databases and the grey literature were searched. we included all randomized controlled, quasi-experimental, and observational studies with control groups. the population of interest was all patients, including children and adults, who have suffered a tbi. studies in which agitation was the presenting symptom or one of the presenting symptoms, studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in tbi patients were included. results: we identified 14 226 references with our search strategy. two authors screened 12 899 after removal of duplicates. after searching the grey literature and secondary databases, a total of 170 potential articles were identified. eleven studies in which agitation or an associated behavior was the presenting symptom, 11 studies where agitation was not the presenting symptom but was measured as an outcome variable, and 3 studies assessing the safety of these pharmacological interventions were identified. overall, the quality of studies was weak. in studies directly addressing agitation, pindolol and propranolol may reduce assaults and agitation episodes. amantadine and olanzapine may reduce aggression, whereas valproic acid may reduce agitated behavior. conclusions: there is weak evidence to support the use of pharmacological agents for the management of agitation in tbi. impact of decompressive craniectomy on neurological functional outcome in critically ill adult patients with severe traumatic brain injury: a systematic review and meta-analysis p bonaventure, ja jamous, f lauzier, r zarychanski, c francoeur, a turgeon chu de québec -université laval, québec, canada critical care 2018, 22(suppl 1):p377 introduction: severe traumatic brain injury is associated with high mortality and functional disability. several interventions are commonly used to control the intracranial pressure to prevent secondary cerebral injuries. among them, decompressive craniectomy (dc) is widely performed; however, its impact on functional outcome is still under debate. our objective was to assess the efficacy and safety of this procedure in adult patients with severe traumatic brain injury. methods: we systematically searched in medline, embase, cen-tral, web of science, conference proceedings and databases of ongoing trials for eligible trials. we included randomized controlled trials of adult patients with severe traumatic brain injury, comparing dc to any other intervention. our primary outcome was the neurological function based on the glasgow outcome scale. secondary outcomes were mortality, intensive care unit (icu) and hospital length of stay, intracranial pressure control, and complications. two reviewers independently screened trials for inclusion and extracted data using a standardized form. we used random effect models to conduct our analyses and the i2 index to assess heterogeneity. results: we identified 5360 citations, from which we included 3 trials for a total of 573 patients. we observed no impact on the [3] . univariate logistic regression analyses were performed to identify predictors associated with the decision for icp monitoring. results: a total of 857 adult patients were included (tables 1 and 2 ). the risk of poor outcome estimated by the impact model was associated to the decision to monitor icp (fig. 1) . icp was more often monitored in patients with severe tbi, with one dilated pupil at admission and positive ct findings (in particular, high marshall scores). conclusions: according to our results, the clinician follows a multifactorial reasoning: the main determinants for the decision to monitor icp are gcs, pupils' abnormalities and, above all, ct findings. future studies will be needed to clarify specific indications for the clinicians in the identification of patients who would benefit from invasive monitoring. trajectories of early secondary insults after traumatic brain injury: a new approach to evaluate impact on outcome. introduction: secondary insults (si) occur frequently after traumatic brain injury (tbi). their presence is associated with a worse outcome. we examined the early trajectories of hypotension (sbp<90mmhg), hypoxia (spo2<90%) and pupillary abnormalities from the prehospital settings to the emergency department (ed), and their relationship with 6-months outcome. methods: in this retrospective, observational study we included all tbi patients admitted to our neuro intensive care unit (nicu) from january 1997 to december 2016. we defined the trajectories of si: -"sustained" if present on the scene of accident and at hospital admission, -"resolved" if present on the scene but resolved in ed, -"new event" if absent on the scene and present in ed, -"none" if no insults were recorded. we investigated the association of si trajectories with 6-months dichotomized outcome (glasgow outcome scale (gos); favorable=4-5; unfavorable=1-3). results: 967 patients were enrolled in the final analysis. hypoxia and hypotension were related with unfavourable outcome when introduction: guidelines for management of pediatric traumatic brain injury recommend maintaining intracranial pressure (icp) <20 mmhg [1] . use of 23.4% sodium chloride (nacl) is considered safe and effective for management of icp in adults, but evidence for concentrations >3% in pediatrics is limited. this study will describe the safety and efficacy of 23.4% nacl in reducing icp among pediatric patients. methods: this retrospective study evaluated patients <=18 years old who received 23.4% nacl and had continuous icp monitoring. cerebral perfusion pressure (cpp), mean arterial pressure (map), icp, and brain tissue oxygenation (pbto2) were recorded hourly and were compared to baseline for 6 hours after each dose. safety outcomes included peak serum sodium, peak serum chloride, and the incidence of stage 1 acute kidney injury (aki) (serum creatinine elevation >=0.3 mg/dl or >=50%) [2] . results: between august 2007 and july 2017, 45 eligible pediatric patients received 235 doses of 23.4% nacl; 215 doses were included in the analysis of perfusion parameters. mean age was 11.6 +/-6 years (2 months to 18 years), and the median initial glasgow coma scale score was 4. subjects received a median of four 23.4% nacl boluses, with a mean dose of 0.5 +/-0.18 ml/kg. significantly lower icp and higher cpp (p<0.001) were observed at all post-treatment time points (fig. 1) ; pbto2 was also significantly increased during 3 of the 6 hours recorded (p<0.05). there was no difference in map. peak post-treatment serum sodium and chloride were 157 +/-6 meq/l and 122 +/-7 meq/l, respectively (fig. 2) . stage 1 aki was observed in 15.6% of patients, and in-hospital mortality was 24.4%. conclusions: our data suggests that 23.4% nacl is a safe and effective therapy for elevated icp in pediatric patients. methods: we performed a prospective study in adult patients with mild head trauma (gcs 14 and 15) qualified for acquisition of urgent head ct scan. the clinical symptoms potentially related to intracranial lesion including abnormal vitals, vomiting, headache, persistent dizziness were recorded. ons as well as head ct were then performed. all ons examinations were executed by an experienced sonographer to eliminating interrater bias. head ct findings were dichotomized as positive or negative finding for ich based on formal radiology reports. the patients' disposition including admission, surgery and safe discharge were followed. results: 78 patients were enrolled for the survey. 16 patients had at least one symptom related to potential intracranial lesion (20.5%). the mean onsd was 44±9mm. 25 patients were found to have ich and 6 underwent neurosurgery thereafter. no significant difference of onsd was found between the groups with and without ich, as well as the group receiving surgery or conservative treatment. with introducing a conventional 5mm threshold of onsd, the sensitivity, specificity, ppv and npv was 0.36, 0.83, 0.50 and 0.73, respectively. while incorporating occurrance of at least one positive clinical symptom with the onsd measurement greater than 5mm as a composite threshold, the sensitivity, specificity, ppv and npv was 0.32, 1.00, 1.00 and 0.76, respectively. conclusions: the diagnostic value of ons in mild head trauma is defective. nevertheless, with the supplemental aid of recognition of clinical symptoms relevant to potential intracranial lesion, the overall accuracy would improve. a correlation between ykl-40 concentrations in cerebrospinal fluid and marshall classification in traumatic brain injurypreliminary results g pavlov 1 , m kazakova 1 , p timonov 1 , k simitchiev 2 , c stefanov 1 , v sarafian 1 1 medical university -plovdiv, plovdiv, bulgaria, 2 university of plovdiv, plovdiv, bulgaria critical care 2018, 22(suppl 1):p382 introduction: establishment of prognostic models in traumatic brain injury (tbi) would improve the classification based on predictive risks and will better define treatment options [1] . in recent years, one of the most intensively studied glycoprotein is ykl-40. it is expressed as a consequence of broad spectrum of inflammatory and malignant diseases [2] . this is study aimed to investigate the level of ykl-40 in tbi patients and its relationship with several clinical models. methods: we determined plasma and cerebrospinal fluid (csf) ykl-40 levels in six (6) patientson the 24th and 96th hour after the tbi. each patient was examined by physical and instrumental methods for somatic and neurological status, clinical assessment and prognostic scales (gcs, marshall classification, apache iii). routine haematological and biochemical tests were also performed. as control served the csf of age-matched suddenly deceased healthy individuals (n = 11), which was examined post mortem for ykl-40 levels. results: we found no significant difference between plasma ykl-40 levels till 24th and 96th in all patients (mean difference ± sd: 57 ± 237 ng/ml 1 ) and calculated cerebral autoregulation (ar) as correlation coefficients (pearson) for each ih wave. z-ratios were divided according to binary ar outcome and correlation calculated with intracranial pressure before, during and after the ih waves. results: our preliminary analysis demonstrated a negative correlation between intracranial pressure and z-ratio in the grouped 6 ih waves with preserved ar, but no correlation in the grouped 9 ih waves with impaired ar (table 2 and fig. 2 ). this indicates a decrease in power in the eeg low frequencies (0-7hz) and/or an increase in the eeg high frequencies (7-30hz) for increased values of intracranial pressure when ar is preserved. conclusions: features of ih waves differ depending on the ability of the injured brain to autoregulate cerebral blood flow. these features might include different signature of eeg frequency changes. the causative links and clinical significance of the different eeg patterns remain unexplored and might represent a signature of neurovascular coupling. introduction: targeted temperature management of patients who have suffered a traumatic brain injury is often used in the hope of preventing further insult to the brain; however, there is no uniform approach to managing temperature either locally, nationally or internationally, and maintenance of goal temperature in this patient population is often challenging due to hypothalamic injury. we sought to evaluate the feasibility and safety of an esophageal heat transfer device (ensoetm, attune medical, chicago, il) to perform temperature management of patients suffering from traumatic brain injury. methods: this was an irb-approved prospective study of patients undergoing temperature management after traumatic brain injury. patients were treated with an esophageal heat transfer device connected to an external heater-cooler, and maintained at target temperature for at least 24 hours. patient temperature obtained via foley catheter was recorded hourly, and the deviation from goal temperature during treatment reported. results: a total of 12 patients were treated from august 2015 to may 2016. temperature targets during treatment ranged from 34.0 to 36.8 degrees c. maintenance of target temperature was successful, with 85% of readings within +/-1 degrees c of target, and 75% of readings within +/-0.5 degrees c of target. one patient developed a small hydrothorax, not attributed to device use. all patients survived to discharge from the icu, with median cpc of 2 (range 1 to 4). conclusions: targeted temperature management of patients with traumatic brain injury using an esophageal heat transfer device was feasible and safe, providing a tight maintenance of goal temperature in this challenging patient population. introduction: traumatic brain injury (tbi) represents a serious problem in europe. it still is the principal cause of death in us and europe. every year in italy 250 people on 100,000 suffers of tbi and 17 on 100,000 dies. disability and incapacity from tbi provides "strong ethicals, medicals, social and health economy imperative to motivate a concerted effort to improve treatment and preventions" methods: our hospital is the hub for modena's county for tbi and we took part in the past 3 year on european project creactive (collaborative researce on acute traumatic brain injury in intensive care medicine in europa) as branch of italian group giviti (gruppo italiano per la valutazione degli interventi in terapia intensiva). our study concerned about patients with tbi dismissed from icu that "personally" or by the family will accepted the consensus to be included in our follow up conducted after 6 months from the dismissal. we collected clinical data from the admission to the dismissale and measured impact of tbi on all day life with gos-e and qolibri-os using telephonical interview. results: we collected data about 63 patients, 33 answered to the telephonical follow-up and only 10 compilated the qolibri-os. we found out that patients admitted with lower gcs has worst outcome in terms of quality of life. it also appears that anisocoria during icu staying represents an odds ratio for death and is connected with worst quality of life after 6 months from the dismissal (tables 1 & 2) . inability to re-start a normal work-activity appeared to be the most important factor on the perception that our patient have of their new lives. conclusions: anisocoria seems to be an indicator of severe brain damage. gcs, despite it's simplicity, still represent the best and easiest way to score tbi. work impairment appear to be the most important disability to determine subjective perception of quality of life after tbi, so efforts have to be made to improve work rehabilitation after the dismissal from hospital. introduction: hyperventilation (hv) reduces elevated intracranial pressure (icp) by changing autoregulatory functions connected to cerebrovascular co2 reactivity. criticism to hv is due to the possibility of developing cerebral ischemia and tissue hypoxia because of hypocapnia-induced vasoconstriction. we aimed to investigate the potential adverse effects of moderate hv of short duration in the acute phase in patients with severe traumatic brain injury (tbi), using concomitant monitoring of cerebral metabolism, continuous brain tissue oxygen tension (pbro2), and cerebral hemodynamic with transcranial color-coded duplex sonography (tccd). methods: a prospective trial was conducted between may 2014 and may 2017 at the university hospital of zurich. adults (>18 years), with non-penetrating tbi, first gcs < 9, icp-monitoring, pbro2 and/or microdialysis (md)-probes were included within 36 hours after injury. data collection and tccd measurements took place at baseline (a), at the begin of moderate hv (paco2 4-4.7 kpa) (c), after 50 minutes of moderate hv (paco2 4-4.7 kpa) (d), and after return to baseline (e) (fig. 1) . repeated measures anova was used to compare variables at the different time points followed by post hoc analysis with bonferroni adjustment as appropriate. p-value < .05 was considered significant. results: eleven patients were included (64% males, mean age 36 ± 14 years). first gcs was 7 (3-8: median and interquartile range). data concerning paco2, icp, pbro2, mean flow velocity (mfv) in the middle cerebral artery, and md values are presented in table 1 . during hv, icp and mfv decreased significantly. pbro2 presented a trend of reduction. glucose, lactate and pyruvate did not change significantly ( table 2) . conclusions: short episodes of moderate hv have a potent effect on the cerebral blood flow, as assessed by tccd, reduce icp and pbro2, and do not induce significant changes in cerebral metabolism. outcome of pediatric patients six months after moderate to severe tbi -results of creactkids study from three picu in israel paco2 arterial partial pressure of co2, cpp cerebral perfusion pressure (mmhg), icp intracranial pressure (mmhg), pbro2 brain tissue oxygen tension (mmhg), mfv mean flow velocity in the middle cerebral artery introduction: delirium is a major cause of complications in postoperative patient in icu. risk factors for delirium include poor cerebral hemodynamics and peri-operative cerebral desaturations. intraoperative target cerebral oximetry monitoring may decrease the incidence of postoperative delirium in elective major abdominal surgery patients. methods: a single-blinded, randomised controlled trial in patients undergo elective major abdominal surgery who received postoperative care in surgical icu with age more than 65 years were randomised into two groups. the intervention group was received intra-operative target cerebral oxygen monitoring using cerebral oximetry whereas the control group was not. delirium was assessed in both group at 24, 48, 72 hour postoperatively. other risk factors for delirium, mechanical ventilator day, length of icu stay, length of hospital stay and post-operative complication were recorded. results: from august 2015-march 2016, 37 patients who met the criteria were randomised to 19 patients in intervention group and 18 patients in control group. overall incidence of delirium was 27.03% (intervention 21.05% vs control 33.34%, p=0.401). baseline cerebral oxygen in intervention group was 66.79 ± 3.11%. desaturation below 10% from baseline was found in 8 from19 patients (42.1%) and was the only significant risk factor associated with delirium (p=.008, odd ratio 1.68). there was no significant different in mechanical ventilator day, icu length of stay, hospital length of stay and postoperative complication between both groups. there was no complication associated with application of the cerebral oximetry probe in the intervention group. conclusions: from this preliminary report can not demonstrated the significant different of intra-operative target cerebral oxygen monitoring by using cerebral oximetry in prevention of delirium. however the reduction of cerebral oxygen more than 10% from baseline in intervention group showed significantly associated with delirium postoperatively. the set score as a predictor of icu length of stay and the need for tracheotomy in stroke patients who need mechanical ventilation introduction: set score was initially developed as an in-house screening tool based on tracheotomy predictors identified in several retrospective studies. it combined the categories of neurological function, neurological lesions, and general organ function/ procedure, and weighed by allocation of certain point values [1] . in our study it was very interesting to us to find a tool to judge application of early tracheotomy, and as we have a good culprit number from stroke cases so we decided to try to apply this score in our icu after discussion with the inventor of this score. methods: 164 stroke patients were prospectively included in the study as they were ventilated or were very little potential for ventilation and assessed by the stroke-related early tracheotomy score (set score, table 1 ) within the first 24 h of admission (table 2) . endpoints were length of stay and ventilation time (vt) after doing early tracheotomy. we examined the correlation of these variables with the set score using standard analytical methods. results: the set score with a value cutoff point of 8 had a significant effect on decision of making tracheotomy and hence decreasing ventilation time and length of stay in icu, which affected outcome (figs. 1 & 2) . conclusions: all efforts must be exhausted in neuro intensie care to decrease the secondary changes of brain injury after stroke,early tracheotomy is a good tool to decrease length of stay in icu and ventilation time in these patients.inventing a tool to judge these decisions of doing tracheotomy was a challenge. set score proved to be valuable.further multi center trials are needed. fig. 2 (abstract p390) . specificity for the cutoff point of set score. cut point of 9 is the best to predict tracheostomy with sensitivity of 85.0% and specificity of 80.4%. cut point of 9 is the best to predict early tracheostomy with sensitivity of 86.1% and specificity of 81.5%. since no patients had score 9 so the previous analysis that consider cut-point of 8 should remain the same but just change the number in the text to 9 contraindication for pharmacological vte prophylaxis (65.4%). overall, ncc patients were more likely to receive mechanical (90.3% icu days) than pharmacological vte prophylaxis (74.1% icu days), however pharmacologic was more likely among younger patients with lower apache ii scores. guideline concordant care varied by recommendation; lower for pharmacological and higher for mechanical vte prophylaxis. conclusions: ncc patients uncommonly receive guideline concordant pharmacological vte prophylaxis. collectively, our findings suggest that current vte prophylaxis prescribing practices may reflect uncertainty around risks associated with vte prophylaxis among ncc patients. methods: we retrospectively analysed prospectively collected data from 134 consecutive ich patients that received dvt prophylaxis in a tertiary hospital. he was defined as an increase of >6ml measured using the abc/2 method or the semiautomatic software based volumetric approach. using multivariate analysis, we analysed risk factors including early dvt prophylaxis for he>24h, hospital mortality and poor 3-month functional outcome (3m modified rankin score>3). results: patients presented with a median gcs of 14 (iqr 10-15), hematoma volume of 11ml (iqr 5-24) and were 71y old (iqr 61-76). 56% received early dvt prophylaxis, 37% late dvt prophylaxis and 6% had unclear bleeding onset. hematoma volume was smaller in the early dvt prophylaxis group with 9.5ml (iqr 4-18.5) vs 17.5ml (iqr 8-29) in the late prophylaxis group (p=0.038) without any other significant differences in disease severity. delayed he (n=5/134, 3.7%) was associated with higher initial hematoma volume (p=0.02) and lower thrombocyte count (p=0.03) but not with early dvt prophylaxis (p=0.36) in a multivariate analysis adjusted for known risk factors. early dvt prophylaxis was not independently associated with 3m outcome. conclusions: although limited by the retrospective design, our data suggest that early dvt prophylaxis (<48h) may be safe in patients presenting with primary ich, which supports the recommendations given by the neurocritical care society. introduction: there is a paucity of literature describing the relationship between clevidipine and its impact on intracranial pressure (icp). the safety of clevidipine in patients with intracranial hemorrhage is often extrapolated from studies using nicardipine, which has demonstrated a neutral effect on icp [1] . the objective of this study was to determine if there was a relationship between clevidipine initiation and changes to cerebral hemodynamic parameters. methods: this study was a retrospective analysis of adults admitted to hennepin county medical center between july 2012 and july 2017. individuals were included if they had intracranial bleeding and icp data recorded prior to initiation of a clevidipine infusion. baseline demographic data was collected, including age, gender, type of injury, and initial glasgow coma score (gcs introduction: aneurysmal subarachnoid hemorrhage (sah) is an acute cerebrovascular event with high mortality and is an important cause of neurologic disability among survivors. many complications in the course of sah, such as hydrocephalus, also play a role in the poor outcome. the aim of the study was to describe the characteristics of patients with sah admitted to the icu to evaluate the factors associated with outcome. methods: this study was conducted in two reference centersone in rio de janeiro and one in porto alegre. from july 2015 to september 2017, every adult patient admitted to the icu with aneurysmal sah was enrolled in the study. data were collected prospectively during hospital stay. the primary endpoint was mortality and dichotomized functional outcome (poor outcome defined as glasgow outcome scale 1 to 3) at hospital discharge and 12 months. dichotomous variables were analyzed using two-tailed fisher's exact test. results: a total of 261 patients were included. demographic characteristics are presented in table 1 . frequency of clinical and neurological complications are presented in table 2 . in univariate analysis, factors most frequently seen in patients with unfavorable outcome were seizure (17% vs 3%, p=0.0003), hydrocephalus (51% vs 17%, p<0.0001), meningitis (30% vs 12%, p=0.0004), rebleeding (17% vs 4%, p= 0.0008), vasospasm (46% vs 26%, p=0.001), pneumonia (37% vs 7%, p<0.0001), sepsis/septic shock (21% vs 4%, p<0.0001), postsurgical neurological deterioration (37% vs 18%, p=0.001) and delayed cerebral ischemia (37% vs 12%, p<0.0001). at 12 months, out of 74 patients with follow-up, 40% had poor outcome. conclusions: sah is associated with high morbidity. both neurological complications as clinical complications were associated with unfavorable outcomes. therapeutic interventions to prevent those may have an impact on clinical outcomes. introduction: brain tissue hypoxia (brain tissue oxygen tension, pbto2<20mmhg) is common after subarachnoid hemorrhage (sah) and associated with poor outcome. recent data suggest that brain oxygen optimization is feasible and may reduce the time with brain tissue hypoxia to 15% in patients with severe traumatic brain injury [1] . little is known about the effectiveness of protocolized treatment approaches in poor-grade sah patients. methods: we present a retrospective analysis of prospectively collected data of 105 poor-grade sah patients admitted to 2 tertiary care centers where pbto2<20mmhg was treated using an institutional protocol. treatment options were left to the discretion of the treating neuro-intensivists including augmentation of cerebral perfusion pressure (cpp) using vasopressors if necessary, treatment of anemia and targeting normocapnia, euvolemia and normothermia. the dataset used for analysis was based on routine blood gas analysis for hemoglobin data matched to 2 hourly averaged data of continuous cpp, pbto2, temperature and cerebral microdialysis (cmd) samples over the first 10 days of admission. results: patients were admitted with a gcs of 3 (iqr 3-4) and were 58 (iqr 48-66) years old. overall incidence of brain tissue hypoxia was 25%. during this time we identified associated episodes of cpp<70mmhg (27%), hyperglycolysis (cmd-lacta-te>4mmol/l, cmd-pyruvate>120μmol/l; 26%), pco2<35mmhg (19%), metabolic distress (cmd-lactate-to-pyruvate-ratio>40; 18%), pao2<80mmhg (14%), hb<9g/dl (10%), and temperature>38.3°c (4%) (fig. 1 ). of these variables only hyperglycolysis was significantly more common (37%) during episodes of normal pbto2 (75% of episodes). conclusions: underutilization of ivt despite the overwhelming evidence that support the effectiveness of such therapy can be partly attributed to the fear of hemorrhagic complications. this fear is not justified by current data. the estrangement of the emergency medicine community regarding ivt and the domination of stroke experts in decision making is also a barrier. regional wall motion abnormalities and reduced global longitudinal strain is common in patients with subarachnoid hemorrhage and associated with markedly elevated troponin k dalla sahlgrenska university hospital, gothenburg, sweden critical care 2018, 22(suppl 1):p402 introduction: stress-induced cardiomyopathy after subarachnoid hemorrhage (sah) is a life-threating condition associated with poor outcome. regional wall motion abnormalities (rwma) is a frequent finding, however, assessment of rwma is known to be difficult. in the present study we hypothesized that global and regional longitudinal strain (gls and rls) assessed with speckle tracking echocardiography can detect myocardial dysfunction indicated by increased levels of the cardiac biomarker troponin (tnt). methods: this prospective study comprised 71 patients with sah. the tnt was followed daily from the admission up to 3 days postadmission and elevated tnt was defined as > 80 ng/l. a transthoracic echocardiography examination was performed within 48 hours after the hospitalization. the peak gls was determined using the three apical projections and presented as the mean of the 18 segments. reduced gls was defined as > -15% and reduced rls was considered present when segmental strain was > -15% in > 2 adjacent segments. introduction: deviations from strict eligibility criteria for intravenous thrombolysis (ivt) in ischemic strokes regarding either license contraindications to alteplase or relative contraindications to thrombolysis have been reported in international literature, with conflicting results on patients' outcome.the aim of our study was to evaluate safety and efficacy for patients receiving ivt outside standard inclusion criteria. methods: retrospective analysis of our department's thrombolysis database.we compared 83 patients with strict protocol adherence (strict protocol group) [mean age 63 years and national institutes of health stroke scale (nihss) at admission 12/range 5-28] and 41 patients with protocol deviations (off-label group) [mean age 68 years and nihss at admission 10/range 2-24],in particular 10 patients >80 years old, 13 patients with mild stroke-nihss< 5,and 22 with symptom-to-needle time 3-4.5 hours (4 patients had 2 deviations). results: patients in the off-label group were older but had no difference in baseline severity scores (sapsii, nihss). they had no statistically significant difference on short-term (nihss at 7 days, need for critical care support, primary adverse event) and long-term (mortality,functional outcome at 3 months) outcome measures when compared to standard protocol patients. conclusions: in accordance with international literature,off-label thrombolysis is save and equally effective to standard protocol thrombolysis.thrombolysis strict protocol needs expansion of inclusion criteria. introduction: most scales (gcs,nihss) don't consider the pathway of secondary acute brain failure (sabf). neuron-specific-enolase (nse) could be usefull in diagnostic and treatment pts. with sabf [1, 2] . methods: prospective study incl. 35 pts. with abf. pts. were identical in condition, age and comorbidies. in main group, nse examed and choline alfoscerate was used, pts. was divided into 2 subgroups ia (n=12) with acute ischemic stroke(ais) and ib (n=10) pts. with posthypoxic encephalopathy. the control group (n=13) pts. with ais treated by loc.protocol №602. clinical, laboratory, and imaging variables were fully compared. pts. examed by abcde algorithm, gcs and nihss. brain ct, carotid doppler performed. considering criteria:nse(days 1,3,5), neurological status, length of stay in icu (icu los). "ss-6.0"was used. results: the baseline nse was higher and correlated to nihss (16.3 ±2.2, ÷2=1.08) in all pts. in ia, ib sbgroups nse decreased for 3-5 days vs. control group 10-12days (÷2=7.93) and correlated with regression neurological deficit. icu los in main group was 3.8±0.9 days vs. control group 5.9±0.9 days. sensitivity and specificity of nse as a marker of brain injury in pts. with ais were 65 and 83% and in posthypoxic pts. were 90 and 90%, respectively, which showed nse as eligible diagnostic criterion of posthypoxic cerebral edema. in ia (ais) pts. and ib (posthypoxic edema) were confirmed by increasing nse in 4fold and 9-fold respectively more vs. pts. who had only brain ct at first day. nse also correlated with regression neurological deficit and improving of the neurological status. although, two pts. in iib group died with nse 150-220 ìg/ml conclusions: 1. nse is an effective marker of the severity of damages even in the sabf, and shoved efficacy efficacy of treatment. 2. negative outcome can be in pts. with sabf and more 3-fold increasing nse and increasing up to 150-220 ìg/ml is a mortality predictor. 3. we included nse in local protocols p405 n-terminal pro-brain natriuretic peptide as a bio-marker of the acute brain injury introduction: the detection of biomarkers levels facilitates an early diagnosis of brain tissues damage, allows assessing the prognosis of the disease and its outcome, and performs the monitoring of the patient treatment. methods: we studied 64 patients (36 m, 28 f.). 1st group comprised 12 patients with severe brain trauma: 1asurvivors with good outcome (on glasgow outcome scale groups i-ii) (n=8), 1bdead or severely disabled (on glasgow outcome scale groups iii-v) (n=4). 2nd group comprises 37 patients with intracranial and sub-arachnoid hemorrhages: assignment to groups 2a (n=14), 2b (n=22) was done using the same criteria as group 1. 3rd group comprises 16 patients operated in conjunction with brain tumor. assignment to groups 3a (n=6) and 3b (n=10) was done using the same criteria as groups 1 and 2. we tested the level of n-terminal pro-brain natriuretic peptide in blood (0-125 pg/ml) between 1st and 3rd days after severe brain injury and then every 2-12 days for the total duration of 21 days. results: : statistical analysis failed to demonstrate noticeable difference in the level of ntprobnp between groups 1,2,3. we detected the differences between subgroups (p<0.01). patients from groups 1a,2a,3a (n=28) ntprobnp level stayed below 700 pg/ml in 20 cases (71%), in the 8 cases (29%) the level was above 700 pg/ml, but by 14-21th day decreased to the normal values. for patients in subgroups 1b,2b,3b (n=36) in 28 cases (78%) ntprobnp level was above 700 pg/ml at least once, in 8 cases (12%) level stayed below 700 pg/ ml but remain high for the entire duration of the study without significant decrease. conclusions: all the patients with acute brain injury show the increased level of ntprobnp above normal values, irrespective of ethiology of injury. in case when ntprobnp level increases above 700 pg/ml and/or does not decrease to the normal values it is possible to predict a negative outcome. introduction: cerebrovascular and coronary artery diseases share many of the same risk factors [1] . cardiac mortality accounts for 20% of deaths and is the second commonest cause of death in the acute stroke population, second only to neurologic deaths as a direct result of the incident stroke. methods: this is a prospective observational study from july 2015 to april 2016 done on 80 adult patients (groupi: 50 pts acute ischemic strokes & group ii:30 pts as control) in kafr-elsheikh general hospital icu. inclusion criteria: all patients with acute ischemic stroke while exclusion criteria: patients with heart or renal failure/sepsis&septic shock/ischemic heart disease or hemorrhagic stroke,full clinical examination&labs including admission quantitative serum cardiac troponin i elisa immunoassay,ecg,2d echocardiography&ct brain on day 0&3,alberta stroke program (asp) early ct (aspect) to predict neurological outcomes and mortality in patient with acute ischemic stroke within 28 days so survivors vs non-survivors in group 1 were divided to g1a & g1b respectively. results: dyslipidemia, hypertension, diabetes mellitus were significant comorbidities in all ischemic stroke pts.tlc, urea, inr and troponin were significantly higher in case group vs control group.gcs was found to be lower in non-survivors at day 0&at 3rd day follow up while aspect was significantly lower only at 3rd day follow up.troponin level was significantly higher in non-survivors g1b, it was also higher in patents who developed convulsion later during their icu stay& it was significantly inversely correlated to gcs and asp. troponin had sensitivity 53% and specificity 87% (roc curve analysis) conclusions: troponin level was predictor for mortality in patient with acute ischemic stroke.it is well correlated to gcs and asp on admission.it was a predictor for occurence of convulsions later in icu stay. introduction: based on examination and treatment of hyperkinetic disorder in patients with uws and mcs, we supposed that hyperkinesis manifesting the formation of the generator of pathologically enhanced excitation in cerebral cortex, basal ganglia, which subsequently causes the formation of hyperkinesis. halogencontaining anesthetic sevoflurane had a good clinical effect in patients with prolonged impairment of consciousness. methods: the study included 5 patients with uws (4 -hypoxia, 1 -encephalitis) and 3 patients with mcs (2 -hypoxia, 1-encephalitis). hyperkinetic disorder presenting as permanent myoclonus of arms and legs, face. all patients were performed head mri and eeg (before, during and after anesthesia), crs-r assessment, 3 patients -[18f]-fgd pet. initial anesthesia: propofol 2-3 mg/kg, rocuronium bromide (esmeron) 0, 6 mg/kg, fentanyl 3-5 mg/kg and clonidine (clophelin) 0.5-0.7 mg/kg. maintenance of anesthesia is carried out due to the following scheme: inhalation anesthesia using sevoflurane (2.0-3.0 vol%, mac 0.8-0.9). additionally, during the 2nd -4th hours of medical anesthesia was prescribed the intravenous injection using ketamine 1-2 mg/kg/hr. the anesthesia is used during 24 hours. the patients were nurtured by balanced mixtures through nasogastric tube. after 24 hours the patients were gradually transferred to the autonomous breathing. the control clinical and instrumental studies to evaluate the therapy effectiveness (eeg, crs-r) were performed. results: in 5 patients (2 mcs, 3 uws) was observed the hyperkinetic disorder regression as decrease of hyperkinesis manifestation, 3 patients didn't have a significant dynamics. conclusions: the artificially formed "pharmacological dominant" (using sevoflurane and ketamine) may decrease the activity of pathological system of the brain, which clinically presented as significant decrease of hyperkinesis manifestation in 5 out 8 patients. 15-year experience of using benzodiazepines in predicting outcomes and targeted treatment of patients in unresponsive wakefulness syndrome (uws). introduction: we accepted a hypothesis that in some patients uws is a consequence of a pathologic system (ps), that limits the brain functional activity. identification of a ps allow to predict consciousness recovery. eeg registration under benzodiazepines test (bt) has become the method of ps identifying in uws patients. methods: we examined 145 uws patients (74 -traumatic, 71 -non traumatic). crs scales assessment, eeg with bt, mri of brain were performed for all patients. the midazolamum was administered iv 0.04 mg/kg,.in 3-4 min after bzd was recorded eeg for 15 min. the test was considered to be positive if against the background of bzd eeg pattern restructuring was observed: the low-amplitude eeg activity was rebuilt with the advent of alpha-and beta-spectrum.in patients with slowwave activity of theta-and delta-spectrum appeared stable fast forms, and in patients with baseline polymorphic eeg pattern was recorded prevalence of alpha activity and (or) the alpha rhythm. in order to confirm the correlation between the bzd effect and eeg pattern restructuring, flumazenil was administrated at rate of 0.1 mg every 1 to 2 minutes until the original eeg pattern has been registered again. results: the bt was true positive (recovery consciousness in 3-12 month later) in 22 traumatic and 19 non traumatic patients. true negative (permanent uws 12 month later) in 27 traumatic and 43 non traumatic patients. false positive -11 traumatic, 4 non traumatic. false negative 14 traumatic, 5 non traumatic patients. sensitivity bt to vs/uws = 74.6% sensitivity to mcs = 43.1% conclusions: our data confirmed the correctness of hypothesis that a ps limits the activity of the brain in patients in a uws. we proposed diagnostic method of a ps activity and suppression. apparently, bzd are the drugs of first stage examination choice in the treatment of uws patients. early identification of sepsis-associated encephalopathy with eeg is not associated with short-term cognitive dysfunction introduction: septic-associated encephalopathy (sae) affects approximately 75% of septic patients. recent studies showed sae is associated with short-term mortality and long-term cognitive disability. however, diagnosis of sae is one of exclusion and its association with short-term cognitive deficit is uncertain. the aim of this study is to evaluate the sensitivity of clinical examination in detecting sae. the association between sae and short-term cognitive impairment is also assessed. methods: prospective observational study enrolling adult septic patients admitted to a mixed icu. exclusion criteria were: encephalopathy from another cause, history of psychiatric/neurologic disease, cardiac surgery. all patients received continuous eeg monitoring and were assessed for sae for up to 7 days after inclusion. we performed a comprehensive consciousness assessment twice daily during the icu (gcs; full outline of unresponsiveness, four; coma recovery scale-revised, crs-r; reaction level scale 85, rls85; confusion assessment method for the icu, cam-icu). we defined altered brain function as gcs<15, no correlation between cognitive function at hospital discharge and severity of eeg alteration was found. conclusions: eeg was more sensitive than clinical assessment in detecting sae. altered eeg was not associated with short-term cognitive function. analysis of the training needs in italian centers that use brain ultrasound in their daily practices: a descriptive, multicenter study r aspide 1 introduction: as mission of siaarti neuroanesthesia and neuroicu group of study, we are mapping out the brain ultrasound training needs in our centers. although brain ultrasound is widely used to study the intracranial vessels and other issues, it is still not clear the homogeneity of the skills required in both neuro and general icu in italy. the aim of this study is to explore the use of us-tcd and validate a collection of criterea which would prove useful in any future national wide survey. methods: starting from sept. 2017 the seven center involved (bologna, catania, pisa, verona, bergamo, cesena, roma) collected clinical and sonographic data, basing on a crf of twenty criteria such as: kind of hospital and icu, number of beds and neuro-patients/year, the physicians specialization trained to perform us-tcd, the kind of us doppler device used and the kind of training course followed. as a second step, data were analyzed by coordination team, as third step, during annual siaarti conference, these centers had a deep discussion on these selected items, further modifying and adapting the content of the items. results: the result is a ready list of 20 items, an available tool for all the participant centers, that are going to start with an internal test survey for a final validation. conclusions: there is more than one path to train a physician on brain us in italy and there are new possible applications, even outside of the neuro sub-speciality. from the preliminary discussion, it is clear that in italy we have a inhomogeneous frame of training and use. this group of study believes that among the anesthesiologists/intensivists, it is possible to find a useful number of physicians interested in training on this topic. the main aim is the production of a validated criterea collection, available for eventually future national survey, useful to help map out the real national training needs in italy on us brain. perinatal neurosurgical admissions to intensive care c nestor, r hollingsworth, k sweeney, r dwyer beaumont hospital, dublin, ireland critical care 2018, 22(suppl 1):p411 introduction: beaumont hospital is the neurosurgical centre for ireland serving a population of 3.6 million. we present data on all perinatal patients who required icu admission for neurosurgical conditions over an 8 year period. our data presents an insight into the incidence and outcome of neurosurgical conditions during pregnancy methods: searching our database identified 11 pregnant and 8 recently pregnant patients admitted to icu with neurosurgical conditions. patient data was collected retrospectively by review of charts and of an electronic database. a further 12 pregnant patients were admitted for neurosurgical intervention but did not require critical care. results: intracranial haemorrhage was the most common diagnosis (5 subarachnoid haemorrhage and 5 had intra-cerebral haemorrhage). 6 patients presented with intracranial tumours and 1 patient had a traumatic brain injury. 1 patient was admitted post spinal tumour resection. 1 patient was referred with an ischemic stroke after iatrogenic injury to the carotid and vertebral artery. the requirement for organ support in this cohort of patients was high; 64% required ventilation and 45% inotropes. 13 patients underwent neurosurgical intervention & 6 medical treatment. 2 maternal deaths occurred at 16 & 37 weeks gestation. the modified rankin score (mrs) on discharge from hospital was <= 2 for 9 of the 17 surviving patients (median=3). of the 11 pregnancies (all singleton) there were 3 foetal deaths. 1 patient miscarried spontaneously at 4 weeks, 1 had a medical termination of pregnancy at 12 weeks to facilitate chemotherapy and 1 foetus died after maternal death at 16 weeks. the 8 remaining patients delivered normal babies. conclusions: neurosurgical disease requiring icu admission during pregnancy is rare; our data suggest an incidence of 1 case per 2 million population. maternal outcomes were mixed with more than half having a mrs>2 on discharge. foetal outcomes were good with only one miscarriage and good neurological outcome in all surviving infants. stepwise multivariable analyses that included interaction between time of day and arrest location were performed in a stepwise manner. results: prehospital als (adjusted or, 1.63; 95%ci, 1.38-1.93) but not good-quality of bystander-performed ccs (1.02, 0.84-1.26) was associated with sustained return of circulation (rosc). neither provison of good-quality ccs nor prehospital als was a major factor associated with on-month survival. however, good-quality of bystanderperformed ccs (2.44, 1.81-5.00) in addition to shockable rhythm (13.3; 8.70-20.4) and bystander-witnessed ohca (4.79; 2.98-8.00) were associated with higher chances of neurologically favourable one-year survival, whereas prehospital als (0.21; 0.10-0.39) and elderly ohca (0.47; 0.31-0.73) were associated with lower chances of the survival (fig. 1) . the impact of good quality ccs on survival were preserved in bystander-witnessed ohcas with shockable initial rhythm. noncentral region (adjusted or for good-quality, 0.46; 95%ci, 0.39-0.54), lack of bls training experience (0.47; 0.36-0.62), elderly-only rescuers (0.53; 0.44-0.65), cc initiation following dispatcher-assisted cardiopulmonary resuscitation (0.71; 0.55-0.91), and female-only rescuer (0.77; 0.65-0.90) were associated with poor-quality ccs. cc quality in athome ohcas remained low throughout the day, whereas that in outof-home ohcas decreased during night-time. conclusions: provision of good-quality ccs before ems arrival but not prehospital als was essential for neurologically favourable survival. new protocol for start of chest compressions before definitive cardiac arrest improved survival from out-of-hospital cardiac arrest witnessed by emergency medical service introduction: healthcare providers including emergency medical service (ems) personnel usually confirm absence of carotid pulse before starting chest compressions. at the end of 2011, ishikawa medical control council implemented new criteria for start of chest compressions encouraging ems to start chest compressions when carotid pulse was week and/or <50/min in comatose adult patient with respiratory arrest or agonal breathing. methods: data were prospectively collected for out-of-hospital cardiac and respiratory arrests during the period of 2008-2015. definitive cardiac arrest was recorded when loss of carotid pulse was confirmed by pulse checks performed every 2 min after the early start of chest compressions. the effect of early chest compressions on the proportions of definitive cardiac arrest was analysed in 243 cases with respiratory arrest and circulatory depression in initial patient evaluation. before/after comparison of neurologically favourable 1-y survival was performed in 619 cases with ems-witnessed ohca. results: the early start of chest compressions did not significantly prevent definitive cardiac arrest that followed respiratory arrest with circulatory depression in the initial patient evaluation (fig. 1) . time interval between start of chest compressions and definitive cardiac arrest confirmation (median; iqr) was 2; 1.5-3 min. the survival rate of all ems-witnessed ohcas after the implementation of new criteria was significantly higher than that before the implementation: adjusted or; 95% ci, 1.86; 1.02-3.40 (fig. 2) . no complications related to early chest compressions were reported during the study period. conclusions: start of chest compressions before definitive cardiac arrest improved survival from out-of-hospital cardiac arrest witnessed by emergency medical service. healthcare providers including ems personnel should be encouraged to provide chest compressions on cases with respiratory arrest and severe cardiovascular depression. introduction: our study sought to determine if there is a difference in time to tracheal intubation between direct and video laryngoscopy during cardiac compressions. guidelines suggest no more than 5 seconds should be taken to perform intubation to minimise any delay in compressions [1, 2] . it is unclear if use of video laryngoscopes results in faster intubation times during cardiac arrest. methods: observational trial involving emergency, anaesthesia and intensive care doctors. participants' baseline data obtained by questionnaire. resusci-anne™ manikin with airway trainer™ head [laerdal] with grade 1 airway was utilised. participants intubated the manikin 3 times, once with each of: macintosh size 3 blade, c-mac video laryngoscope (karl storz, germany) with size 3 blade and portable mcgrath mac enhanced video laryngoscope (medtronic, usa) with size 3 blade. order of laryngoscopes was randomised by computer generated sequence. continuous cardiac compressions were performed throughout attempts. results: total 54 participants. there was a statistically significant difference in time to intubation between the 3 devices using friedman test (p<0.01). wilcox signed-rank test demonstrated time to intubation with videolaryngoscopy was longer, c-mac (p=0.032) and mcgrath (p=0.011) compared with direct laryngoscopy. there was no significant difference between the two videolaryngoscopes (p = 0.401). when controlled for participants level of seniority and previous experience with device, direct laryngoscopy was still significantly faster than c-mac (p = 0.009) and mcgrath (p = 0.017) conclusions: our study showed a disadvantage of video laryngoscopy during cardiac compressions. faster intubation times with direct laryngoscopy could result in less pause in compressions and decrease periods without perfusion. direct laryngoscopy is an appropriate first choice for tracheal intubation during cardiac arrest. introduction: the aim of this study was to describe the coronary angiographic findings in relation to specific ecg changes and comorbidity in survivors after cardiac arrest. methods: a retrospective cohort study of out-of-hospital cardiac arrest patients with data retrieved between 2008-2013 from national registries in sweden. unconscious patients with coronary angiography performed within 28 days after return of spontaneous circulation and available ecg were included (fig. 1) . results: after exclusion, 1133 patients were analyzed (fig. 1) , (table 1) . 249 (22%) were women and mean age were 64 years. patients without st-elevation were separated into groups with specified ecg changes and comorbidities. differences were observed in the incidence of any significant stenosis, total occlusion and pci performed, between the specified ecg changes, as well as between the comorbidity groups ( introduction: fewer women after return of spontaneous circulation from out-of-hospital cardiac arrest (ohca) are undergoing coronary angiography (cag) with possible percutaneous coronary intervention (pci). the aim was to investigate gender differences in comorbidity, cag findings and outcome after ohca in comatose patients with a shockable first ecg rhythm. methods: a retrospective cohort study of out-of-hospital cardiac arrest patients with data retrieved between 2008-2013 from national registries in sweden (fig. 1) . results: there was no difference in age or comorbidity except for men having more ischemic heart disease, 21.5 vs 15.0% (p=0.006). rates of previous myocardial infarction did not differ, 8.2 vs 6.3%. no difference was seen in rates of ecg indicating prompt cag according to guidelines. still, more men underwent cag but no difference in numbers of cag leading to pci was seen (table 1) . furthermore, in patients with st elevation or lbbb, no gender difference in cag and subsequent pci was found. men had lower rates of normal cag findings but more triple vessel and left main coronary artery disease ( table 2) . 1 year survival did not differ, 49.1 vs 45.0%. conclusions: our study suggests, that despite no gender differences in rate of ecg findings indicating a prompt cag, men seems to have a more severe coronary artery disease while women have more frequently normal angiograms. however, this did not influence 1 year survival. introduction: the circadian clock influences a number of cardiovascular physiological processes. a time-of-day variation in infarct size has recently been shown in patients with st segment elevation myocardial infarction. however, there is no clinical evidence of circadian variation in patients with out-of-hospital cardiac arrest (ohca) of cardiac etiology. methods: we performed retrospective analysis using data from japan's nationwide ohca registry from january 2005 through december 2012, which includes all ohca patients presented with ventricular fibrillation as first documented rhythm, and consequently confirmed cardiac etiology. in order to eliminate the night and weekend effects, we enrolled only patients suffered ohca in the morning we conduct a retrospective cohort study focusing on the association between ohca outcome and icu bed availability. the ohca data was acquired from a regional emergency operation center, and the icu bed information was obtained from a regional sur it exceeds physiological levels in order to avoid insufficient oxygenation [1] . hyperoxia has been associated with increased in-hospital mortality, though uncertainty remains about this association. multiwave pulse co-oximetry has safely been studied intraoperatively as a guide to monitor hyper-and hypoxia by calculating an oxygen reserve index (ori) which could add information to pulse oximetry measures when spo2 is >98% [2] . methods: this is a monocentric prospective study including 12 patients with successful resuscitation following ohca. the aim of our study is to evaluate the feasibility and assess the availability of novel non invasive oxygen and hemodynamic variables. collected data principally concern blood oxygen and circulation such as ori, spo2, total hb, perfusion index and pulse rates. recording is ideally started at time of rosc. results: we monitored 12 consecutive patients for a total time of 456.8 min during transport from ohca place to the er. spo2 signal was present for 82.3% of transport time.oxygen reserve index signal was present for 58.5% of the total transport time. pleth variability index (pvi) signal was present 59.8% of the total transport time. sphb signal was present 44.7% of total time from rosc to hospital. the confidence interval for each variable is given in fig. 1 . conclusions: our pilot study shows that noninvasive measurements of hyperoxia, fluid responsiveness and hemoglobin are readily available from the prehospital phase of post-rosc care allowing for early tailored and goal directed interventions. increase in sofa score was associated with 170€ (95% ci 150-180€) increase in the cost per day alive in the first 12 months after ca. the sofa score is a good indicator of disease severity but the overlap between outcome groups does not allow its use for early prognostication in ca patients. the association of sofa and its sub-scores with 12-month outcome and healthcare costs highlights that in addition to neurologic damage the full spectrum of multiple organ failure affects the survival and morbidity of ca patients. public opinion on cardiopulmonary resuscitation decision and outcome in out-of-hospital cardiac arrest patientsquestionnaire study ty li 1 introduction: metabolomics is a novel approach that can characterize small molecules (metabolites) and has the potential to explore genotype-phenotype and genotype-environment interactions, delivering an accurate snapshot of the subject's metabolic status. in this context, the aim of metabolomics is to improve early diagnosis, classification, and prediction over the development of a pathological condition. to this end, metabolomics have not been used in the characterisation of cardiac arrest (ca), cardiopulmonary resuscitation (cpr) and return of spontaneous resuscitation (rosc). the aim of the present study was to explore whether metabolomics can characterize the ca versus rosc in a swine model of ventricular fibrillation (vf). methods: ten animals were intubated and instrumented and vf was induced with the use of a cadmium battery. vf was left untreated for 6min and the animals were then resuscitated according to the 2010 guidelines. defibrillation was attempted in all animals. venous blood was drown at baseline, 2 min, 4 min, 6 min during untreated ca and finally at 2min, 30min, 2h, 6h after rosc in order to determine the metabolomic profile during ca and during the early post-resuscitation period. rosc was defined as the presence of an organized cardiac rhythm with a mean arterial pressure of at least 50 mmhg for >5 min. blood was centrifuged and serum was analysed by high resolution 1h-nmr spectroscopy. nmr spectral data were submitted to multivariate discriminant analysis. results: eight animals survived the experiment and were included in the analysis. metabolites upregulated in the immediate rosc versus ca were succinate, hypoxanthine, choline and lactate. metabolites upregulated in the 2 hour rosc versus ca were ornithine and alanine. the 3 measured phases are shown in fig. 1 introduction: early outcome prognostication in successfully resuscitated out-of-hospital cardiac arrest (ohca) patients remains challenging. prediction models supporting the early decision to continue with full supportive treatment could be of major interest following ohca. we constructed prognostic models able to predict good neurologic outcome within 48 hours after icu admission. methods: upon icu admission, targeted temperature management at 33°c, hemodynamic and neuromonitoring (cerebral oxygen saturation measured with near-infrared spectroscopy and bispectral index (bis)) was initiated. prediction models for good neurologic outcome at 180 days post-ca were constructed at hour 1, 12, 24 and 48 after admission using variables easily collectable and known to be predictive for outcome. after multiple imputation, variables were selected using the elastic-net method. each imputed dataset was divided into training and validation sets (80% and 20% of patients, respectively). cut-off probabilities yielding a sensitivity above 90% were determined and performance of all logistic regression models was assessed using misclassification rates. introduction: in many venues, ems crews limit on-scene care for pediatric out-hospital cardiac arrest (pohca), attempting treatment during transport. hypothesizing that neuro-intact survival can be improved by prioritizing on-site care, strategies were effected to expedite on-scene drug delivery and intubation (with controlled ventilation). methods: from 1/1/2012 to 4/30/2017, data for pohca cases were collected. in 2014, new training prioritized on-site resuscitation (phase i) using expedited drug delivery and intubation with controlled ventilation (~6 breaths/min). training included psychological and skills-enhancing tools to boost confidence in providing on-scene care. in 2016, drugs were prepared while responding (phase ii). 2010 american heart association guidelines were used throughout and no other modifications were made. neuro-intact survival in 2012-13 was compared to phase i & ii outcomes. results: over the 5.33-years, ems faced 143 consecutive pohca cases. the great majority presented in asystole throughout. in those resuscitated, mean time from on-scene arrival to the 1st epinephrine infusion fell from 16.5 min (2012-13) to 7.3 min (phase i) and 5.0 min (phase ii). by 2017, it was 2 min. for resuscitated patients and 3.33 min. for all patients. intubation and intraosseous insertion occurred more frequently in phase i/ii, but there were no significant differences in age, sex, etiology, response times, bystander cpr or drug sequencing. neuro-intact survival improved significantly from 0/38 in 2012-13 to 23.2% (13/56) in phase i and 34.7% (17/49) in phase ii (p < 0.0001; 2-tailed fisher's exact test) (fig. 1) . conclusions: although historically-controlled, the sudden appearance of neuro-intact survivors following a renewed focus on rapid on-site care was profound, immediate and sustained. beyond skillsenhancing strategies, physiologically-driven techniques and supportive encouragement from leadership, pre-arrival psychological and clinical tools were also likely contributors to the observed outcomes. fig. 1 (abstract p429) . effecting neurologically-intact survival for children with out-of-hospital cardiac arrest p430 improved outcomes with a bundled resuscitation technique to enhance venous return out of the brain and into the heart during cardiopulmonary resuscitation pe pepe 1 , ka scheppke 2 , pm antevy 2 , d millstone 2 , c coyle 2 , c prusansky 2 , s garay 2 , jc moore introduction: lowering intracranial pressure to improve brain perfusion during cpr has become a focus for our team. combined with devices that enhance venous return out of the brain and into the thorax during cpr, outcomes have improved using head/chest elevation in the laboratory (fig. 1) . this study's purpose was to confirm the safety/clinical feasibility of this new approach involving mechanical cpr at an angle. methods: 2,285 consecutive out-of-hospital cardiac arrest (oohca) cases (all rhythms) were studied for 3.5 years (1/1/14 to 30/6/17) in an expansive, socio-economically-diverse u.s. county (pop. 1.4 mill). in 2014, ems crews used the lucas© and impedance threshold (itd) devices on such patients, but, after april 2015, they also: 1) applied o2 and deferred +-pressure ventilation several min; 2) raised the backboard~20°; and 3) solidified a pit-crew approach to expedite lucas© placement. neuro-intact survival was not recorded until 2015, so resuscitation by ems to hospital admission was used for consistency. quarterly reports were run to identify any periodic variations or incremental effects during protocol transition (quarter 2, 2015). results: no problems were observed with head/torso-up positioning (n=1,319), but rates of resuscitation rose steadily during the transition period with an ensuing sustained doubling (fig. 2 ) over the ensuing 2 years when compared to those studied (n=806) prior to the head-up approach (mean 35.2%; range 30-40% vs. 17.9%, range 15-20%; p < 0.0001). outcomes improved across subgroups. response intervals, indications for attempting cpr and bystander cpr rates were unchanged. resuscitation rates in 2015-17 remained proportional to neuro-intact survival. conclusions: the head/torso-up cpr bundle was not only feasible, but also associated with an immediate, steady rise in resuscitation rates during the transition phase with a sustained doubling of resuscitation rates, making a compelling case that this bundled technique may improve oohca outcomes in future clinical trials. introduction: cardiac arrest (ca) often requires intensive care unit (icu) treatment, which is costly. while there are plenty of data regarding post-ca outcomes, knowledge of cardiac arrest associated healthcare costs is virtually non-existent. methods: we performed a single-center registry-based study to determine expenditure data for icu-treated ca patients between 2005 and 2013. healthcare cost evaluation included costs from the initial hospital treatment, rehabilitation costs and social security costs up to one year post-ca. we calculated mean healthcare costs for one year survivors and for hospital survivors who died within the first year after cardiac arrest. we calculated effective costs per independent survivor (ecpis) as an indicator of cost-effectiveness. we adjusted all costs according to consumer price index (cpi) in finland as of 2013. all costs are presented as 2013 euros (€). results: we identified 1,314 ca patients eligible for the analyses. at one year after ca 52% of the patients were alive and 40% were alive and independent in daily activities. one year survival stratified by cardiac arrest location group was 59% for out-ofhospital ca patients, 47% for in-hospital ca patients and 27% for in-icu ca patients. for the whole study population, mean healthcare costs were 50,211€ per patient. healthcare costs for hospital survivors were 67,928€ per patient and for hospital non-survivors 22,100€ per patient. healthcare costs for those who survived to hospital discharge but died within the first year were 56,490€ per patient, while for one year survivors they were 70,148€ per patient. healthcare costs stratified by ca location are presented in fig. 1 . mean ecpis were 65,684€. conclusions: for icu-treated cardiac arrest patients, the mean ecpis were close to 65,000€. the best prognosis and the lowest costs were observed for out-of-hospital ca patients. introduction: in lithuania the incidence of out-of-hospital cardiac arrest (ohca) is unknown, as there is no official coding for ohca as a cause of death in the national death registry. kaunas emergency medical service (ems) underwent major stepwise changes since 2011, including implementation of medical priority dispatch system and dispatcher-assisted cpr instructions. we sought to describe the epidemiology and outcomes from ohca in kaunas, the second largest lithuanian city. methods: the incidence, demographics and outcomes of patients who were treated for an ohca between 1st january 2016 and 31st december 2016 in kaunas ems, serving a population of almost 0.3 million, were collected and are reported in accordance with 2014 utstein recommendations. results: in total, 313 ohca cases of ems treated cardiac arrests were reported (105 per 100.000 of resident population). the mean age was 67.7 (sd=15.7) years and 64.9% were male. 70% ohca cases occurred at home and 52.7% were witnessed by either ems or a bystander. in non-ems witnessed cases, 43.8% received bystander cpr, whilst public access defibrillation was not used. medical dispatcher identified ohca in 71.3% of all cases and provided over-the-phone cpr instructions in 60.2% of them. average ems response time (90% fractile) was 13 min. cardiac aetiology was the leading cause of cardiac arrest (84.3%). the initial rhythm was shockable (vf or pvt) in 26% and non-shockable (asystole or emd) in 70.5% of all cases. return of spontaneous circulation (rosc) at hospital transfer was evident in 24.9% and survival to hospital discharge was 8.6%. conclusions: rosc and survival to hospital discharge in kaunas were similar to those reported in united kingdom in 2014 [1] . routine ohca data collection and analysis will allow us to track the efficiency of service improvements and should become a standard practice in all lithuanian regions. outcomes of patients admitted to intensive care following cardiac arrest j mcloughlin, e landymore, p morgan east surrey hospital, surrey, uk critical care 2018, 22(suppl 1):p433 introduction: patients who have return of spontaneous circulation following a cardiac arrest are haemodynamically unstable and require critical care input. outcomes are often poor, with unadjusted survival to hospital discharge at 18.4%, following an in hospital cardiac arrest [1] . the aim of the study was to assess the survival of patients admitted to intensive care following a cardiac arrest, reviewing whether age and gender impacted on their outcome. methods: the inarc database for a general intensive care unit (icu) at a district general hospital was reviewed. since 1993, 519 patients were admitted following a cardiac arrest (both in and out of hospital). their age, gender and survival to icu discharge and overall hospital discharge were recorded. results: 210 female patients and 309 male patients of varying ages were admitted to our icu following a cardiac arrest. the mortality for both genders increased with increasing age. overall survival to the time of icu discharge following a cardiac arrest was similar for both females (44.3%) and males (48.5%). figures 1 (female) and 2 (male) below show the number of patients who survived or died on icu discharge, by age and gender. mortality rates increased when reviewing hospital outcome, as some patients died following discharge to the ward. conclusions: overall mortality in our icu following a cardiac arrest at any age is at least 50%, with the general trend appearing to rise with increasing age. more male patients were admitted to icu following a cardiac arrest than female, with similar survival rates for both male and female patients. more research could be undertaken to assess whether survival rates following a cardiac arrest have improved since 1993 and also to compare outcomes following either an in or out of hospital arrest. introduction: raw simplified eeg tracings obtained by a bispectral index (bis) device significantly correlate with standard eeg [1] . this study aimed to investigate whether simplified bis eeg tracings can predict poor neurologic outcome after cardiac arrest (ca). methods: bilateral bis monitoring (bis vistatm, aspect medical systems, inc. norwood, usa) was started following icu admission. six, 12, 18, 24, 36 and 48hrs after targeted temperature management (ttm) at 33°c was started, raw simplified bis eeg tracings were extracted and reviewed by two neurophysiologists for the presence of burst suppression, cerebral inactivity and epileptic activity. at 180 days post-ca, neurologic outcome was determined using the cpc scale, where a cpc1-2 and cpc3-5 corresponded to good and poor neurologic outcome, respectively. results: of the 75 enrolled ca-patients enrolled, 40 had good and 35 poor neurologic outcome. with a positive predictive value (ppv) of 1.000 and a negative predictive value (npv) of 0.606, epileptic activity within 6-12hrs predicted a cpc3-5 with the highest accuracy. epileptic activity within time frames 18-24hrs and 36-48hrs showed a ppv for poor outcome of 0.917 and 0.938, respectively. cerebral inactivity within 6-12hrs had a poor predictive power (ppv=0.545, npv=0.566). in contrast, cerebral inactivity between 36-48hrs predicted a cpc3-5 with a ppv of 1.000 and a npv of 0.597. the pattern with the worst predictive power at any time point was burst suppression with a ppv of 0.363, 0.529 and 0.500 at 6-12hrs, at 18-24hrs and at 36-48hrs, respectively. conclusions: based on simplified eeg derived from a bis device, both the presence of epileptic activity at any time as well as cerebral inactivity after the end of ttm can be used to assist with poor outcome prognostication in successfully resuscitated ca patients. the helicopter as first response tool -rio de janeiro fire department experience. (interquartile range=28) min, followed by tih with 552 flights (34%) and median time of 65 (iqr=70) min, and 270 (17%) were neo missions with median time of 120 (iqr=92) min. total time of aircraft usage was higher for tih (39%), followed by neo (32%). evam was the most frequent mission, however it accounted for 29% of aircraft utilization time, where most victims had traumatic brain injury (tbi) followed by other traumatic injuries (216 and 187 cases respectively). tbi victims were predominantly males (83%) with a median age of 30(iqr=23) years. most commonly, tbi is a consequence of transportation accident (75%), where a motorcycle was involved in 31%, car collision in 24% and pedestrian run over 24% of the cases. conclusions: goa utilizes the air ambulance helicopter as a first response tool in 49% of total missions, where respect for the trauma golden hour is paramount. traumatic brain injury is the most prevalent diagnosis at the scene of event. therefore, goa training and equipment must be tailored to meet this demand, which translates in stabilization of critical patients outside hospital environment with limited resources. introduction: the intra-hospital transport of critical patients is associated with adverse events and worse outcomes. the objective of this study was to evaluate the safety profile of intrahospital transport after the creation of a specific group for this purpose. methods: evaluated all the transports of critical patients from october 2016 to september 2017, in a large hospital, after the creation of a group consisting of intensive care physician, nurse and physiotherapist. clinical and non-clinical complications related to the transport and outcome of the patients were evaluated. results: a total of 1,559 transports were performed, 54.7% of the male patients and 60.9% of the patients being hospitalized. 10.6% were under mechanical ventilation and 19.8% under vasoactive drugs. at the time of transport, 78.8% were clinically stable. during transport, 7.5% presented clinical complications, being more frequent hemodynamic instability (43 patients) and respiratory failure (21 patients). non-clinical complications occurred in 125 patients (8.0%), and communication failures were responsible for 79.2% of the occurrences. in 29 cases (1.9%) there was worsening of the clinical conditions during transportation, and in only one case this worsening resulted in an increase in the length of stay in the icu and in the hospital, with no correlation with deaths. conclusions: the implantation of a group specialized in critical patients to carry out in-hospital transport made the process safer with complications rates lower than literature and guarantee better quality of care. clinical profile of patients admitted to icu due to acute poisoning mp benitez moreno 1 , e curiel balsera 1 , mc martínez gonzález 1 , s jimenez jimenez 2 1intensive care unit, hospital regional universitario carlos haya, malaga, spain; 2 hospital regional universitario carlos haya, málaga, spain critical care 2018, 22(suppl 1):p438 introduction: patients suffering from acute intoxication, whether voluntarily for autolytic or accidental purposes, often require life support in intensive care units. methods: retrospective observational study of all patients admitted for acute intoxication who required admission to the icu of the regional hospital of malaga between january 2012 and august 2016, older than 14 years with admission to the icu for intoxication of any kind. we study patient characteristics in terms of age, sex and medical history, type of toxicity, severity and evolution in our unit. results: we found 70 cases of patients who required admission to the icu due to acute intoxication, of which 55.6% were women. the average age was 47.36 (standard deviation 18.22). the average stay in icu was 5.04 (standard deviation 8.09). 54.2% of patients had a psychiatric history. as other background highlights, 19.4% were addicted to illegal drugs and 25% were hypertensive. most patients took more than one toxic 83.3% and intoxication was voluntary in 84.7% versus accidental in 12. 5% of cases. the toxic was known in 68%. the most used benzodiazepines in 26.4% of the total. the main cause of admission to the icu was due to neurological deterioration in 49 of the cases registered and mechanical ventilation was necessary in 44 patients. the maximum time in mechanical ventilation was 34 days. the infection occurred in 24.3%, with the majority being respiratory infection. the 4.7% died in icu. the hospital stay presented an average of 9.3 days. conclusions: the profile of a patient admitted to the icu due to acute intoxication is that of a woman of middle age and psychiatric history, with voluntary intoxication of several toxic substances and requiring mechanical ventilation for a low level of consciousness for an average of 3 days. the survival is very high and it would be necessary to analyze the possible relapses of these patients. mushroom that break hearts: a case report e karakoc, k demirtas, s ekemen, a ayyildiz, b yelken eskisehir osmangazi university, eskisehir, turkey critical care 2018, 22(suppl 1):p438a introduction: because of the high mortality and morbidity mushroom poisoning is a significiant medical emergency [1] . amanita phalloides (a. phalloides) is responsible for the 20% of the mortality in adults caused by mushroom poisoning. it causes damage in liver, kidneys and rarely pancreas, causing encephalopathic coma, disseminated intravascular coagulation, hemorrhage, hypovolemic shock and death but its effect on cardiac functions has not been established yet. there are three main groups of toxins;phallotoxins, virotoxins and amatoxins;amatoxin is the common responsible toxin from the fatality. we aimed to present a 44-year-old woman poisoned by mushroom complicated with hepatic,renal and cardiac toxicity methods: patient with nausea and vomiting started 48 hours after mushroom eating,creatine kinase mb 2.73 ng/ml and cardiac troponin i 0.02 ng/ml her blood urea nitrogen, creatinine levels and liver enzymes were higher than upper limits in lab tests (table 1) ; she was admitted to icu, treated for acute renal failure by hemodialysis.plasmapheresis was applied against potent mushroom toxins. at 5.day in icu, hypoxemia and severe swelling resistant to ultrafiltration was evaluated as a global left ventricular hypokinesia with ejection fraction(ef) 20%, end-diastolic diameter of 5.9 cm, and systolic pulmonary artery pressure (spap) of 40 mmhg. oxygen was administrated to treatment.urine output improved at 6.day, three more plasmapheresis sessions were performed. hypoxemia was recovered,liver enzymes and creatinin levels decreased results: at control ef measured was 44%, end-diastolic diameter of 4.9 cm, spap of 25 mmhg.than at the 15.day patient discharged from the icu.after a year follow up assessment she has no complaints conclusions: one of the major problems for amanita poisoning is diagnosis. patients who had mushroom poisoning should also be evaluated especially in terms of cardiac dysfunction with clinic signs, ecg, cardiac enzyme tests and eco introduction: the characterization of clinical and/or biological variables found in the emergency room predictive of a secondary admission in icu would help to improve the identification of patients at risk of aggravation in order to avoid the associated consequences, such as, an increased mortality and increased hospital stay. methods: this is a retrospective monocentric study of 3 years with patients admitted secondarily to a medical icu within 48 hours of admission to the general wards from the emergency department in the pitié-salpêtrière hospital in paris. each case was matched to 2 controls. 62 different variables were collected in the emergency room. results: 319 patients, of whom 107 were cases and 212 controls were studied. pneumonia is the diagnosis the most frequent in cases followed by sepsis (in 23 and 16%, respectively). 6 conclusions: the risk of being admitted secondarily to intensive care is higher if patients consult for dyspnea or fever, if they are old smokers, if they have a high igs2 score, if an arterial blood gas is requested and if an icu medical advice is taken. the meds score under 7 and being an active smoker seems to be protects for the unexpected transfer. introduction: managing the special needs of patients who present with agitation or psychosis can pose a greater challenge to an already busy emergency department as their symptoms can escalate rapidly. traditional antipsychotics used in the ed, such as haloperidol or ziprasidone often do not fully relieve patient's symptoms and may require administration of repeat doses or additional medications such as benzodiazepines to achieve effective results. this can induce excess sedation which can lead to longer length of stay in the ed and requires additional time at the bedside by the ed physicians and staff to manage these patients. adasuve® is an antipsychotic drug that works in a single-use device providing an aerosol form of loxapine that is rapidly absorbed by the lungs which may offer faster symptom relief, allowing subsequent earlier psychiatric evaluation and disposition. methods: to test this hypothesis, data including time of physician assignment and time physician documented discharge disposition and number of hours physician was assigned to the patients was retrospectively collected from 407 patients who arrived to the emergency department presenting with agitation or psychosis that received adasuve or other types of antipsychotic medication such as ziprasidone, haloperidol and benzodiazepines or a combination of the three. results: we found that physicians who administered adasuve spent an average of 8.30 hours assigned to their patient compared to 11.42 hours when the physician administered any other type of antipsychotic medication. this resulted in a significant 3.12-hour difference (p < 0.002) between the two groups. conclusions: in conclusion, less time spent assigned to a patient that received adasuve can be attributed to faster symptom relief which allowed the physicians to complete their psychological evaluations and develop dispositions more rapidly than with patients that received other antipsychotic agents. clinical work in language-discordant emergency department introduction: emergency residents are particularly vulnerable to sleep deprivation due to persistent conflicts between work schedule and the biological clock. recent approaches to address fatiguerelated risk mainly focused on reducing work hours and ensuring sufficient recuperation time. such approach has demonstrated its limits due to growing emergency rooms visits and emergency residents' shortage. dawson & mcculloch (2005) introduced the notion of proofing as a complementary approach to manage fatigue-related risk [1] . fatigue proofing strategies (fps) aim to reduce the likelihood a fatigued operator will make an error, in contrast of reduction strategies (frs) aiming to reduce the likelihood a fatigued operator is working. most formal risk control systems do not encompass the notion of proofing and fps typically develop as informal practices. in this study, we aim to 1) identify informal reduction and proofing strategies used by residents and 2) to investigate how they relate to fatigue-related risk indicators. methods: first, we organized 4 focus-group with a total of 25 residents in order to identify informal strategies used to manage fatigue-related risk. second, we designed a questionnaire assessing the frequency of use of each reported strategy. introduction: this randomized controlled study assessed the impact of a 3-hour intravenous medication safety simulation-based learning (sbl) on self-efficacy, stress, knowledge and skills of nursing students. medication administration error is a worldwide concern [1], that has been linked with a lack of knowledge and skills in safe medication administration among new graduate and student nurses [2] [3] [4] . preventing medication errors could therefore involve training through simulation. methods: participants (n=99) were randomly assigned either to the control group (cg, n=50) or the experimental group (eg, n=49). while cg and eg both had a traditional clinical internship, eg beneficiated in addition the 3-hour sbl, using standardized patients in the context of an intensive care unit. the two groups were assessed twice: at t0 and t1 (four weeks later), through an objective structured clinical examination (osce) and questionnaires. two blinded experts rated the students osce with an evaluation grid. results: mean participants age was 21,2. there were no statistically differences between groups at t0. compared to the cg (0%), the eg increased its self-efficacy (+19.35%) with a significantly difference (p<0.001) at t1. the sbl conducted to a greater increase of knowledge and skills in the eg (respectively +150%, +128%) than in the cg (respectively +46% and +47%), with a statistically significant difference (p<0.0001). conclusions: results reinforce the interest of a short sbl using standardized patients to improve medication administration. clinical impact of these observations requires further evaluation to determine potential transfer in clinical settings and retention over time. introduction: medication errors occur frequently in the intensive care unit (icu) and during care transitions. medication reconciliation by a pharmacist could be useful to prevent such errors. therefore, the aim of this study was to determine the effect of medication reconciliation at the icu. methods: a prospective 8-month intervention study with a pre-and post-phase was performed in haga teaching hospital (2013) and erasmus university medical center (2014). the intervention consisted of medication reconciliation by pharmacists at icu admission and discharge. the severity of potential harm of the medication transfer errors (mte) (pade=0; 0.01; 0.1; 0.4; 0.6) was scored. primary outcome measures were the proportions of patients with >= 1 mte at icu admission and icu discharge. secondary outcome measures were the proportions of patients with a pade score >= 0.01, the severity of the pades and a cost-benefit analysis. odds ratio and 95% confidence intervals were calculated. results: table 1 shows patient characteristics. figure 1 shows the primary outcome measures (oradj admission =0.18 [95% ci 0.11-0.30] and oradj discharge = 0.24 [95% ci 0.15-0.37]). the proportion of patients with a pade >=0.01 at icu admission reduced from 34.8% to 8.0% and after icu discharge from 69.5% to 36.2%. the pade reduction resulted in a potential net cost benefit of € 103 per patient. conclusions: medication reconciliation by pharmacists at icu transfers is an effective safety intervention, leading to a significant decrease in the number of errors and a cost effective reduction of potential adverse drug events. introduction: in intensive care unit, administration of numerous drugs in icu patients via a central venous catheter provide a high risk of drugs incompatibilities. it has been reported in experimental studies [1] that particles issued of drug incompatibilities could induce thrombogenesis, microcirculation impairment and inflammatory response which could aggravate the occurrence of organ dysfunctions [2] . the objective of this study was to evaluate the occurrence of particles by reproducing in vitro the intravenous system and the drugs combination used in icu for patients suffering either septic shock or acute respiratory distress syndrome (ards). methods: first, we registered during a period of 6 months the most common central venous catheter system used in patients admitted for septic shock or ards in three university hospital in lille. the second part of the study was to reproduce in vitro the previous infusion system in order to quantify the amount of particles generated during a simulated period of 8 hours infusion. the egress of the iv line was connected to a dynamic particle counter qicpic analyser (sympatec inc ; clausthal zellerfeld, germany) (fig. 1) . results: the most common intravenous system observed was a three lumen central catheter. the proximal lumen was dedicated for vasoactive agents, the medial lumen for sedation and the distal lumen for the other drugs infused continuously and discontinuously..among the drugs infused via the distal lumen of the central venous catheter, introduction: insufficient identification of possible organ donors in the icu is one of the main factors contributing to the loss of donors after brain death [1] . up to 50% of potential donors might not be identified [2] . the aim of this study was to evaluate how active search of possible brain dead donors affect the potential deceased donor pool. methods: the strategy implemented at university hospital with 5 specialized icus from december 2016 to october 2017 and data compared to the matching period of the previous year. donor coordinator visited all icus every day and selected patients who met possible brain dead donor criteria: 1) gcs <= 5; 2) severe brain injury. all data registered in original color coded follow-up system according to the patient status. results: a total of 237 patients were identified as possible donors. there was no significant difference of potential donor numbers in study period comparing to previous year (32 vs 31). main causes of brain death remain intracranial hemorrhage and subarachnoid hemorrhage. the length of hospital stay of potential donors was significantly longer in study period comparing to previous year (4±4.86 vs 2.29±2.2, p=0.004). there was no significant difference of donor's demographic data, conversion rates to actual donor or frequency of family refusals and medical contraindications. conclusions: active search of brain dead donors neither increased total number of potential donors nor increased conversion rates and did not change a donor profile in our donor center. longer observational period and more sophisticated follow-up system might be required. a fast hug bid a day keeps the patient ok! e sousa, t leonor, r pinho centro hospitalar de entre douro e vouga, santa maria da feira, portugal critical care 2018, 22(suppl 1):p461 introduction: regardless the underlying diagnose, providing meticulous supportive care is essential to critically ill patients management. in 2005, vincent jl introduced the fast hug (feeding, analgesia, sedation, thromboembolic prophylaxis, head of bed elevation, ulcer prevention, glucose control) mnemonic for recalling what he considered the key issues to review in daily clinical practice. our intensive care unit (icu) decided to add bid (bowel regimen; indwelling catheter removal; de-escalation of antibiotics) indicators following some published data. since 2013, the adequate use of this mnemonic became an instrument for quality of care evaluation. objectives for each variable were designed; regular annual audits done. the present study aims to audit the use of this mnemonic in a portuguese tertiary hospital icu, in 2017. methods: a prospective observational study was performed. admissions in icu staying at least one 00h00min and 23h59min period, during the first six months of 2017 were included. all mnemonic variables were recovered from icu medical record database, as well as demographics, severity scores and clinical information. data was analyzed with microsoft office excel software. results: we included 119 admissions. the predictable global fast hug bid assessment was 1086 entries [one per each full day (00h00-23h59) in the unit, per patient]. the mnemonic was used in about 65% of the opportunities. the target thresholds were considered as achieved in 95% of entries (concordance equal or superior to 80%). looking to individual variables, the best performance was achieved in h and u; worse performance was seen in s. the daily use of this mnemonic aims to revisit important intervention sectors in critical patient. applying the "plan-do-check-act" policy, this study allowed us to identify growth opportunities, reviewing or creating protocols, adopting more frequent training measures and seeking to take this model to other hospital areas. impact of incidents and adverse events in intensive care unit and its characteristics on outcomes e siqueira, l taniguchi, j vieira junior hospital sírio libanês, sao paulo, brazil critical care 2018, 22(suppl 1):p462 introduction: critically ill patients are usually exposed to adverse events (ae) due to acuity and complexity of care. ae might potentially result in disability or death, and increase in length of stay. our aim was to assess the incidents and ae in a general intensive care unit (icu). methods: this is a prospective cohort study conducted in a private tertiary hospital (hospital sírio-libanês) in são paulo, brazil. all consecutive patients who were admitted to the icu and all incidents and ae reported in the study period were evaluated. univariate and multivariate analysis were used to identify risk factors associated with hospital mortality. results: between may to november 2016 we studied 890 patients and 533 reported incidents and ae. overall, 267 patients (30%) experienced some incident or ae during icu stay. we found higher severity of illness (saps3 of 48 versus 44; p<0.001), mechanical ventilation (mv), use of vascular lines, drains and catheters, physical restraints, delirium and also an increased length of icu (4 vs 2 days; p<0.001) and hospital stay (20 vs 11 days; p<0.001) and hospital mortality (24% vs 11%; p<0.001) among patients who experienced any incident or ae. independent risk factors for hospital mortality in our logistic model were: higher saps3, mv and at least one adverse event during the icu stay. mortality was higher among patients who experienced late ae (>48 hours after icu admission) compared to patients who experienced early ae (37% vs 19%; p<0.003). saps3, sofa and mv were predictors of moderate and/or severe ae and a negative correlation between these events and icu occupancy rate was found. conclusions: patients who experienced incident or adverse event during icu stay had poorer outcome. ae, mainly moderate or severe, mv and severity of illness were independent risk factors to mortality. there was a negative correlation between moderate or severe adverse event and icu occupancy rate. monte carlo modelling of patient flow can aid complex intensive care bed and workforce capacity planning. introduction: models for icu populations based on the queuing model use arrival rate, length of stay, and bed number [1, 2] . these models lack the complexity of specialised icus with different admission types, and patient subpopulations. results: >98% of patients reported satisfaction on all areas except noise, patient facilities for hand hygiene and being informed about timing of operations. staff survey results revealed confusion regarding the interventions that are provided. baseline capacity for new patients was 53%, bed occupancy varied between 1 and 12 per day (overflow to recovery) with overall capacity at 93.5% and mean length of stay (los) was 1.3 days (sd=0.7, n=481, =range 1-5). following intervention, the los was reduced to 1.18 days (sd=0.4, n=112, range 1-3). new patient capacity was increased to 62% with a bed occupancy range 1-8. introduction: in clinical practice, when harm or potential harm occurs to patients, this can adversely impact upon the morale of staff involved and thereby affect clinical care delivered to subsequent patients. the personal narratives behind clinical incidents contain learning opportunities and individuals involved may reflect on the course of events and make changes to their practice to avoid recurrence. the aim of this study was to evaluate whether sessions enabling trainees to discuss their mistakes in a confidential environment improved trainee morale and safe clinical practice in an anaesthetic trainee cohort. methods: we conducted a survey amongst anaesthetic trainees in a london teaching hospital before and after a monthly, hour long, confidential, semi-structured, trainee lead "confession session" was introduced. results: initial results demonstrated that 68% of respondents (n=30) had made a mistake resulting in patient harm with 84% of these individuals describing negative feelings about themselves as a consequence. additionally, 97% of respondents had made a mistake causing a near miss, with 96% of these describing negative feelings as a result. of note, only 55% of respondents felt comfortable discussing errors with more senior colleagues, whilst 78% felt comfortable discussing errors with their peers. a follow-up survey identified that 100% of respondents (n=13) agreed that the session had the potential to improve clinical practice and trainee morale with 77% agreeing that their own clinical practice had improved from attending the sessions. conclusions: clinical mistakes leading to harm and "near misses" are common and provide opportunities to improve care. this trainee lead "confession session" appears to improve trainee morale and may improve patient care by encouraging trainees to engage in a process that seeks to understand error through sharing stories in a non-judgmental setting. funnel plots for quality control of the swiss icu -minimal data set introduction: a clinical database should be representative of the labelled population and guarantee completeness and accuracy of collected data. without explicit permission of the patients, swiss laws regarding data protection do not allow external audits based on periodic checks of random samples, supposed to give a general pattern of accuracy. to test alternative methods for quality control we introduced the principles of statistical process control to derive funnel plots from the swiss icu -minimal data set (mdsi). the mdsi from all certified adult swiss icus (2014 and 2015) was subjected to quality assessment (completeness and accuracy). for the analysis of accuracy, a list of logical rules and cross-checks was developed as e.g. range of saps ii according to age. errors were classified in coding errors (e.g. nems score > 56 points) or implausible data (nems without basic monitoring). we also checked for icus producing significantly more errors -outliers -(> mean ± 3 standard deviations [sd] or > 99.8% confidence interval [ci] of an adapted version of the funnel plots, which allows the presence of trends depending of the icu's size. results: a total of 164'415 patient mdsi (31 items/patient; 32 items for trauma patients) from the 77 certified icus.were investigated. we detected 15'572 patients (9.5%) with an overall sum of 3121 coding errors and 31'265 implausible situations. implausible situations related to supposedly inaccurate definitions (diagnostic and patient's provenance prior to icu admission) and discrepancies in the logical rules between diagnostics and treatments. figure 1 is an example for imprecise coding of the diagnostic: 11 icus declared having treated 14-61% of their patients without a defined diagnosis. conclusions: accuracy of data in mdsi needs further improvement. funnel plots may be useful for meaningful interpretation of data quality and permit to identify icus disproportionately generating inaccurate and/or implausible data. introduction: lung cancer is the leading cause of intensive care unit (icu) admission in patients with the advanced solid tumors. this study was aimed to elucidate the clinical factors associated with icu mortality of advanced lung cancer patients and the effect of intensivist's contribution on their clinical outcomes. methods: we included patients with advanced lung cancer including non-small cell lung cancer (nsclc) with stage iiib or iv and small cell lung cancer (sclc) with extensive stage who admitted to icu from 2005 to 2016. multivariate logistic regression analysis was performed to find the variables associated with icu mortality and in-hospital mortality. we applied autoregressive integrated moving average (arima) for time-series analysis of the intenvention of intensivists. results: among total 264 patients with advanced lung cancer, 85 patients (32.2%) were admitted icu before introduction of organized intensive care at 2011, and 179 (67.8%) were admitted after 2011 (fig. 1) . the leading cause of admission was the respiratory failure (77.7%) and cancer-related event (34.5%) in terms of intensivist's and oncologist's perspective. before and after 2011, the 30-day icu mortality rate was 43.5% and 40.2% (p = 0.610), and the hospital mortality rate changed from 82.4% to 65.9% (p = 0.006) (fig. 2) introduction: decisions when to refer and to admit patients to the intensive care unit (icu) care are very challenging. demand typically exceeds supply in icu beds, which results in a constant need for evaluation of the processes involved in icu referral and admission with a view to optimising resource allocation and patient outcomes. the aim of this study was to evaluate the theoretical impact of a newly designed triage tool for icu referrals on a cohort of patients referred to icu (fig. 1) . methods: we reviewed all patients consecutively referred to our icu, whether admitted or not, in february 2017. demographics, referring speciality, role of the referrer, comorbidities, the presence of advanced disease or terminal illness, the presence of acute organ failure, dnr status, reason for not admitting, and icu mortality were recorded. a retrospective analysis of icu referrals using a pilot triage tool was carried out independently by three authors. results: forty-six patients were referred to our icu over the study period. of these, 34 (74%) were admitted. patients were declined icu if their admission was deemed unnecessary (50%), futile (33%), or were transferred due to bed shortage (16%). of the patients referred, 25 (54%) had an advanced disease or a terminal illness. of those, 18 (72%) were admitted, dnr status was unclear in 22 (88%), family was involved in 12 (48%) and their icu mortality was 48%. by analysing retrospectively these referrals with the aid of a triage tool, we propose that the overall referrals could have decreased from 46 to 30 (42% percentage difference). dnr status and family involvement would have been clarified in all patients with advanced disease or terminal illness before icu referral. kappa score for inter-rater agreement was 0.78. conclusions: adopting a triage tool for icu referrals could reduce the overall proportion of inappropriate referrals and admissions. end-of-life discussion would also be proactively clarified prior to icu admission. introduction: intensive care unit (icu) admission triage occurs frequently worldwide and often involves decisions with high subjectivity, possibly leading to potentially inappropriate icu admissions. in this study, we evaluated the effect of implementing a decision-aid tool for icu triage on icu admission decisions. methods: urgent icu referrals before (may, 2014 to november, 2014, phase 1) and after (november, 2014 to may, 2015, phase 2) the implementation of a decision-aid tool were prospectively evaluated. our primary outcome was the proportion of potentially inappropriate icu referrals (defined as priority 4b or 5 patients, as described by the 1999 or 2016 society of critical care medicine [sccm] guidelines) that were admitted to the icu in 48 hours following referral. we conducted multivariate analyses to adjust for potential confounders, and evaluated the interaction between phase and triage priorities to assess for differential effects in each priority strata. results: of 2374 urgent icu referrals, 110 (5%), 161 (7%), 284 (13%), 726 (33%) and 928 (42%) were categorized as priorities 4b, 4a, 3, 2 and 1 (sccm 1999) or 110 (4.6%), 115 (4.8%), 887 (37%), 169 (7%) and 928 (39%) were categorized as priorities 5, 4, 3, 2 and 1 (sccm 2016), respectively. overall, 1184 (54%) patients were admitted to the icu in 48 hours following referral. the implementation of the decision-aid tool was associated with a reduction of admission of potentially inappropriate icu referrals [adjor (95% ci) = 0.36 (0.13-0.97), p = 0.043] (fig. 1) . there was no difference on hospital mortality for the overall cohort between phase 1 and phase 2. conclusions: the implementation of a decision-aid tool for icu triage was associated with a reduction of potentially inappropriate icu admissions. introduction: the aim was analyze the icu bed rotation pattern, the epidemiological characteristics of patients and to correlate them with prognostic score after software implementation methods: this is an epidemiological and retrospective study. data were collected between june 2016 and november 2017, using epimed® monitor software, applied in an adult icu of a public hospital in bahia/brazil. authorization for collection and use of data was granted by the institution. all patients hospitalized in the period were included regardless of other exclusion criteria. results: during the period evaluated, there were 1.011 new hospitalizations, 649 men (64.19%) and 362 women (35.81%). 46.38% (469) were in the age group of 18 to 44 years, followed by 28.28% of the patients (286), who were between 45 and 64. the mean duration of hospitalization in our unit was approximately 8,45 days. during the period covered, 1.009 exits occurred: 701 patients (69.47%) were introduction: early debriefing after stressful events holds great value in reflection on both an individual and team-based level. our objective was to implement routine structured debriefing sessions for doctors working in intensive care in order to optimise learning and develop strategies to improve practice. methods: 100% of junior doctors (n=10, pre-implementation questionnaire) on the intensive care unit expressed a need for regular debriefing sessions to discuss challenging and complex cases. weekly sessions were implemented and structured using the sharp performance tool [1] . key learning points were collected and added to a debrief list to track progress and assimilate learning. informal feedback was obtained on a weekly basis with formal feedback assessed following one month of implementation. results: 30min sessions occurred on a weekly basis supported by a consultant intensivist. desired outcomes included assessment of team performance, identification of key learning points and psychological support. following one month, 100% doctors involved felt that debriefing sessions were important and should continue. 75% felt that they left every session with a key learning point applicable to future clinical practice. common themes in perceived benefits included improved team communication and creation of an open environment to address concerns. conclusions: working in intensive care exposes doctors to challenging and stressful situations. implementation of a regular structured debrief session provides an opportunity for clinicians to address concerns, consolidate learning and develop strategies to improve clinical practice. nurse staffing patterns, outcomes and efficiency in resource use in the context of icus with a "low-intensity" nurse staffing: a multicenter study in brazilian icus m soares 1 introduction: studies investigating nurse staffing and outcomes were often conducted in high-income countries with low bed/nurse ratios. our objective was to investigate the association between nurse staffing patterns, outcomes and resource use in brazilian icus. methods: retrospective cohort study in 129,680 (68% medical) patients admitted to 93 medical-surgical icus during 2014-15. we retrieved patients' data from an icu registry (epimed monitor system) and surveyed participating icus about characteristics related to icu organization. we used multilevel logistic regression analysis to identify factors associated with hospital mortality. we evaluated efficiency in resource use using standardized mortality rates (smr) and resource use (sru) based on saps 3. results: saps 3 score was 44 (34-54) points and hospital mortality was 18.2%. intensivists were present 24/7 in 83% icus. median bed/ nurse ratio was 5.8 (4.2-7.3) and at least the chief nurse was boardcertified in critical care (bccc) in 47% icus. bed/nurse technicians ratio was 1.9 (1.8-2.1). adjusting for relevant characteristics at patientlevel (age, admission type, sofa, performance status, comorbidities, hospital days before icu) and icu-level (hospital type, checklist use, 24/7 intensivist, protocols), bed/nurse ratio was not associated with mortality [or=0.99 (95% ci, 0.95-1.03)]. however, mortality was lower in icus with at least the chief nurse bccc [or=0.78 (0.65-0.74)]. in multivariate analysis, bed/nurse ratios <=6 [or=3.53 (1.19-10.53)] and having the chief nurse bccc [or=6.36 (2.13-19.02)] were associated with higher efficiency. conclusions: in a "low intensity" nurse staffing scenario, bed/nurse ratios were not associated with mortality. however, having at least the nurse chief bccc was associated with higher survival. moreover, bed/nurse ratios <=6 and presence of chief nurse bccc were associated with higher efficiency in resource use. methods: a systematic search on the value of acute non-physician provider on the icu was conducted. the methodological quality of the included studies was rated using the newcastle ottawa scale (nos). the agreement between the reviewers was assessed with cohen's kappa. results: in total 145 studies were identified. twenty comparative cohort studies were identified which compared non-physicians with either residents or fellows. all studies comprised adult intensive care. most of the included studies were moderate to good quality. a random effects meta-analysis from all studies regarding length of stay and mortality showed no differences between non-physicians and physicians, although there was a trend to better survival when implementing acute non-physician providers in the icu (figs. 1 & 2) . mean difference for length of stay on the icu was 0.36 (95% ci -0.07 -0.79; i2=88%) and for in hospital -0.15 (95% ci = -0.90 -0.61; i2=83%); while the odds ratio for icu mortality was 0.94 (95% ci = 0.73 -1.20; i2=60%) and for hospital mortality 0.94 (95% ci 0.89 -1.00; i2=0). conclusions: the acute care non-physician provider in the icu seems a promising clinician on the icu with regard to quality and continuity of care. whether they also can reduce mortality remains to be determined by designing studies, which adequately measure the contribution of the non-physician providers in icu care overall and per task. their role in europe remains to be elucidated. burnout and depression in icu staff members n bahgat menoufia university hospital, shibin elkom, egypt critical care 2018, 22(suppl 1):p479 introduction: family and success in work are the most important sources of person satisfaction in life, chronic prolonged exposure to stressful high workload in intensive care units (icu), create a bad psychological state named burnout syndrome in which person is depressed, exhausted and thinks to leave job. in this study we made a survey on icus staff members in egypt menoufia university hospital to explore and find risk factors increase depression and burnout among nurses and doctor. methods: questionnaires were given to all intensive care staff for estimating the prevalence and associated risk factors of burnout using maslach burnout inventory (mbi) with its three subscales emotional exhaustion (ee), lack of accomplishment (la), and depersonalization (dp). depressive symptoms using the beck depression inventory scale. blood sample was taken for assessing depression biomarkers including il-6, tumor necrosis factor (tnf)-alpha, and coenzyme q10 (coq10), which appears to be one of the most reliable peripheral biomarkers. results: 100 participants were respond in our survey from 127 icu members the response rate was 78.7%, the depression symptoms found increased in nurses more than physicians in icu with more desire to leave the job. there was strong correlation between the degree of depression symptoms and decrease percent of personal accomplishment. impaired personal relationships at work and increased night shifts were major risk factors of burnout syndrome. levels of the proinflammatory cytokine (il6 and tnf alpha) were elevated in members who recorded sever degree of depression score with decrease in concentration of co-enzyme q10. conclusions: the health workers in icu had high liability for depression and burnout syndrome. the risk factors differ between nurses and doctors. il6, co-enzyme q10 and tnf alpha concentrations had god correlation with degree of severity of symptoms. impact of a tailored multicomponent program to reduce discomfort in the icu on post-traumatic stress disorder: a casecontrol study p kalfon 1 , m alessandrini 2 , m boucekine 2 , m geantot 3 , s renoult 4 , s deparis-dusautois 5 , o mimoz 6 , j amour 7 , e azoulay 8 , c martin 9 , t sharshar 10 , m garrouste-orgeas 11 , k baumstarck 2 , p auquier 2 introduction: reducing discomfort during the icu stay should be beneficial on long-term outcomes. the aim of this study was to assess the impact of the implementation of a tailored multicomponent program to reduce discomfort in the icu [1] on the occurrence of posttraumatic stress disorder (ptsd) 12 months after discharge from the icu. methods: design: case-control study; the cases were patients hospitalized in the icus which implemented the tailored multicomponent program; the controls were patients hospitalized in the icus which did not implement the program. exposition: the tailored multicomponent program consisted of assessment of icu-related self-perceived discomforts by using the iprea questionnaire, immediate and monthly feedback to healthcare teams, and tailored site-targeted measures under control of a duo of local champions. general procedure: eligible patients were recalled 12 months after the icu stay. data collection: sociodemographics, clinical data related to the icu stay, discomfort's levels assessed the day of discharge from the icu, life situation (home/care center), pstd (ies-r) and anxiety-depression symptoms (hads) 12 months after the icu discharge. results: from the 617 eligible cases and 847 eligible controls, 344 cases and 475 controls were included (reason for exclusion: deaths after discharge from the icu, lost to follow-up, patient refusal, cognitive incapacity). a total of 6.1% of the cases and 12.2% of the controls presented certain symptoms of ptsd at12 months (p=0.004). after adjustment for age, gender, iprea score, mccabe score, presence of invasive devices during the icu stay and considering anxietydepression symptoms at 12 months, cases are less likely to have ptsd symptoms than controls. conclusions: our tailored multicomponent program for discomfort reduction in the icu can reduce long-term outcomes as ptsd. diffusion of such a program should be enhanced in the icus paving the way for a new strategy in care management. introduction: cognitive dysfunction is a major factor leading to disability and poor quality of life in icu survivors. in order to identify patients at risk for developing cognitive dysfunction due to critical illness or icu treatment, one has to discriminate between patients with pre-existing cognitive dysfunction and those developing new cognitive dysfunction or worsening of cognitive function during icu treatment. we investigated the incidence of pre-existing cognitive dysfunction in icu patients using the informant questionnaire on cognitive decline in the elderly (iqcode) and its relation with delirium during icu treatment. methods: patients relatives were asked to fill in the iqcode on admission. an overall score on cognitive dysfunction was calculated by the average of the score on each item of the questionnaire. the incidence of delirium was based on the cam-icu score. statistical analysis was performed using the fisher's exact test. p-values of less then 0.05 were deemed significant. results: in total 452 consecutive patients admitted to our icu were analyzed, of whom 47.8% (n=216) showed decline in cognitive function prior to icu admission. cognitive function was divided in four groups; no change 52.2% (n=236), slight decline 34.1% (n=154), moderate decline 9.7% (n=44) and severe decline 4.0% (n=18) (fig. 1 ). incidence of delirium is shown in fig. 2 . patients with moderate to severe cognitive dysfunction showed significant more delirium during icu treatment than patients with no change in cognition (44.2% and 21.1% respectively, (p=0.023)). conclusions: almost half of the patients admitted to the icu have cognitive dysfunction prior to icu admission. to assess ones cognitive function after icu treatment one has to take in to account the patients pre-existing cognitive functioning. patients with a moderate to severe pre-existing cognitive dysfunction develop significantly more delirium during icu treatment. introduction: our aim was to identify and analyse patients treated for pocd admitted to a thoracics/urology intensive care unit at university college london, uk. pocd is rising in the ageing high-risk surgical patient. early identification of those at risk and timely intervention could help reduce associated morbidity and mortality [1] . methods: we identified patients treated with haloperidol, midazolam, lorazepam, olanzapine, clonidine or chlordiazepoxide from our electronic data system. these pharmacological interventions were used as surrogate markers of primarily hyperactive pocd, acknowledging other forms of delirium may be unaccounted for. 111 of 808 admissions (13.7%) were shortlisted from august 2016 to july 2017. patients were excluded if the drugs had been used for other indications. prevalence of known pocd risk factors were then detailed. on these data we performed a cluster analysis using r. results: of the 58 patients (7.17%) suitable for analysis, the mean age was 72. 41 patients underwent elective procedures. 39 were male and 19 were female. 75% patients had thoracic surgery. the mean pain score in the first 24 hours post-op was 1.6 (sd=1.1), (with 0= no pain, 4= very severe pain). 62% had evidence of poor sleep and 14% evidence of anxiety. in the 24 hours prior to evidence of pocd, the mean pain score remained 1.6 (sd=0.99), 76% had evidence of poor sleep and 22% had evidence of anxiety. 66% of our population was septic during their itu admission. conclusions: our analysis demonstrates pocd is highly prevalent in male patients over 70 undergoing thoracic procedures. we will now develop a pocd pathway targeting improved postoperative management of pain, sleep, anxiety and infection in this patient population. introduction: our objective was to determine the feasibility of employing family-administered tools to detect delirium in the critically ill. the use of family-administered delirium detection tools has not been assessed in the icu where patients are critically ill and frequently intubated. family members may be able to detect changes in patient cognition and behavior from pre-illness levels earlier than unfamiliar providers. these tools may be a valuable diagnostic adjunct in the icu. methods: consecutive patients and family members (dyads) in the largest adult icu in calgary, canada were recruited (aug. 9-sept. 11, 2017). inclusion criteria were: patients with a richmond agitation sedation scale (rass) >=-3; no primary brain injury and glasgow coma scale score of <9; ability to provide informed consent (patient/ surrogate); and remain in icu for 24 hours. data were collected for up to 5 days. family-administered delirium assessments were completed once daily (family confusion assessment method & sour seven). to assess feasibility, we assessed proportion of eligible patients and percent family member enrollment. barriers to enrollment were categorized. results: of 99 admitted patients with family, 37 (37%) met inclusion criteria and 17 (46%) dyads consented. 20% of admitted patients did not have family and were thus ineligible. 73% of enrolled dyads assessed delirium at least once, with a median of 5 (of 10 total) assessments. the most common reason for non-enrollment was refusal by the family, who commonly reported feeling overwhelmed by the icu environment. barriers with nursing staff were encountered, including not providing access to patients and patient exclusion. conclusions: these data suggest that employing family-administered delirium detection tools in the icu is feasible for a subset of the population. future studies will validate the use of these tools in the icu, decrease modifiable barriers to enrollment, and test strategies to overcome attitudinal barriers towards employing these tools. introduction: psychological impact of critical illness and icu stay on patients can be severe and frequently results in acute distress as well as psychological morbidity after discharge [1] . however, the stressful experience in icu and its influence on patient recovery, remain relatively understudied. we assessed patients in icu for acute distress and psychological symptoms with validated tools. methods: we conducted an observational study in a group of awake icu adult patients admitted in a tertiary centre for at least 48 hours, from january 2017 until october 2017, with mixed diagnosis on admission. we collected demographic factors, saps ii at admission, mechanical ventilation, day of sedation, history of psychopathological disorder. un-sedated and alert, critical care patients were assessed with tools such as intensive care delirium screening checklist (icdsc), hospital anxiety and depression scale (hads) and intensive care psychological assessment tool (ipat). results: 68 patients were recruited, (mean age 51.2±17.9 years, 66.2% males). saps ii at admission was 32.2±16.7, 60.3% was mechanically ventilated (mean duration 6.1±14), mean duration of sedation was 2.8±3.9 days and a rate of 22.05% had an history of psychopatological disorder. 10.3% of the sample had clinical delirium (icsdc>3) and was not assessed with others tools, 20.6% had subclinical delirium (icsdc <=3). regarding psychological outcomes, 26.2 % (mean score 6.1±2.5) reported a score (>=8) on hads that indicates a possible diagnosis of anxiety and 54.1% (mean score 7.9 ± 3.7) of depression. a rate of 24.6% reported a score >= 7 on ipat suggesting an acute distress. conclusions: the study's key finding was that acute psychological distress was high in awake icu patients. further work is needed to determine the efficacy of early psychological interventions to reduce the incidence of acute distress and psychological outcomes after icu stay. introduction: a high percentage of polytrauma patients require surgery within the first 24 hours to stabilize primary traumatic injuries. one of the main intraoperative complications in this type of patients is due to hemodynamic instability [1] . thus, it is necessary to implement multimodal monitoring involving both hemodynamic monitoring and monitoring of general anesthesia. the objectives of this study were to identify the possible implications of entropy monitoring on hemodynamic stability in critically ill polytrauma patients. methods: prospective observational study, deployed in the clinic of anesthesia and intensive care, emergency county hospital "pius brinzeu" timisoara, romania. clinicaltrials.gov identifier. there were two groups, group a (n = 37), in which the depth of hypnosis was monitored through entropy (ge healthcare, helsinki, finland) and group b (n = 35). results: the incidence of hypotension and tachycardia episodes was statistically significantly lower in group a, unlike the control group (p <0.05). moreover, a statistically significant (p <0.05) consumption of inhaled anesthetic agent was recorded in group a compared with group b. consumption of vasopressor was also lower in group a (p <0.0001, difference between means 0.960 ± 0.063, 95% confidence interval 0.8334 -1.0866) conclusions: deploying monitoring for the depth of hypnosis in general anesthesia using entropy can significantly increase the hemodynamic stability of critically ill polytrauma patients. introduction: the use of methadone as a potent analgesic has been gaining ground in the intensive care setting, such as where it is possible to properly select the group of patients who will benefit from the drug, as well as monitoring of possible complications. the objective of this study is to evaluate the safety of the use of methadone in critically ill patients in a large hospital. methods: a retrospective analysis of all patients who used methadone in a neurological intensive care unit for a period of four months and the results were evaluated. results: in the four-month period, 52 patients used methadone during intensive care. 65 % of the patients were male, with a medical age of 59.7 ± 17.4 years. the main indication for the use of the medication was for analgesia in patients who were weaned from mechanical ventilation. the mean time of use was 6.1 days. in all cases evaluated, analgesia was effective, with methadone being used alone or in combination with other drugs, according to an institutional protocol. among the complications found, 20 patients presented hypotension (38 %); 20 presented bradycardia (38 %); 15 presented constipation (29%); 4 had excessive sedation (8 %) and 7 had other complications. all complications were reversible. 10 patients of the studied population died, however, without correlation with the use of methadone. conclusions: the use of methadone, in the studied group, was effective in the control of analgesia, with no impact on patient safety when used in a monitored way. introduction: renal colic is a common disorder which presents with dramatic acute pain. providing rapid relief, using effective pain control medications is the clinical priority to treat the patients. this study aims to compare the effect of iv ketorolac versus morphine in releasing renal colic pain by measuring pain severity and duration and also the need for additional doses. methods: we performed a clinical pilot cohort study from during 2014 on patients with the clinical diagnosis of renal colic who recruited from the emergency department (ed) of rasool-e-akram hospital and firoozgar hospital. participants who were candidate to receive either morphine or ketorolac were divided into two groups who received either 30 mg ketorolac iv or 5 mg morphine. the pain was evaluated using the visual analog scale (vas) at four time points: before drug injection (vas-1), 20 minutes (vas-2), 40 minutes (vas-3), and 60 minutes (vas-4) after injection. in cases when the pain was not controlled with the first injection of drug beyond 60 minutes; additional doses (rescue) were injected. statistical analyses were performed using spss 21. results: one-hundred-fifty patients treated with morphine and 150 ones with ketorolac were studiedthe group treated with morphine scored on average 9.91 before the injection, which was roughly 2.4 points higher than ketorolac. morphine reduced patients' vas scores more intensely (median: 10, iqr: 0 versus median: 6, iqr: 1; p value<0.001). in general, patients treated with morphine were more likely to need a second (rescue) dose, when compared to ketorolac group (38.6% vs 20%, p value= 0.001). conclusions: morphine is a better option for pain release in cases of renal colic. ketorolac released the pain to an acceptable level; but, because of its slower action time, we recommend it in cases with moderate than severe pains. effect of analgesics on cardiovascular and hormonal response to operative trauma d loncar stojiljkovic, mp stojiljkovic sgh, 11000, serbia critical care 2018, 22(suppl 1):p493 introduction: objective of this study was to compare the effects of two analgesic regimens, one opioid and one non-opioid, on cardiovascular and hormonal reaction of patients undergoing elective surgery under general endotracheal anaesthesia. methods: a total of 40 elderly patients, asa 2, scheduled for elective abdominal surgery were assigned to receive on induction a single dose of either fentanyl (0.2 mg, +0.1mg) or a fix combination of etodolac and carbamazepine (novocomb, dose 100mg+100mg iv bolus). haemodynamic parameters and concentrations of prolactin cortisol and growth hormone (gh) [1] were determined at critical points and 24 h after operation. results: both fentanyl and novocomb blocked the hypertensivetachycardic response to surgical trauma. cortisol was a more appropriate endocrine marker of stress than prolactin or gh since fentanyl as an opioid analgesic increased secretion of prolactin [2] , while carbamazepine from novocomb did the same with gh [3] (figs. 1 & 2) . conclusions: cortisol plasma concentration correlates positively with cardiovascular parameters in patients undergoing elective abdominal surgery who received fentanyl or novocomb as intraoperative analgesic. its suppression is better marker of analgesia than prolactin and gh. volatile anaesthetic consumption and recovery times after long term inhalative sedation using the mirus system -an automated delivery system for isoflurane, sevoflurane and desflurane introduction: the new mirus system as well as the anaconda uses a reflector to conserve volatile anaesthetics (va) [1, 2] . both systems can be paired with icu ventilators, but mirus features an automated control of end-tidal va concentrations (etva). we compare feasibility and recovery times for inhalational long term sedation with isoflurane (iso), sevoflurane (sevo) or desflurane (des). methods: 30 asa ii-iv patients undergoing elective or emergency surgery under general anaesthesia were included. patients were randomized into three equal groups iso, sevo and des. the mirus system was started with a targeted etva of 0.5 mac. we used the puritan bennett 840 icu ventilator and performed a spontaneous breathing trial. if successful, the target concentration was set to 0 mac and recovery times measured. results: patients were comparable in demographics, tidal volume, respiratory rate and sedation time (total 696h: iso 19±9h; sevo 22 ±19h; des 29±29h; p=0.55). in all patients, a mac of 0.5 was reached. conclusions: mirus could automatically control end-tidal va concentrations in ventilated and spontaneously breathing patients. the recovery times are only prolonged in the iso group and could be shortened by removing the reflector. the higher etva required for a 0.5 mac using des and sevo were associated with an increased va consumption. introduction: intranasal analgesia is increasingly used in order to relieve pain in the emergency department. this non-invasive approach avoids discomfort, stress and risks related to the parenteral route of administration. the objective is to compare intranasal (in) fentanyl versus any parenteral opioid (intravenous, subcutaneous, intramuscular) for the effectiveness of acute pain relief in an adult population. methods: the systematic review was registered in prospero (crd42016052976). the research of articles was conducted through embase, central, and medline databases. randomized clinical trials comparing the effectiveness of in fentanyl to any parenteral opioid for acute pain relief (<= 7 days) in an adult population (>= 18 years old) were considered for inclusion. studies on breakthrough cancer pain were excluded. two different reviewers extracted data and analyzed the quality of the selected articles. the main outcome was the difference between pain levels before and after analgesia. the effect size was approximated using the inverse of variance of standardized mean differences, based on a random-effect model. heterogeneity was quantified using a test of i2. results are presented with 95% confidence interval. results: eight randomized clinical trials with 11 cohorts and a total of 613 patients were selected (320 in fentanyl vs 293 control group). selected articles contained a low risk of bias. there is no significant difference between the average levels of pain before and after analgesia comparing the two groups (smd 0.12 [ic 95% -0.04 à 0.28], p=0.14; i2 = 0%) (fig. 1) . conclusions: in fentanyl is as effective as other parenteral opioid to relieve pain during the first hour of treatment. introduction: the aim of this study is to underline the importance of sedation protocol when performing the pegj procedure in advanced parkinson's disease (pd) patients. research about the use of sedation in endoscopy is getting more and more widespread as to answer to the increasing grade of complexity and duration of endoscopic procedures as to offer comfort to the patient in terms of analgesia, tolerability, and amnesia. sedation is also a way to assure quality and safety examination and to improve its outcome [1] . methods: this observational retrospective study includes 40 pd patients scheduled for pegj procedure (fig. 1 ) in order to start therapy with duodopa gel. we propose an anesthetic technique (table 1) to support pegj with both local anesthesia and moderate sedation so as to provide analgesia and patient's comfort. this technique ensures mean duration of pegj procedure was 35'±5'. mean stay time in recovery room 12'±2'. compared to our old experience, we collected lack of patient's discomfort, anxiety, and memory, high procedure compliance and improvement of the quality of procedure without use of opioids. conclusions: based on our experience, we consider this sedation protocol effective for different reasons: to relieve or abolish patient's discomfort, anxiety, and memory, to ensure compliance with the procedure, to ensure patient's analgesia and patient's safety and, finally to assure procedure's quality and rapid discharge. anyways, a multicentric study should be done to test our protocol. introduction: studies have shown that icu survivors exhibit longterm neurocognitive impairment and perceived reduction in quality of life after icu discharge, but studies examining sleep architecture and sleep disordered breathing (sdb) in icu survivors after icu discharge are scanty. the aim of our study was to assess sleep architecture and sbd in icu survivors. methods: icu survivors were screened for eligibility. inclusion criteria were: age 18 -80 yrs, mechanical ventilation >= 48 hours, gcs of 15 at the time of hospital discharge. patients with a history of sbd, chronic neuromuscular disorders, chronic restrictive lung disease, congestive heart failure and respiratory failure at hospital discharge were excluded. patients were evaluated within one week after hospital discharge and 6 months later. at both visits patients completed health related quality of life questionnaires (sf36 and epworth sleepiness scale), underwent a physical examination, lung function tests including maximum inspiratory and expiratory mouth pressures, and an overnight full polysomnography (psg). results: sleep quality at 7 days of hospital discharge is poor, characterized by severe disruption of sleep architecture and excessive sdb, mainly of obstructive type which in 76% of patients was classified as moderate or severe. although at six months after hospital discharge sleep quality remained relatively poor, significant improvement in n3 stage and ahi was observed, with more patients to be classified as normal or mild sdb. both at hospital discharge and 6 months later quality of life was reduced but there was no relationship between the health related quality of life and sleep disturbances. conclusions: icu survivors experience significant deterioration in their quality of life status with minor improvement 6 months later and a variety of sleep disturbances that seems to start getting better 6 months later. introduction: disrupted sleep in critically ill patients may be associated with delirium, prolonged stay in icu and increased mortality. polysomnography (psg), the criterion standard method of sleep monitoring, is challenging in icu due to interpretation difficulties, as the patterns defined by the standard classification for scoring sleep are absent in many critically ill patients. the aim of this study was to investigate if the presence of atypical patterns in critically ill patients' psg is associated with poor outcome measured by 90-days mortality in conscious critically ill patients on mechanical ventilation. methods: 70 psgs (median duration 20 hours) recorded in conscious critically ill mechanically ventilated patients were scored by an expert in sleep medicine blinded to patient characteristics. standard sleep scoring classification was used if possible. otherwise, modified classification for scoring sleep in critically ill patients proposed by watson et al. was applied [1] . the association of sleep patterns (normal or atypical) and micro-sleep phenomena (sleep spindles and kcomplexes) with 90 days mortality was assessed using weibull model by calculation of hazard ratios (hr). results: hr analysis showed twice as high mortality risk in case of atypical sleep compared to normal sleep; this was however not significant (hr 2.5; 95% ci 0.95-4.44; p=0.08). the presence of sleep spindles in psg significantly reduced mortality risk to 1/3 (hr 0.33; 95% ci 0.13-0.86; p=0.02). the presence of k-complexes in psg reduced mortality risk to ½, though not significantly (hr 0.52; 95% ci 0.24-1.12; p=0.1). conclusions: the absence of normal sleep characteristics in psg in conscious critically ill patients on mechanical ventilation is associated with poor short-term outcome. antipsychotics (aps) prescribing in critically ill delirious patients, the reported versus the perceived practice e almehairi 1 , g davies 1 , d taylor introduction: aps are the most commonly prescribed drugs in hyperactive/mixed delirium and agitation in critical care (cc) [1] . yet evidence in cc is scant, there are known adverse effects (ade) and prescription is out with the european license. meticulous observation of ap selection, prescribing and safety, alongside delirium assessment/plan is essential to gain new knowledge and patients. when accompanied by prescribing clinicians perspective of delirium ap treatment results are more interpretable. we conducted a two-part single centre cohort study that aimed to describe/compare real to perceived delirium assessment/plan, aps prescribing and safety in cc adult patients at gstt. methods: part 1: a prospective survey, of cc prescribing clinician's beliefs and attitudes to delirium assessment/plan, aps prescribing and safety over previous 12 months. part 2: a meticulous audit of aps prescribing and safety and delirium/agitation assessment and plan, over period of 4 months. results: part 1 survey. 43 of 82 prescribers (53.6%) completed survey. 88% of reported using aps to treat delirium, with 83% selecting atypical aps as first option. part 2 audit. there were 2400 admissions to cc. aps were prescribed in 6.4% (188 prescription), 3.8% (113 prescription) were in delirium/agitation patients (table 1) . survey (vs.) audit: in the survey 67% reported daily delirium screening whereas only 12.3% undertook daily screening in audit (fig. 1) . higher quetiapine and lower iv haloperidol maximum daily dose were prescribed in audit in comparison with survey reported doses ( table 2) . 12 lead ecg was used to monitor ap ade. in survey 34% reported assessing ecg once or more daily. audit revealed only 19% actually did so (fig. 2) . conclusions: authors believe perceived vs actual can identify key areas for quality improvement (qi). major differences were in delirium assessment/plan and safety monitoring sedation practices in turkish icus, the aim was to provide knowledge on this matter. methods: an electronic survey form was generated with google forms. first part of the form included questions about demographics, and choices and routines of sedation administration. this part mostly contained multiple choice questions, which more than one choice could be indicated. second part was comprised of some statements to investigate the attitudes of physicians, which were indicated on a five-point likert scale. the link for the survey was posted to all email addresses registered in the turkish society of intensive care member database. results: of 1700 members, 429 (25%) completed the survey form. demographics are given in table 1 . sedation was generally applied by the physicians (96%). the indications were mechanical ventilation (94%), agitation (87%), seizures (77%), anxiety (61%), delirium (59%). drug choices of the respondents are shown in fig. 1 . sedation level was evaluated daily by 73% of respondents, mostly using ramsay scale (57%). daily established sedation level was indicated in 63.8%, and daily interruption of sedation was indicated in 71.4% answers. sedation protocol was not used in 62.7% of the answers. analgesics applied commonly, while 63% routinely evaluated pain and visual analogue scale (vas) was the preferred method in 69% of the answers. 77.2% of physicians indicated routine use of neuromuscular blockers. in 50.5% answers routine evaluation for delirium was indicated, mostly using cam-icu.when the knowledge of 2013 sccm guideline pain, agitation and delirium management, 38% indicated a positive answer.the respondents indicated their opinion for some comments on sedation, the answers are shown in the table 2 . conclusions: it may be concluded sedation practices may need to be improved by increasing awareness on novel concepts in this area. fig. 1 (abstract p504) . the prediction-corrected vpc plots for dexmedetomidine pk. the vpc plots show the simulation-based 95% confidence intervals around the 10th, 50th, and 90th percentiles of the pk data in the form of blue (50th) and gray (10th and 90th) areas. the corresponding percentiles from the prediction corrected observed data are plotted in black color methods: a prospective multinational cohort study was performed in 10 icus in sweden, denmark and the netherlands. all adult patients with an icu stay >= 12 hours were screened for inclusion. primary outcome was psychological problems three months after discharge from the icu, assessed with the questionnaires hospital anxiety and depression scale (hads) and post-traumatic stress symptoms checklist-14 (ptss-14). a subscale score >10 in the hads and a score >45 in the ptss-14 part b indicate clinically significant symptoms of depression, anxiety and pts and was considered an adverse outcome. we collected data on 21 known risk factors for psychological problems post-icu. univariable and multivariable logistic regression modelling of risk factors was performed in order to create an instrument to be used bedside, predicting individual risk for adverse psychological outcome. results: 573 patients were included and 404 (71%) returned follow-up questionnaires. 14% of patients scored above the predefined cut-offs having symptoms of depression, anxiety or pts. age, lack of social support, depressive symptoms and traumatic memories at discharge remained significant after multivariable modelling and constituted the screening instrument ( table 1) . the predictive value of the instrument was fairly good with an area under the receiver operating characteristics curve (auroc) of 75% (fig. 1) . we developed an instrument to be used at icu discharge, predicting individual patients' risk for psychological problems three months post-icu. the instrument can be used as a screening tool for icu follow-up and enable early rehabilitation. improving the patients hospitalization experience in an intensive care unit by contact with nature w yacov 1 , y polishuk 2 , a geal-dor 2 , g yosef-hay 2 1 kaplan medical center, rehovot, israel; 2 kaplan medical center, rehovot, israel critical care 2018, 22(suppl 1):p508 introduction: the intensive care unit is characterized by a noisy and threatening work environment using multi tecnologic equipment.the staff works very intensively caring for very complicated and unstable patients.whilst caring for the patients physical needs one must not forget the patients mentally needs.the improvement of the patients hospitalization experience by changing the environment improves the mood and responsiveness to treatment gives hope for healing to the patient and family. methods: a quality questionare with open questions relating to the subjective sensory experience of the patients and their families. the patients were transferred to the "sun balcony" for a period of 30-60 minutes having their families alongside. music was transmitted and the patients were offered food and drinks if their condition allowed. results: the patients reported a significant improvement of hospilizaton experience following their exposure to the "nature environment". patients described the sensory experience as a positive, pleasant, quiet and relaxing experience. the contact with the sun, wind, sky and grass and being outside on the "sun balcony" allows a disconnection from the threatening icu environment. conclusions: the "sun balcony" gave the patients a sense of hope and wish for healing. mobilizing complicated patients to the "sun balcony" is a big challenge which requires planning and preparation by the staff. yet by the proactive and creative thinking of the staff the patients are tranferred to the "sun balcony" to give them encouragement, a feeling of well being and hope for recovering. this intervention is costless and a routine procedure in the intensive care unit. introduction: long-term psychological outcomes of patients(pts) discharged from icu represent an emergent relevant matter of concern.systematic reviews refer prevalence of 23%-48% for anxiety,17%-43% for depression and 8%-35% for posttraumatic symptoms in ards patients.the onset of psychiatric symptoms after discharge, might be associated with patient's competence to process memories related with hospitalization and with memories. methods: we selected 35 ards pts in icu of a tertiary centre (jan 2014-dec 2016) at least 72 hour, for 6 months follow-up and 26 pts for 12 months follow-up after discharge. the psychopathological assessment was performed using scale as: impact event scale-revised (ies-r), hospital anxiety and depression scale (hads), icu memory tool (icu-mt). results: mean age was 53.11±14.32 at 6 months follow-up and 51,19±14,83 at 12 months. ptsd symptoms was fund respectively in 24% and 34.6% pts at 6 and 12 months; anxiety symptoms 24% and 23.1% of pts;depression symptoms in 24% and 30.8%. significant correlations were fund between psychopathology at 6 months and memories of icu: hads anxiety with delusion memories (r 0.45,p<0.01); hads depression with factual (r 0.46,p<0.05), feeling (r 0.49,p<0.01) and delusion memories (r= 0.59,p<0.01); feeling (r 0.45,p<0.05). at 12 months significant correlations was fund between hads anxiety and feeling memories (r 0.48,p<0.05); ies-r and factual (r 0.45,p<0.01), feeling (r 0.68,p<0.01) and delusion memories (r 0.64,p<0.01). the results of the study confirmed the importance of assessing psychopathology after discharge from icu. the onset of these symptoms appeared to be mediated by specific traumatic memories related with icu hospitalization. the main clinical recommendation emerging from this study is to investigate psychiatric history and develop psychological strategies to manage frightening or delusional experiences during icu stay. introduction: the aging of the population is a fact. the subgroup of very old (>= 80 years (ys)) is the one that increases the most rapidly. intensive care unit (icu) admission of these patients is an ongoing discussion worldwide. our icu has designed the voolcano aiming its characterization and reviewing outcomes, to find some predictive indicators. the purpose of this first analysis is to evaluate specifically the group of very old patients (volds) admitted to a tertiary portuguese hospital icu. methods: retrospective observational study was preformed, included all volds admitted in icu during 15 years (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) (2016) . demographic data, admission diagnosis, severity scores, charlson comorbidity index, length of stay and outcomes were considered. data analysis used spss software. results: we found a total of 460 admissions. the median age was 83.0 ys with iqr 4; mostly male with medical admission diagnosis (sepsis and respiratory failure due to infection). there was a median acute physiology and chronic health evaluation ii of 18 (iqr 8) and simplified acute physiology score ii of 49 (iqr 16). median charlson comorbidity index was 6.0 (iqr 2). median length of stay was 3.9 days (iqr 8.2). concerning outcomes, we found intra-icu mortality of 36%; intra-hospital after icu discharge mortality of 12% and mortality after hospital discharge of 41%. identified as predictors of intra-hospital mortality the use of mechanical ventilation (p < 0.001), urgent surgical admission or medical admission versus schedule surgical admission (p < 0.001) and the absence of oncologic disease (p = 0.024). on multivariate analysis, only mechanical ventilation (p = 0.002, hr 0.35, 95% c.i. 0.18-0.68) and urgent surgical admission versus schedule surgical admission (p = 0.002, hr 0.29, 95% c.i. 0.14-0.63) remain significant. conclusions: recognizing the need to understand what is the biologic|funcional age (opposed to chronologic age) would be beneficial in the selection of volds to icu admission. organ failure and return to work after intensive care s riddersholm 1 , s christensen 2 , k kragholm 1 , cf christiansen 2 , bs rasmussen 1 1 aalborg university hospital, aalborg, denmark; 2 aarhus univeristy hsopital, aarhus, denmark critical care 2018, 22(suppl 1):p515 introduction: organ failure is associated with an unfavorable prognosis. nevertheless, the association with capability to return to work remains unclear. therefore, we investigated the association between organ support therapy as a proxy for organ failure and return to work in a nationwide cohort of icu survivors. methods: we linked danish registry-data on icu-and hospitalsurvivors working prior to hospital admission during 2005-2014, 18-65 years of age, with an icu length of stay > 24 hours and not previously treated with dialysis, to data on return to work. we reported cumulative incidences (chance) of return to work with death as competing risk, and compared rate of return to work in adjusted cox regression-models by number of organ support therapies including renal replacement therapy, cardiovascular support and mechanical ventilation and stratified on primary hospital-admission diagnosis. results: of 24,795 patients 18-65 years of age, 35% (8,660) survived to hospital discharge (tables 1 and 2 ). among these, the chance of return to work was 72.2% (95% ci [71.3-73.2]) within two years (fig. 1 (fig. 2) . when stratified an increasing number of organ support was associated with a decreased chance of return to work among patients with infection, respiratory failure or trauma but not among patients with neoplasms or endocrine, gastrointestinal and cardiovascular diagnoses. introduction: mortality rates among people with moderate to severe learning disabilities (ld) are 3 times higher than in the general population [1] [2] [3] . this study was designed to examine critical care admissions with learning disabilities in terms of mortality, demographics and reason for admission. methods: data was retrieved for adult patients (>16 years old) between sept 1993 and 2016. the ward watcher database for icus within surrey and sussex healthcare nhs trust was interrogated using search words including, learning disability, cerebral palsy, down's syndrome and autism. results: there were 154 episodes (1.4% of all admissions) of patients admitted with ld. 10% of the ld patients had more than 1 admission. respiratory is the most common system affected (46%). logistic regression suggests survival is highest in those with a neurological reason for admission (p=0.007). proportionally ld patients were young compared to the total population (fig. 1) . we found that mortality appears to increase rapidly in those over 60 years of age and overall mortality is greater in those with ld (fig. 2) . conclusions: from april 2018 all uk trusts will be required to complete a detailed review for patients with ld who die whilst in hospital care. this follows mencap's report 'death by indifference' which exposed deficiencies in the care of 6 people with lds who died whilst in nhs care and the subsequent confidential inquiry into premature deaths of people with learning disabilities. in our population, ld patients have an earlier death than the general population and the overall mortality from critical illness is greater. a multidisciplinary approach at the emergency department to admit potential organ donors for introduction: the aim of the present study is to improve the recognition of potential organ donors by implementing a multidisciplinary approach for organ donation at the emergency department (ed) [1] . methods: in a prospective intervention study, we implemented this approach in six hospitals in the netherlands. when the decision to withdraw life sustaining treatment was made at the ed in patients with a devastating brain injury without contra indications for organ donation, an intensive care unit (icu) admission for end-of-life care was considered. every icu admission for end-of-life care was evaluated. interviews were conducted with emergency physicians, neurologists and icu physicians according to a standardized questionnaire. this interview focused on medical decisions that were made and difficulties arising during hospitalization. results: from 1 january 2016 to november 2017 data were collected on the number of patients admitted to the ed with acute brain injury. in total, 50 potential organ donors were admitted to the icu for end-of-life care. donation was either requested in the ed (12%), icu (78%), neurology department (4%), or donation was not requested (6%). out of 48 donation requests, 26 families (51%) consented to donation. this led to 21 successful organ transplantations. in four of these 21 patients family consent was obtained to intubate them solely for the purpose of organ donation. the most important points raised during the interviews were: explaining the non-therapeutic icu admission to the family, the location where donation should be requested (ed/icu) and utility of icu resources. conclusions: a close collaboration between the ed, neurology department and icu is necessary and achievable in order not to miss potential organ donors in patients with acute brain injury with a futile prognosis in the ed. introduction: there is a relationships between intensive care patients losing the ability to speak and negative emotions [1] . nursing care is challenging when patients are unable to verbalise and factors like pain and comfort are misjudged.. our intensive care unit has introduced a communication tool intelligaze grid 3 which enables patients with primary motoric disorders to communicate their needs. a quality improvement study reviewed the methods of communication and interactions that our nurses use for patients who are ventilated. the objective of the study was to promote areas of improvement with communication in the icu. methods: we used a mixed-methods qualitative and quantitative study to evaluate the communication tools used by our nursing staff to interact with ventilated patients. a convenient data sample for all nurses working on particular dates was collected which is 66% of the nursing workforce. the study has been approved as a quality assurance project by the human research ethics committee of nepean hospital. results: sixty registered nurses (66%) participated in the study. the most common communication tool used with patients was closed yes/no questions(27%), followed by hand gestures(21%), magnetic writing board(19.8%), lip reading(14.4%) and alphabet board(7.2%). the descriptive analysis identified challenges were levels of sedation, weakness, non-english speaking patients and delirium. a significant finding was that only 6% of nurses identified the patients message being understood and 5% acknowledged listening as effective communication. conclusions: communication is a vital aspect of icu nursing and is achieved through dialogue and specialised skills. the study concluded that icu nurses find it difficult to communicate effectively with ventilated patients. the introduction of intelligaze grid 3 has improved patient communication and promotes holistic nursing care. p525 withdrawn introduction: substantial variability in eolp occurs around the world [1] . differences in eolp were previously reported in europe in the ethicus i study [2] . methods: icus worldwide were invited to participate through their country societies. consecutive admitted icu patients who died or had treatments limitations during a 6 month period from 1.9.2015 to 30.9.16 were prospectively studied. regions included north, central and southern europe (ne, ce, se), north and latin america (na, la), asia (as), australia (au) and africa (af). previous eolp definitions were used [2] . results: 199 icus in 36 countries participated enrolling 12,857 patients. figure 1 shows differences in eolp by region and figure 2 in patient competency by region. conclusions: worldwide differences included more cpr in af, la, and se and less cpr in ne, au and na. there was more withdrawing (wd) in ne and au and less wd in la and af. more patients were competent in au and ne and less were competent in af, se and la. introduction: the decision of end-of-life care in the icu is very tough issue because the law, ethics, traditions and futility should be concerned involving family's will. especially, stop or withdraw therapy is a quite difficult operation in japan because of our traditions. recently there are few legal issues due to some guidelines. our hypothesis is some difference over time exists in thoughts about end-of-life care in the icu. the purpose of this study is to know changing methods: a questionnaire survey, which consists of 11 questions with 5 optional answers related to the thoughts of participants about end-of-life care of hopeless or brain death patients, was performed to nurses and doctors in our icu. the questions were; whether accept to withdraw therapy or not and with family's will, whether positive or not to donate of organs from brain death patient, necessary of icu care for brain death patient, feel guilty and stress for doing stop or withdraw therapy. the optional answer has 5 gradations from 'yes' to 'no' for all questions. it was guaranteed to be anonymous for them in the data analysis. we conducted entirely same survey in 2012. the answers between in 2012 and in 2017 were fig. 2 (abstract p528) . patient mental compentency by region kidney disease: improving global outcomes acute kidney injury working group references 1 nice clinical guidelines: idiopathic pulmonary fibrosis in adults: diagnosis and management references 1. zambon et al annual update in inten care references 1 references 1 references 1 damage control management in the polytrauma patient crash-2 trial collaborators guidelines for the management of severe traumatic brain injury references 1 references 1 references 1. soar et al; european guidelines for resuscitation we acquired the confirmed date of death from the finnish population register centre database and gross 12-month healthcare costs from the hospital billing records and the database of the finnish social insurance institution. results: a total of 5814 patients were included in the study and 2401 were alive at 12 months. median (interquartile range, iqr) 24-hour sofa score was 8 (6-10) in 12-month survivors and 10 (8-13) in non-survivors. the sofa score had an area under receiver operating characteristic curve of 0.68 (95% ci 0.66-0.69) for predicting 12-month mortality. in multivariate regression model with age and gender, sofa score had an odds ratio, or (95% confidence interval, ci) of 1.21 (1.19-1.23) for predicting 12-month mortality. all except cardiovascular sub-score also had p439 predictive factors for secondary icu admission within 48 hours after hospitalization in a medical wards from the emergency room m cancella de abreu 1 hôpital saint antoine p441 acquired neuromuscular weakness in eldery patients with femoral bone fracture, could we decrease the incidence? d pavelescu, i grintescu, l mirea emergency hospital floreasca p445 adasuve enables quicker dispositions of acute psychiatric patients in the emergency department k hesse 1 , e kulstad 2 , k netti 1 , d rochford 1 isi web of science and clinicaltrials.gov. data extraction: eligible studies were case reports and randomised controlled trials (rcts) that evaluated the effects of drug incompatibilities in critically-ill patients on morbidity or mortality as primary or secondary outcomes, or adverse events. two investigators independently reviewed the eligibility of the study from abstracts or manuscript data. data synthesis: twelve articles met the selection criteria (fig. 2). the six articles reporting rcts concern only four rcts. rcts were single-centre studies comparing infusion with or without filter. two of them included adult patients. the others included pediatric and neonatal intensive care unit patients. primary endpoints were systemic inflammatory response syndrome (sirs), organ failure, overall complication rate, bacteremia, sepsis, phlebitis and length of stay. results: the results are mixed with one rct reporting a reduction in sirs, organ failure and overall complication rate, two studies in disagreement over the occurrence of sepsis and one study reporting no impact on length of stay. the six articles on case reports show different drug incompatibility situations european directorate for the quality of medicines & healthcare of the council of europe. guide to the quality and safety of organs for transplantation p459 current status and problems of organ transplantation before and after the enactment of the revised organ transplant law in p465 morale: introducing the anaesthetic trainee confession session results: of total 1857 patients admitted during study period, 1356 were eligible for study; 53.9% were males and 383(28%) patients were transferred during after-hour. mean age of two groups (daytime vs. after-hour 65.7±15.2vs.66.3±16.2 years) was similar(p=0.7) methods: retrospective analysis of prospectively collected data between october2016 to february2017 of a tertiary care icu in india. patient data collected on all consecutive icu admissions. primary and secondary outcomes were icu los and hospital mortality respectively. icu patients payer status were categorized as self-paid, corporate (paid-fully or partially-by-employer), and insurance (paid-fully or partially-by-third-party-payer). all analyses were adjusted for illness severity and icu support (vasopressor use, mechanical or noninvasive ventilation, blood transfusion). results: of 580 patients admitted during study period significantly higher number of patients received icu support in self-paid and corporate groups compared to insured group (53.7%and 52.8% vs. 39.8%; p=0.02) braden scale is predictive of mortality in critically ill patients, independent of its efficiency as a predictive tool of pressure ulcer risk d becker 1 , tc tozo 2 discharged and 308 died (30.53%). the turnover rate of the icu was 59.35. the occupancy rate calculated during the period was 101.39%. there were only 5 readmissions (0.49%) within 24 hours of admission. regarding the hospital evolution of these patients we had 837 exits in this period, 429 (51.25%) were discharge and 408 (48.74%) were deaths, of these, 100 (11.95%) were after discharge from the icu. the mean saps score was 51.11 (ranging from 17 to 99). the probability of death, according to the standard equation was 24.60% and the adjusted for latin america of 32.10%. conclusions: the icu has a high occupancy rate and rotation turnover, as well as a higher mortality than predicted by the score. these indicators show the great population demand that we have and alert to the impact on the sustainability of the unit and patient safety methods: research/ethics approvals were obtained. surveys, interviews, round tables, targeted delphi exercises and non-participant observation were conducted across four adult critical care units, involving 860 professionals. these methods were used to describe the baseline 'paper-based' workflow/inter-professional communication systems; and semi-quantitative quality improvement measures. secondly, 10 critical care services worldwide were visited to generate a database of experience, lessons and models of optimised informatics delivery. results: key challenges at baseline in relation to workflow/communication information transfer between different healthcare professionals site visits revealed the importance of human resources; lead time technology advances; the prioritisation of nursing workflow and pharmacy medicines/prescribing database creation/testing and the importance of the hardware interface and ergonomics. improvements included patient safety/experience p475 work-related stress amongst doctors and nurses in intensive care, a&e, acute medicine, anaesthetics and surgery i lever 1 *, h nawimana 1 introduction: work-related stress is associated with anxiety, depression, days off-work, errors and 'near misses' [1]. our objective was to references 1. kerr et al p481 pre-existing cognitive dysfunction in critically ill patients and the incidence of delirium during icu treatment p483 validation of the sos-pd scale for assessment of pediatric delirium: a multicenter study e ista 1 , b van beusekom 1 children's hospital, rotterdam, netherlands; 2 umc groningen -beatrix children's hospital p483 introduction: delirium in critically ill children has gained attention in the last few years and the incidence seems higher than anticipated before. the sophia observation withdrawal symptoms-pediatric delirium (sos-pd) was developed to combine assessment of delirium with iatrogenic withdrawal syndrome, two conditions with overlapping symptoms. the current study evaluates the measurement properties of the pd component (pd-scale) of the sos-pd scale. methods: in a multicenter prospective observational study in four dutch picus, patients aged 3 months to 17 years and admitted for more than 48 hours were included. these patients were assessed with the pd-scale three times a day. criterion validity was established: if the pd total score was 4 or higher the child psychiatrist was consulted to confirm the diagnosis of pd using the diagnostic and statistical manual-iv criteria as the "gold standard". the child psychiatrist was blinded to outcomes of the pd-scale. in addition, the child psychiatrist assessed a randomly selected group of patients to establish false-negatives the pediatric delirium scale had an overall sensitivity of 92.2% and a specificity of 96.9% for a cut off score of 4 points. the positive predictive and the negative predictive value were respectively, 76.3% and 99.1%. the icc of 75 paired nurse-researcher observations was 0.99 (95% ci 0.98-0.99). in total 48 patients were diagnosed with delirium during the picu stay. conclusions: the pd scale shows a good validity for early screening of pd. so, the pd scale is a valid and reliable tool for nurses to assess delirium in critically ill children p489 frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically ill neonates, children and adults: a systematic review of clinical trials ma duceppe 1 , m perreault 1 we also examined the grey literature. we included studies reporting frequency, risk factors or symptomatology of iatrogenic withdrawal of opioids, benzodiazepines (or both) in critically ill patients. we considered all study designs except case reports and case series. pairs of reviewers independently abstracted data and evaluated methodological quality using the cochrane collaboration tool, newcastle-ottawa or quadas-2. pros-pero (registration number: crd42016042746). results: we identified 21210 unique citations through database search and 146 full-texts were assessed for eligibility. thirty-three studies were included; the majority were observational and only a few included adults proportion of perfused small vessels at to p491 use of methadone in critically ill patients p495 the use of intranasal fentanyl versus parenteral opioid for acute pain relief in adults: systematic review and meta-analysis p497 sleep disorders in icu survivors c alexopoulou, a proklou p503 impact of dexmedetomidine on the duration of invasive mechanical ventilation in pediatric intensive care patients -dexped trial m genest 1 peri-operative dexmedetomidine in high risk cardiac surgerymulticentre randomized double blind placebo controlled pilot trial y shehabi 1 we compared vasopressors, inotropes, pacing and cardiac complications for safety and severe acute kidney injury (aki), dialysis and death (major adverse kidney events make) for efficacy. methods: adults patients undergoing cardiac surgery [combined (valve + coronary bypass) or complex] or with preoperative glomerular filtration rate (egfr) < 60 mls/min/1.73m2 were included. salvage or transplant surgery, dialysis, egfr < 15 mls/min/1.73m2 and those on extracorporeal support were excluded. dex (0.7 ug/kg/hr) was started at induction of anaesthesia and continued up to 24 hours after surgery. equivalent volume of saline was given to control group. standard intra and post-operative care was provided. results: we randomized 44 patients in the dex group and 44 in the placebo (pgp). the mean(sd) age 70.1(11.3) and egfr 59.6(20.4) in all patients. no significant differences at baseline. in the dex, 38.7% underwent complex surgery vs 19.7% pts in the pgp. the mean(sd) bypass time and aortic clamp was comparable 140(62) and 106(49) min. the vasopressor requirements methods: nine tracheostomized copd patients ready to be weaned from ventilation were enrolled.for each patient, the sleep architecture was studied by polisomnography (sleep profiler-advanced brain monitoring) performing 3 recordings:basal registration, continuos infusion of propofol or dexmetomidine from 22 pm to 6 am. rass target was -1/-2. results: the mean dose was 0.8mg/kg/h for propofol and 0.7 mcg/ kg/h for dexmedetomidine.quantitative analysis showed, a statistically significant longer total sleep time (tst) and less sleep fragmentation (awakenings/hour) using dexmedetomidine. qualitative analysis showed non statistical differences between the two regimens: longer n1 and n3 stage with propofol and a longer n2 and rem phase with dexmetedomidine. furthermore, a reduced number of dosage adjustment was needed during dexmedetomidine sedation methods: a 1-year prospective observational cohort analysis was performed. all patients consecutively admitted to the medical or surgical icu or burn unit of a university hospital with an icu-los of >= 8 days were included. qol was assessed at baseline (bl) and at 3 months (m), 1 year (y) and lt (median 7.2 years (iqr 6.8-8.3)) after icu discharge with eq-5d and sf-36 surveys. at lt, questions about daily life were added. in subanalysis, we compared 2 groups (g1 and g2) based on median icu-los. results: 374 patients (66% men) with a median age of 59, an apa-che ii score of 22 and a sofa score of 7 at icu admission were included. 5 patients (1.3%) were lost to follow-up. median icu-los in the cohort, g1 and g2 was 16 (iqr 10-26), 10 (iqr 9-12) and 26 days (iqr 20-37) respectively. during icu stay, g2 had significantly more and longer need for any type of organ supportive therapy (p<0.001) and had higher maximum sofa scores (p<0.001). icu, hospital, 3m, 1y and lt-mortality rates in the cohort were 16, 26, 29, 39 and 62% respectively. these rates were similar in g1 and g2 and the outcomes were assessed by telephone interviews at 1 month after discharge. factors associated with readmission and post icu mortality are presented as odds ratios. results: during the study period, 102 elderly patients were discharged alive. the follow up was possible for 80 (78.43%) patients. predictors of one-month readmission in univariate analysis were coronary disease (p=0.027), sapsii (p=0.019) and decline in functional status (p=0.00). in multivariate analysis ) were the independent predictors of early readmission. mortality rate at 1 month was 22.5%. risk factors of onemonth mortality in univariate analysis were sapsii (p=0.002), heart rate at discharge (p=0.031), world health organization(who) performance status at discharge (p=0.000) and decline in functional status (p=0.000). in multivariate analysis p=0.005), decline in functional status (or, 7.7 ; 95%ci comorbidities don't have an important impact on short term outcome after critical illness, which is most strongly predicted by severity of illness and physiological reserve at discharge. p513 characteristics and outcome of elderly patients in intensive care unit i coelho health inequalities & people with learning disabilities in the uk: 2010 emerson & baines cipold 2013 p518 comparison of home and clinic follow-up visits after hospital discharge for post-icu patients: a cross-sectional study r rosa 1 , c robinson 1 , p berto 2 , p cardoso 2 , l biason 3 in a post-icu follow-up service which is reference for 4 tertiary hospitals in southern brazil. post-icu patients with a icu stay >72 h (for medical and emergency surgical icu admissions) or >120 h (for elective surgical icu admissions) who were discharged alive from the hospital were invited by telephone to participate in a clinic-based multidisciplinary appointment 4 months after icu discharge. home visits were offered to patients who claimed impossibility to attend the clinic appointment due to the severity of their disabilities graph of total mortality in ld vs all patients fig. 1 (abstract p517). graph of admission age in ld vs all patients references p523 evaluation of family satisfaction instrument in multicultural middle eastern critical care units a p524 breaking bad news in the emergency department: a randomized controlled study of a training using role-play simulation i bragard 1 , jc servotte 1 , i van cauwenberghe 2 p524 introduction: this is a randomized controlled study aiming to assess the impact of an e-learning and a 2-hour role-play training in breaking bad news (bbn) each assessment included a video-recorded role-play with two actors playing the role of relatives, and questionnaires. two blinded experts rated the videos. results: out of 80 participants, 80% were trainees and 20% were anaesthesia residents. eg (n=43) and cg (n=37) were not different at baseline on the several variables. there were significant group and time interaction effects. only eg increased their selfefficacy p526 deficits of end-of-life care (eolc) perceptions among physicians in intensive care units managed by anesthesiologists in germany m weiss 1 , a michalsen 2 , a toenjes 1 p528 ethicus end-of-life practices (eolp) in worldwide intensive care units (icus)-the ethicus ii study a avidan 1 p529 multidisciplinary team perceptions about terminal extubation in a teaching hospital in brazil s p530 changing thoughts about end-of life care in the icu; results of a survey the feel guilty for withdraw therapy in nurses was also significantly decreased in 5 years (10% vs. 30%, p<0.05). conclusions: some of end-of-life thoughts in the icu were shown differences in nurses compared with 5 years ago introduction: workload resulting from in-flight emergencies has not been quantitatively analysed in the literature. for hospitals local to major airports, this may have significant financial implications. methods: review was carried out of all cases admitted to east surrey hospital from gatwick airport over a 23 year period beginning in 1993. data were collected by interrogating the icnarc database. demographics, presenting pathology and length of stay for each patient were recorded. in addition, the cost of care for patients admitted during 2016 was calculated using recent median figures for intensive care admission (local ccg rates). results: since 1993, 196 patients were admitted from gatwick airport. this was approximately 2% of our critical care admissions. the mean (sd) age was 58.3 (14.5) years, and the median [iqr] length of stay 3 [1.1 -6.7] days. around 24% of these patients were non-uk or eu nationals and therefore not entitled to nhs care. reasons for admission included cardiac (37.2%), respiratory (23.6%), central nervous system (12.6%), and gastrointestinal issues (12%). during 2016, 11 patients were admitted resulting in a total of 48.4 patient days in critical care. the total cost attributable to this group of patients was calculated to be £60,500. conclusions: there is a substantial additional financial burden on hospitals that regularly receive admissions from major airports simply due to their geographical location. there is no additional funding available for providing this service. the pattern of presenting conditions in our population is similar to that seen in previous reports describing inflight emergencies [1]. given the increasing accessibility of air travel and the economic pressures on healthcare providers, further analysis of the financial impact of this patient group on certain hospitals would be welcome. methods: we developed a monte-carlo simulation [3] with separate referral rates for emergency, elective, and ventilated patients. bed occupancy is classified according to admission type with a conversion to prolonged ventilated stays at a rate of 4% [4]. we used data from our neurointensive care unit to complete the parameters required for the model e.g. 13 beds and 1,725 referrals/day. outcome measures were bed occupancy, and failed admissions. we tested two scenarios: increased referral rate (4.5/day), and increasing to 20 beds. results: the model simulated our intensive care where we have a high occupancy rate. increasing referral rate led to a consumed icu and an increase in failed admissions (fig. 1) . lastly, increasing bed numbers eased pressures with fewer failed admissions. conclusions: we recommend a personalised icu monte-carlo population model for specialist units for a more accurate representation of icu bed occupancy. these icu specific models should be more useful for predicting staff, bed and financial requirements in specialist units where healthcare resources are changing e.g. increasing geographical referral radius. conclusions: better patient flow increased occupancy and standards. staff education and clear protocols are needed to improve patient booking and efficiency. assess stress levels and causes of stress among doctors and nurses at university hospital lewisham and queen elizabeth hospital woolwich. we surveyed staff using uk health and safety executive's management standards (hsems), a 35-question validated tool which identifies stressful work conditions requiring intervention. methods: we conducted an anonymous survey of doctors and nurses working in intensive care, accident and emergency (a&e), acute medicine, anaesthetics and surgery over six weeks. results were analysed using the hsems analysis tool and broken down into seven areas: job demands, managers' support, peer support, relationships, role, level of control and possibility of change. each area was scored from 1-5 (5 represents lowest stress). we compared the trust's results against national standards. results: 283 healthcare professionals completed the survey. intensive care had the lowest stress levels and scored above average in all areas (n=55, mean 3.80, s.d. 0.39). this was followed by a&e (n=90, mean 3.63, s.d. 0.45), anaesthetics (n=57, mean 3.58, s.d. 0.54), surgery (n=42, mean 3.33, s.d. 0.47) and acute medicine (n=39, mean 3.25, s.d. 0.53) which had the highest stress levels. when compared to hsems targets peer support exceeded national standards. however, there is a clear need for improvement in staff's ability to control and change their working environment. conclusions: stress levels on intensive care were reassuringly low when compared to other departments as well as national standards. we identified areas that need improvement and with the support of hospital management we will initiate hsems-validated measures to reduce stress. p279 tools for sepsis-associated mortality in hematological patients and should be studied in larger cohorts.conclusions: our results present clinical data of protocolized pbto2-targeted therapy and show that there is room for further optimization. a larger cohort with predefined interventions is needed to proof the effect on longterm outcome after sah. impact of phone cpr on rosc outcome a giugni 1 , s gherardi 2 , l giuntoli 1 introduction: early cardiopulmonary resuscitation (cpr) improves survival in out-of-hospital cardiac arrest, and phone-cpr instructions can increase the number of victims receiving cpr before emergency medical service (ems) arrival. little is known about the impact of cpr phone instructions on the outcome of patients (pts) with return of spontaneous circulation (rosc). the target of this study is to investigate the impact of phone instructions on mortality, and on neurological outcomes of patients who survived an out-of-hospital cardiac arrest. methods: we enrolled pts admitted to icu after rosc following out-of-hospital-cardiac-arrest, from 1/1/2008 to 30/06/2016; pts younger than 18, in-hospital cardiac-arrest-victims, pts who underwent cardiac arrest in health facilities, and missing data records were excluded. written informed consensus was obtained for all pts during follow up. data about comorbility, mortality, neurologic outcome, cpr timing according to utstein style, complications in icu, metabolic state on er admission, were collected. study population was divided into two groups for statistical analysis: pts with immediate cpr guided by phone instructions (phone-cpr group) and those who did not underwent immediate cpr by laic bystanders. data were extracted from icu, ems databases and registered ems phone calls. results: 172 pts met study criteria. phone cpr were given in 25 cases, 15% of the whole study population. results are summarized in tables 1 and 2 conclusions: phone-cpr significantly reduced cpr-free interval. it correlates with a significative increase in shockable rhythms on ems arrival. there is no significative reduction in mortality and in disability, even if a decrease trend can be observed. phone-cpr seem to be a promising, effective and easy to use tool to improve survival and disability in rosc, and should be widely applied. early hemodynamic complications in cardiac arrest patients-a substudy of the tth-48 study j hästbacka 1 introduction: our aim was to determine the incidence and severity of hemodynamic complications during therapeutic hypothermia and analyze whether these complications can be predicted from data available on admission. methods: this is a substudy of the tth-48 study, where cardiac arrest (ca) patients were randomized to receive therapeutic hypothermia treatment for either 24 or 48 h [1] . hypotension within four days from admission was recorded and defined as mild, moderate, severe or circulatory failure. arrhythmias were recorded and classified as mild, moderate or severe. we calculated the incidence and distribution of severity of the events. we used multivariate logistic regression analysis to test association of admission data with any hypotension or any arrhythmia. results: of all patients, 55.1% had hypotension which was mild in 58.2%, moderate in 27.3%, severe in 7.7% cases. 6.7% had circulatory failure. an arrhythmia was present in 44% of patients. of these, 45.1% were mild, 29% moderate and 25.8 % severe. bradycardia (n=3), new ca (n=1) and circulatory shock (n=1) were hemodynamic reasons for preterm rewarming. in multivariate analysis age (p=0.005, or 1.033) and admission map (p=0.005, or 1.020) were significantly associated with hypotensive complications. only use of mechanical compressions was significantly associated with risk for arrhythmia (p=0.007, or 0.380). conclusions: hypotension and arrhythmias were frequent in cardiac arrest patients during days 1-4 from admission, but mostly mild or moderate in severity. age and admission map were associated with hypotension. only the use of mechanical compressions was independently (negatively) associated with arrhythmias. introduction: in a retrospective study from the pittsburgh clinic, which analyzed survival data from 591 patients admitted to a hospital with a cardiac arrest outside the hospital, it was found that patients with opioid overdose showed significant improvements in neurological status when discharged from the hospital compared with patients who did not receive opioids [elmer j. et al., 2015] . methods: after local ethic committee approval 190 case-records of patients with cardiac arrest and subsequent resuscitation for the period 2006 -2017 in the clinic of traumatology and orthopedics in astana were analyzed. criteria for inclusion in the study were hospital cardiac arrest, trauma to the musculoskeletal system. results: out of 190 case-records, 17 (8.9%) patients with out-ofhospital cardiac arrest were excluded. among all hospital stops of blood circulation, we found only 25 successful cpr (14.5%). among the patients who were successfully resuscitated, 2 groups were identified: i -16 patients (64%) who received ketamine or/and opioids before the blood circulation stopped (0-180 minutes); ii -9 patients (36%) who did not receive these medicines. the mean age in group i of patients was 39.1 ± 5.7 years, in group ii -43.2 ± 6.2 years (p> 0.05). patients of the second group had an average life expectancy of 2.7 ± 0.9 days, with a maximum postresuscitation life of 4 days. patients of the first group were in the hospital for 17.9 ± 2.1 days (p < 0.05), with a maximum period of 98 days. in the first group, the final neurologic evaluation according to the glasgow scale was 11.4 ± 2.3 points, while in the second group it was 6.2 ± 1.2 points (p < 0.05). conclusions: a retrospective analysis revealed a better survival and neurological outcome in patients who received ketamine or/and opioids before circulatory arrest.introduction: the revised organ transplant law was enacted in japan in 2010. under the revised law, it is now possible to donate organs with the consent of the family even if the intention of the potential donor is unknown. organs from brain-dead children under the age of 15 can also be donated. methods: the aim of this study was to assess how to provide prompt transplant medical care and improve the donor's condition. this was achieved by clarifying the problems encountered in the process leading to brain-dead organ transplantation at our institute before and after the enactment of the revised organ transplant law. there were 79 cases of organ donation at our institute from january 2003 to june 2015. among them, the background factors of 42 cases leading to organ donation were examined. results: the causes of the brain-dead condition were cerebrovascular disease (n = 15; 11 subarachnoid hemorrhage, 4 intracerebral hemorrhage), trauma (n = 8), suffocation (n = 5), cardiopulmonary arrest on arrival (n = 5), suicide by hanging (n = 3), cardiomyopathy (n = 1), and lethal arrhythmia (n = 1). the organs donated for transplantation were 54 kidneys, 32 eyes, 12 lungs, 8 livers, 7 hearts, and 6 tissues (i.e., heart valve, bone, and skin). the time lapses were as follows. the number of days from informed consent to family acceptance was 0.6 days before the enactment of the revised organ transplant law and 1.5 days after the revision. the number of days from informed consent to organ removal was 2.5 days before the revision and 3.1 days after the revision. even after the enactment of the revised organ transplant law in japan, it still takes about 3 days from informed consent to organ removal, with no current initiatives to shorten the time to organ removal. conclusions: although 7 years have passed since the enactment of the revised organ transplant law in japan, there are still administrative and management problems that need to be addressed to achieve optimal organ transplantation. the financial impact of proximity to a major airport on one critical care unit introduction: in septic patients, increased plasma levels of cell-free hemoglobin (free-hb) are associated with a reduction of perfused vessel density (pvd) of sublingual microcirculation and to adverse outcomes caused by hemoprotein-mediated lipid peroxidation. recent studies show that acetaminophen protects from damage due to lipid peroxidation in sepsis [1] . the aim of this study is to detect changes in sublingual microcirculation after the infusion of a standard dose of acetaminophen in febrile septic patients. methods: prospective observational study on 50 adult septic patients admitted to our intensive care unit. pre-infusion (t0), 30 minutes (t1) and 2 hours (t2) after the end of the infusion of acetaminophen, sublingual microcirculation was assessed with incident dark field illumination imaging; vital signs, plasma levels of acetaminophen and free-hb were assessed. results: preliminary descriptive analysis on the first 7 patients shows a median sequential organ failure assessment (sofa) score of 8 (interquartile range iqr 7-11) and baseline temperature of 38,6 c°( iqr 38.1-39°c). an increase of the proportion of perfused vessels (ppv) was evident both at t1 and t2 ( introduction: in common sedation is required during mri for adult uncommunicative patients or those with different psychiatric disorders [1] . although it can be challenging to obtain the deep sedation level required to prevent the patient's movement while maintaining respiratory and hemodynamic stability. limited access to the patient may pose a safety risk during mri. objectives: to compare efficacy and safety of dexmedetomidine sedation versus propofol during mri in adults.methods: this prospective randomized study was conducted at department of anesthesiology and intensive care at postgraduate institute of bogomolets national medical university (kyiv, ukraine) during 2015-2017. uncommunicative conscious patients with acute ischemic stroke were included in the study and randomly allocated to 2 groupsdexmedetomidine (d) and propofol (p). the sedation goal was the same in the both group (rass 0 to -2). patients in group d receive dexmedetomidine infusion in dose 0. conclusions: in this prospective randomized study dexmedetomidine comparing to propofol was associated with higher sedation quality and lower incidence of complication during acute ischemic stroke patients sedation for mri. the usefulness of dexmedetomidine after lung transplantation in intensive care unit. introduction: dexmedetomidine (dex) showed some advantages in the sedation of patients in intensive care unit (icu) [1] . other studies described efficacity of dex in icu delirium [2] . the aim of this study was to evaluate the efficacity and safety of dex after lung transplantation in icu. methods: we conducted a prospective monocentric study in our surgical icu between november 2015 at november 2017. in the first part of the study (november 2015 at november 2016), lung recipients did not received dex; in the second part of the study dex was used for the sedation in mechanically ventilated patients after lung transplantation. we compared the duration of mechanical ventilation in the two groups and the occurence of adverse effects. results: in total 59 lung recipients were enrolled. there was no difference between the two groups in demographic data, one or double-lung transplants, the cause of lung transplantation and the use of epidural infusion. in the dex group, mechanical ventilation support was 118 hours versus 98.5 hours in the other group (p=0.55). there was no difference between delirium in the two groups (3/5, p=0.7). the occurence of adverse events like hypotension and bradycardia was significantly higher in the dex group (4/0 for hypotension, p=0.013; 6/0 for bradycardia, p=0.0012). conclusions: the use of dex after lung transplantation in icu was not more efficience for the mechanical ventilator weaning. lung recipients delirium was significantly the same in the two groups. the most notable effect was the occurence of bradycardia and hypotension in the dex group.introduction: dexped evaluated the impact of a prolonged exposure (>= 24 hours) to dexmedetomidine on the duration of invasive mechanical ventilation (imv), length of picu and hospital stay and use of other sedative agents. methods: dexped is a retrospective cohort study that included patients aged 0 to 18 years, admitted to the picu of the montreal children's hospital between november 1st 2011 and april 25th 2015, requiring imv and sedative agents for >= 48 hours. patients exposed to dexmedetomidine during imv (n=53) were compared to non exposed patients (n=159) using a propensity score analysis (1:3 ratio). , and received more opioids and benzodiazepines. however, a secondary analysis redefining exposure as initiation of dexmedetomidine within the first 48 hours from intubation suggested that exposure was associated with a greater short-term probability of extubation, although this study was not powered to perform this analysis. conclusions: dexmedetomidine was associated with a longer duration of imv. however, the association was inversed when patients received dexmedetomidine as a primary sedative agent. it is uncertain whether this difference of associations is due to immortal time bias or clinical features. timing of initiation of dexmedetomidine in relationship to other sedatives may impact patient outcomes and should be considered in the planning of future trials. is an α2-agonist which has been increasingly used for analgosedation. despite of many papers published, there are still only a few concerning the pk of the drug given as long-term infusion in icu patients. the aim of this study was to characterize the population pharmacokinetics of dex and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in icu. methods: all the subjects were sedated according to modified ramsay sedation score of 3-4. blood samples for dex assay were collected on every day of the infusion and at the selected time points after its termination. the dex concentrations in the plasma were measured using lc-ms/ms method. the following covariates were examined to influence dex pk: age, sex, body weight, patients' organ function (sofa score), catecholamines and infusion duration. non-linear mixed-effects modelling in nonmem (version 7.3.0, icon development solutions, ellicott city, md, usa) was used to analyse the observed data. results: concentration-time profiles of dex were obtained from 27 adult patients ( table 1 ). the dex pk was best described by a twocompartment model (fig. 1) . the typical values of pk parameters were estimated as 27 l for the volume of the central compartment, 87.6 l for the volume of the peripheral compartment, 38.5 l/h (9.2 ml/min/kg for a 70 kg patient) for systemic clearance and 46.4 l/h for the distribution clearance. those values are consistent with literature findings. we were unable to show any significant relationship between collected covariates and dex pk. conclusions: this study does not provide sufficient evidence to support the individualization of dex dosing based on age, sex, body weight, sofa, and infusion duration. seems to reduce the wakefulness time and the sleep fragmentation but, while we haven't found differences in sleep architecture using dexmedetomidine or propofol. introduction: the early mobilization program during intensive care hospitalization presents numerous benefits related to the outcome of the patient. the objective of this study is to evaluate the safety of the implementation of an early mobilization protocol within the first 24 hours of admission and its impact on high functional status of the icu. methods: retrospective study, from march 2013 to may 2017, evaluating patients admitted to the neurological icu, assessing the hemodynamic, respiratory and neurological variables in patients submitted to the early mobilization program, consisting of progressive therapeutic activities, including sedestation and orthostatism assisted on the board and evaluated the impact on the functional status/degree of high muscle strength of the icu. results: from march 2013 to may 2017, 11,219 patients were admitted to a neurological intensive care unit, of whom 9,873 were included in the early mobilization program. the mean age of the patients was 66.5 years, with saps 3 of 43.98 points (estimated mortality risk of 22.3%) and real mortality of 11.2%. during the program, 3% presented clinical instability, which was promptly reversed in all situations. ninety-one percent of the patients presented maintenance or gain of muscle strength/functional status. conclusions: the application of an early mobilization program within 24 hours of patient admission was shown to be safe, positively influencing the rehabilitation of neurological patients. introduction: given the worldwide rapidly aging of the population, the demand of critical care for elderly is increasing. data on short -term outcomes of elderly patients after icu discharge are sparse. the objective of our study was to assess short term outcomes of elderly after icu discharge and their potential risk factors.introduction: patients aged 80 years or older presently account for approximately 10-15% [1] of all intensive care unit (icu) admissions in europe. the major challenge nowadays is to admit those elderly patients who will benefit from icu treatment. the objective of this study is to describe the characteristics and outcomes of patients >=80years old admitted to the icu. methods: retrospective observational study of all patients aged >= 80 years admitted for >24h in 2016. demographic data, admission diagnosis, apache ii and saps ii scores, use of icu resources and mortality were collected. results: 152 patients (25%) were included, with a mean age of 85,06. female gender was more prevalent (51.3%). mean length of stay was 4,48 days with mean saps ii and apache ii scores of 40,23 and 38,82 respectively. the most prevalent type of admission was medical, 70,4% (n=107) and from these the main reasons for admission were respiratory disease (n=45; 29,6%) and sepsis (n=32; 21%). icu mortality rate was 29,6% (n=45), whereas 6-month mortality was 31,5% (n=48).survival rate was often related with cardiovascular (23 [15,1%], p<.001) and respiratory diseases (32 [21%], p=.01), whereas nonsurvivors were admitted due to sepsis and neurologic causes. mortality rate was independent from the mean length of stay, noninvasive ventilation and renal replacement therapy, but dependent for previously comorbidities. mechanical ventilation was an independent predictive factor of icu mortality (p<.001) and 6-month mortality (p=.008). conclusions: nearly 70% of patients aged >= 80 years were discharged alive from icu, and less than 50% survived 6 months after icu admission.our study revealed a better prognosis for admissions due cardiovascular and respiratory diseases. efforts should be done to identify earlier septic and neurological patients that benefit icu treatment, and reevaluate the critical patient pathway, in this special population.conclusions: more than 70% of icu-survivors returned to work. overall, the chance of return to work within two years was independent of the number of organ support therapies in patients with at least one organ support therapy. however, in subgroups, the chance of return to work decreased with increasing number of organ-support therapies. factors associated with non-return to work among general icu survivors: a multicenter prospective cohort study r rosa 1 introduction: critical care patients may develop long-term health problems associated to their illness or icu treatments, which may affect their work capacity. unfortunately, studies evaluating the impact of critical illness on work-related outcomes are scarce.therefore, we aimed to investigate factors associated with non-return to work among icu survivors. methods: a prospective cohort study involving icu survivors of 6 brazilian tertiary hospitals was conducted from may 2014 to august 2017. patients with a icu stay >72 h (for medical and emergency surgical icu admissions) or >120 h (for elective surgical icu admissions) who were discharged alive from the hospital were evaluated through a structured telephone interview 3 months after discharge from the icu. a stepwise multivariate poisson regression analysis adjusted by age, gender and years of education was used to evaluate the association of sociodemographic-and icu-related variables with nonreturn to work. results: in total 986 icu survivors completed the 3-month follow-up. of these, 285 (29%) were working before icu admission. only 113 of 285 patients (39%) returned to work within the first 3 months after discharge from the icu. percentage of risk of death at icu admission (relative risk [rr], 1.85; 95% confidence interval [ci], 1.04-3.29), decrease in physical functional status in relation to the pre-icu period measured by barthel index (rr, 1.86; 95% ci, 1.48-2.35), not having a introduction: the aim of this study was to assess the accuracy of physician's prediction of hospital mortality in critically ill patients in an intensive care unit (icu) scarcity setting. methods: prospective cohort of acutely ill patients referred for icu admission in an academic, tertiary hospital in brazil. physicians' prognosis and other variables were recorded at the moment of icu referral. results: there were 2374 analyzed referrals. physician's prognosis was associated to hospital mortality. there were 593 (34.4%), 215 (66.4%) and 51 (94.4%) deaths in the groups ascribed a prognosis of survival without disabilities, survival with severe disabilities or no survival, respectively (p<0.001) (fig. 1) . sensitivity was 31%, specificity was 91% and the area under the roc curve was 0.61 for prediction of mortality. after multivariable analysis, severity of illness, performance status and icu admission were associated to an increased likelihood of incorrect classification, while worse predicted prognosis was associated to a lower chance of incorrect classification. physician's level of expertise had no effect on predictive ability. conclusions: physician's prediction was associated to hospital mortality, but overall accuracy was poor, mainly due to low sensitivity to detect mortality risk. icu admission was associated to increased incorrect classification, but there was no effect of physician's expertise on predictive ability. what are physicians in doubt about? an interview study in a neuro-intensive care unit. introduction: inescapable prognostic uncertainty, lack of decisionmaking capacity, risk of death or disability and long recovery trajectories complicate decision-making after traumatic brain injury. methods: to elicit experienced physicians' perspective we interviewed 18 neurosurgeons, intensive care-and rehabilitation physicians from oslo university hospital about being in doubt about whether to offer, continue, limit or withdraw life-sustaining treatment and on how such cases were approached. interviews were audiotaped and transcribed verbatim, coded and analysed using systematic text condensation by a clinician (ar) and a medical ethicist (rf). results: the difficulty of decision-making when there is prognostic uncertainty was acknowledged, leading to adaptive approaches; willingness to change and adjust plans along the way. to have access to different opinions within the physician group was seen as constructive. time-critical decisions were based on team discussions and physician's discretion. none-time critical decisions were reached through a process of creating common ground between the medical team and family. themes physicians where in doubt about or expressed different opinions towards: 1) appropriate aggressiveness of treatment in a given situation. 2) if and when to initiate discussions on appropriateness of treatment. some believed that even addressing the issue in young patients or if small improvements were seen was inappropriate due to the possibility of late recovery. physicians questioned the value of previously expressed patient's wishes in this context. 3) optimal timing and type of decisions. the need for nuanced individualized plans was recognized. to have a plan as opposed to just "wait and see" was seen as especially important in medical unstable patients. conclusions: physicians expressed different views on appropriateness and optimal timing of level of care discussions and decisions in traumatic brain injury. a need for a more structured approach was exposed. fig. 1 (abstract p520) . association of physician's prognosis with hospital mortality (p<0.001).introduction: this cross sectional study was designed to investigate the level of family satisfaction in 3 intensive care units in a tertiary hospital in the united arab emirates (uae), which is a multicultural society methods: family members of patients who were admitted to intensive care unit for more than 48 hours or over were included in the study. families were approached with a validated fs24-icu family satisfaction survey questionnaire [1] . one hundred questionnaires were collected over a period of 3 months from january 2016 to march 2016 in our pediatric medical surgical and cardiac, adult cardiac and adult medical/surgical intensive care units. results: the overall level of satisfaction rate was comparable to other high-income and developed countries with total satisfaction score, medical care score and decision making score of 75.1 ± 14.2, 80.1 ± 18.6, and 68.1 ± 11.5 respectively (table 1) . conclusions: this is the very first study from the uae demonstrating a high level of patient family satisfaction in both adult and pediatric intensive care units. this study also highlighted areas where further improvement needed to occur.introduction: in order to apprehend the structural aspects and current practice of end-of-life care (eolc) in german intensive care units (icus) managed by anesthesiologists, a survey was conducted to explore implementation and relevance of these items. methods: in november 2015, all members of the german society of anesthesiology and intensive care medicine (dgai) and the association of german anesthesiologists (bda) were asked to participate in an online survey to rate 50 items. answers were grouped into three categories: category 1 reflecting high implementation rate and high relevance, category 2 low implementation and minor relevance, and category 3 low implementation and high relevance. results: five-hundred and forty-one anesthesiologists responded, representing just over 1/3 of anesthesiology departments running icu's. the survey revealed new insights into current practice, barriers, perceived importance, relevance, and deficits of eolc decisions. only four items reached >= 90% agreement as being frequently performed, and 29 items were rated "very" or "more important". 28 items attributed to category 1, 6 to category 2, and 16 to category 3, representing a profound discrepancy between current practice and attributed importance. items characterizing the most urgent need for improvement (category 3) referred to desirable quality of life, patient outcome data, preparation of health care directives and interdisciplinary discussion, advanced care planning, distinct aspects of changing goals of care, standard operating procedures, implementation of practical instructions, continuing eolc education, and inclusion of nursing staff and families in the process. conclusions: the survey generated awareness about deficits in eolc matters in critical care. consequently, already available eolc tools have been made available through the website of the german society of anesthesiology and intensive care medicine (dgai): http:// www.ak-intensivmedizin.de/arbeitsforen.html.introduction: this study evaluated differences in eolp after 15 years in european icus that also participated in the ethicus i study [1] . methods: all previous ethicus i centers were invited to participate in the ethicus ii study. consecutive admitted icu patients who died or had treatment limitations during a 6 month period from 1.9.2015 to 30.9.16 were prospectively studied. previous eolp and region definitions were used [1] . eolp in the different regions of the ethicus i study [1] were compared to the same icus in the ethicus ii study. results: 22 of the original 37 icus participated again in this study. figure 1 shows the differences in eolp by region. figure 2 notes differences in patient mental competency at the time of decision, information about patient's wishes and patient discussions in both ethicus studies. conclusions: changes included less cpr (especially in the south) with more withholding and withdrawing therapies. there was a greater number of competent patients with discussions and knowledge of their wishes.introduction: palliative extubation is performed in patients with terminal ilnesses in which mechanical ventilation might prolong suffering. even though the procedure involves nurses, respiratory therapists and doctors, some professionals feel unconfortable performing a palliative extubation. the concept of withdrawing life support can be easily confounded with euthanasia, specially in low income countries, where there is usually less education on palliative care. methods: a questionary containing 6 open ended questions concerning a hypotetical case of intracerebral hemorrhage and prolonged coma, with potential indication for palliative extubation was applied to 13 members of an emergency department intensive care unit staff (6 doctors, 4 nurses, 3 respiratory therapists (rt). results: more than half of the professionals (61%) had never participated in a palliative extubation. four professionals (30%) believed palliative extubation is euthanasia. when asked about their own preferences in such a situation, only two (15%) would like to be tracheostomized. symptoms anticipated by most professionals were dyspnea and respiratory secretions. four (30%) would feel very uncomfortable performing palliative extubation because they either felt to be killing the patient or unable to manage symptoms conclusions: most professionals in this tertiary emergency intensive care unit never witnessed a palliative extubation. however, most of believe this procedure is beneficial. some still cannot understand the difference between palliative extubation and euthanasia. education in palliative care and withdrawal of life support can be helpful to clear concepts and relieve moral distress in the team.